Breast Cancer Research and Treatment

Transcription

Breast Cancer Research and Treatment
CONTENTS VOL. 106, Supplement 1, December 2007
Special issue
30th Annual SAN ANTONIO BREAST CANCER SYMPOSIUM –
December 13–16, 2007
Program
iii–xlviii
Invited Abstracts
S1–S4
Abstracts
General Sessions [#11-82]
Poster Discussion Sessions [#101-511]
Poster Session I [#1001-1119]
Poster Session II [#2001-2121]
Poster Session III [#3001-3113]
Poster Session IV [#4001-4117]
Poster Session V [#5001-5119 (excl. 5015)]
Poster Session VI [#6001-6119 plus 5015]
S5–S23
S24–S40
S41–S83
S84–S125
S126–S165
S166–S206
S207–S246
S247–S287
Author index for abstracts
S288–S302
Breast Cancer Res Treat (2007)
DOI 10.1007/s10549-007-9793-3
© Springer Science+Business Media, LLC. 2007
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Breast Cancer Research and Treatment is published monthly plus 1 additional issue in January, March, May, July, September
and November (Volumes 101–106, 3 issues each, 2007).
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Printed on acid free paper
30t Annual
December 13 – 16, 2007
Henry B. Gonzalez Convention Center
200 E. Market Street, San Antonio, Tx 78205
Sponsors
and
an NCI-designated Clinical Cancer Center
a partnership of
&
Industry And Agency Support (at press time)
Donors
Angel Plus
Adjuvant, Inc.
Almac Diagnostics
AlphaMed Press
AmeriPath, Inc.
Aptium Oncology
Biocare Medical LLC
Biogen Idec
Breakthrough Breast Cancer
Cambridge University Press
Care Wise Medical Products
Cianna Medical
Clinical Oncology News
Coalition of Cancer Cooperative Groups
Congressional Directed Medical Research Programs(CDMRP)
CURE Media Group
Diplomat Specialty Pharmacy
Elsevier, Inc.
Faxitron X-Ray LLC
Hem/Onc Today/SLACK Incorporated
ImpediMed, Inc
Informa Healthcare
Jones and Bartlett Publishers
KUBTEC X-Ray
Lippincott Williams & Wilkins
MedPage Today, LLC
National Accreditation Program for Breast Centers
The Oncology Group
Oncology Nursing Society
Springer
TRIO (CIRG/TORI)
Wiley-Blackwell
Women’s Health Boutique, Inc.
Abraxis Oncology
AstraZeneca
Bristol-Myers Squibb
Eli Lilly and Company
Genentech BioOncology
Genomic Health, Inc.
GlaxoSmithKline
Novartis Oncology
Pfizer
Roche
sanofi-aventis
Patron Plus
Amgen
Patron
Eisai, Inc.
Major Supporter Plus
Merck Oncology
Veridex, A Johnson and Johnson Company
Major Supporter
Aperio Technologies, Inc.
Bayer HealthCare PharmaceuticalsCarl Zeiss Surgical, Inc.
Cytogen Corporation
Cytyc CorporationGE Healthcare
Monogram Biosciences
Valeant Pharmaceuticals.
Contributors
Agendia B.V.
CBCE
CRI
Cytori Therapeutics
Exagen Diagnostics
Gamma Medica-Ideas
Molecular Profiling Institute
Myriad Genetic Laboratories, Inc.
Naviscan PET Systems
NeoMatrix
Nichols Institute for Oncology
North American Scientific
Ortho Biotech
PhenoPath Laboratories
Physicians’ Education Resource
Projects in Knowledge, Inc.
RadPharm, Inc.
Research to Practice
SenoRx, Inc.
SiteSelect Medical
SurgRx, Inc.
Sysmex
TopoTarget USA, Inc.
University of Florida Jacksonville Healthcare, Inc.
US Labs
Ventana Medical Systems, Inc.
Visual Med Clinical Solutions Corp.
Conference Grants
National Cancer Institute
Future Symposium
Meeting Dates
31st Annual SABCS
December 11-14, 2008
(Thursday-Sunday)
32ⁿd Annual SABCS
December 10-13, 2009
(Thursday-Sunday)
33rd Annual SABCS
December 9-12, 2010
34t Annual SABCS
December 7-10, 2011
30th Annual
San Antonio Breast
Cancer Symposium
Program Schedule
10:15
10:30-12:00
Jenny Chang, MD, Co-Moderator
Baylor College of Medicine, Houston, TX
and
Michael Lewis, PhD, Co-Moderator
Exhibit Halls A, B, C & D,
Ballrooms A & B: Street Level
Bridge Hall: Street Level
12:00-7:00
10:30
Introduction
10:30
Breast cancer stem cell: Targets for prevention & therapy
Max Wicha, MD
University of Michigan Comprehensive Cancer Center
Ann Arbor, MI
11:00
Cancer stem cells in therapeutic resistance and as cellular
targets
Jeremy Rich, MD
Duke University Medical Center
Durham, NC
11:30
Epigenetic stem cell signatures in breast cancer
Peter Laird, PhD
USC/Norris Comprehensive Cancer Center
Los Angeles, CA
REGISTRATION – Bridge Hall
Pre-registered attendees can obtain materials. Those who have
not yet registered may do so.
Thursday, December 
9:00-9:10
WELCOME – Exhibit Hall D
Opening Remarks
C. Kent Osborne, MD
Charles A. Coltman, Jr., MD
9:10-9:30
PLENARY LECTURE 1 – Exhibit Hall D
The worldwide overview: new results for systemic
adjuvant therapies
12:00-1:00
LUNCH [Ticket Required] – Exhibit Hall A
1:00-1:30
Richard Peto, for the Early Breast Cancer Trialists’ Collaborative
Group (EBCTCG)
University of Oxford
Oxford, UNITED KINGDOM
9:30-10:30
9:30
Radiation treatment planning for breast cancer: A
journey through time
Lori Pierce, MD
University of Michigan Medical School
Ann Arbor, MI
GENERAL SESSION 1 – Exhibit Hall D
11. High-dose chemotherapy with autologous stem-cell
support versus standard-dose chemotherapy: meta-analysis
of individual patient data from 15 randomized adjuvant
breast cancer trials.
Berry DA, Ueno NT, Johnson MM, Lei X, Lopez V, Caputo J,
Bregni M, Demirer T. MDACC-EBMT Meta-Analysis Group,
Houston, TX.
9:45
12. Extended follow-up and analysis by age of the US
Oncology Adjuvant trial 9735: docetaxel/cyclophosphamide
is associated with an overall survival benefit compared to
doxorubicin/cyclophosphamide and is well-tolerated in
women 65 or older.
Jones S, Holmes F, O’Shaughnessy J, Blum J, Vukelaj S, McIntyre K,
Pippen J, Bordelon J, Kirby R, Sandbach J, Hyman W, Khandelwal
P, Negron A, Richards D, Mennel R, Boehm K, Meyer W, Asmar
L, Muss H, Savin M. US Oncology Research, Inc., Houston, TX;
Vermont Cancer Center, Burlington, VT.
10:00
13. Role of anthracycline-based therapy in the adjuvant
treatment of breast cancer: efficacy analyses determined by
molecular subtypes of the disease.
Slamon DJ, Mackey J, Robert N, Crown J, Martin M, Eiremann
W, Pienkowski T, Bee V, Taupin H, Villalobos I, Lindsay M-A,
Riva A, Hurvitz S, Glaspy J, Pauletti G, Sauter G, Press M. Cancer
International Research Group (CIRG), Edmonton, AB, Canada.
MINI-SYMPOSIUM 1 – Exhibit Hall D
STEM CELLS IN BREAST CANCER
Room Locations
Wednesday, December , 
14. Outcome of breast cancer therapies for adjuvant
versus advanced disease: how much do they differ? Critical
comments towards the present process of randomized trials
as a pre-requisite for adjuvant therapy guidelines.
Ragaz J, Spinelli JJ. McGill University Health Centre, Montreal,
QC, Canada; British Columbia Cancer Agency, Vancouver, BC,
Canada.
1:30-3:45
1:30
21. Long-term results of a randomized trial of accelerated
hypofractionated whole breast irradiation following breast
conserving surgery in women with node negative breast
cancer.
Whelan T, Pignol JP, Julian J, Grimard L, Bowen J, Perera
F, Schneider K, Fyles A, Gulavita S, Shelley W, Freeman C,
Szechtman B, Levine M. Juravinski Cancer Centre, Hamilton,
ON, Canada; McMaster University, Hamilton, ON, Canada;
Toronto Sunnybrook Regional Cancer Centre, Toronto, ON,
Canada; Ottawa Regional Cancer Centre, Ottawa, ON, Canada;
Northeastern Ontario Regional Cancer Centre, Sudbury, ON,
Canada; London Regional Cancer Centre, London, ON, Canada;
Windsor Regional Cancer Centre, Windsor, ON, Canada; Princess
Margaret Hospital, Toronto, ON, Canada; Northwestern Regional
Cancer Centre, Thunder Bay, ON, Canada; Kingston Regional
Cancer Centre, Kingston, ON, Canada; McGill University Health
Centre, Montreal, QC, Canada.
1:45
22. dHER2 cancer immunotherapeutic: clinical response in
breast cancer patients is associated with an induction of
functional antibodies and the generation of specific T cells.
Limentani SA, Curigliano G, Campone M, Dorval T, Romieu G,
Vogel C, White S, de Boer R, Lehmann F, Cormont F, Louahed J.
Blumenthal Cancer Center, Charlotte, NC; Ist Eur Oncol, Milan,
Italy; Cent R Ganducheau, Nantes, France; Inst Curie, Paris,
France; CRLCC, Montpellier, France; Cancer Res Network, Boca
Raton, FL; Austin Hosp, Heidelberg, Australia; Royal Melbourne
Hosp, Parkville Vic, Australia; GSK Bio, Rixensart, Belgium.
2:00
23. Fulvestrant 500 mg vs 250 mg: first results from NEWEST,
a randomized, phase II neoadjuvant trial in postmenopausal
women with locally advanced, estrogen receptor-positive
breast cancer.
Kuter I, Hegg R, Singer CF, Badwe R, Lowe E, on behalf of the
NEWEST investigators. Massachusetts General Hospital, Boston,
MA; University of Sao Paulo & Perola Bygton Hospital, Sao
Paulo, Brazil; Medical University of Vienna, Vienna, Austria; Tata
Memorial Hospital, Mumbai, India; AstraZeneca, Wilmington, DE.
5:00-7:00
101.
Serial detection and characterization of circulating tumor
cells in an animal model.
Eliane JP, Luker KE, Brown M, Repollet M, Doyle GV, Hayes DF,
Luker GD. University of Michigan Medical School, Huntingdon
Valley, PA.
2:15
24. Anti-estrogens promote an invasive phenotype in
intercellular adhesion deficient breast cancer cells.
Borley AC, Barrett-Lee PJ, Gee JMW, Shaw VE, Nicholson RI,
Hiscox SE. Velindre Cancer Centre, Cardiff, United Kingdom;
Tenovus Centre for Cancer Research, Cardiff, United Kingdom.
102.
2:30
25. The VEGF-R inhibitor PTK787/ZK222584 (PTK/ZK)
also inhibits aromatase: preclinical studies of PTK/ZK in
combination with endocrine therapy.
Banerjee SN, Thornhill A, Evans DB, Littlewood-Evans AJ, Dowsett
M, Martin L-A. Institute of Cancer Research, London, United
Kingdom; Novartis Institute for BioMedical Research-Basel, Basel,
Switzerland.
A new system for enrichment and detection of circulating
tumor cells in the peripheral blood of patients with
metastatic breast cancer.
Deng G, Burgess D, Manna E, Krag D, Herrler M. Applied Imaging
Corp., San Jose, CA; University of Vermont, College of Medicine,
VT.
103.
MagSweeper: an automated system for high efficiency and
specificity capture of live circulating tumor cells.
Powell AA, Talasaz AAH, Mindrinos M, Carlson R, Pease FW,
Davis RW, Jeffrey SS. Stanford University, Stanford, CA.
104.
26. Bone mineral density (BMD) at 5 years after diagnosis in
premenopausal patients with endocrine-responsive breast
cancer, after 3 years of adjuvant endocrine treatment with
goserelin and tamoxifen or anastrozole or both treatments
in combination with zoledronic acid - new results from
ABCSG-12.
Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F,
Kaessmann H, Piswanger-Soelkner C, Seifert M, Schippinger W,
Menzel C, Dubsky P, Fitzal F, Steger G, Greil R, Marth C, Kubista
E, Samonigg H, Jakesz R, on behalf of the ABCSG. Austrian Breast
and Colorectal Cancer Study Group, Vienna, Austria.
Circulating tumor cells as a reliable assessment of treatment
efficacy in metastatic breast cancer.
Liu MC, Shields P, Isaacs CJD, Warren R, Cohen P, Wilkinson M,
Ottaviano Y, Zhang Y, Shen R, Jasti M, Gallagher A. Lombardi
Cancer Center, Georgetown University Hospital, Washington,
DC; Franklin Square Hospital, Baltimore, MD.
105.
Disseminated tumor cells correlate with estrogen receptor
positivity in operable breast cancer patients.
Alvarado MD, Brissaud C, Scott J, Magbanua M, Moore D, Ewing
CA, Hwang S, Esserman LJ, Park JW. University of California, San
Francisco, CA.
106.
27. The effect of zoledronic acid on aromatase inhibitorassociated bone loss in postmenopausal women with early
breast cancer receiving adjuvant letrozole: the Z-FAST study
36-month follow-up.
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore
H, Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group;
Novartis Pharmaceuticals, East Hanover, NJ.
Features of patients (pts) with metastatic breast cancer
(mBC) and a circulating tumor cell count (CTCc) of 0.
Bubis JA, Marsland TA, Justice KM, Edwards D. Integrated
Community Oncology Network, Orange Park, FL.
107.
Bone marrow micrometastasis and circulating tumor
cells are respectively strong prognostic factors in early
and metastatic breast cancer, a comparative study on 759
patients.
Bidard F-C, Vincent-Salomon A, Sastre X, Sigal-Zafrani B, Nos C,
Mignot L, Dieras V, Asselah J, Thiery JP, Pierga J-Y. Institut Curie,
Paris, France; IMCB Biopolis, Singapore, Singapore.
108.
Prognostic value of the detection of circulating tumor cells
using a multimarker RT-PCR (CK19, mammaglobin A, HER2/
neu) in early breast cancer.
Ignatiadis M, Kallergi G, Ntoulia M, Apostolaki S, Perraki M,
Xenidis N, Stathopoulou A, Lianidou E, Georgoulias V, Mavroudis
D. University General Hospital of Heraklion, Heraklion, Crete,
Greece; School of Medicine, University of Crete, Heraklion, Crete,
Greece; University of Athens, Athens, Greece.
109.
Circulating CK-19 mRNA (+) cells in patients with stage
I and II breast cancer after the completion of adjuvant
chemotherapy: evaluation of their prognostic relevance.
Xenidis N, Apostolaki S, Perraki M, Politaki E, Kalbakis K,
Ignatiadis M, Kalykaki A, Agelaki S, Georgoulias V, Mavroudis
D. University General Hospital of Heraklion, Heraklion, Crete,
Greece; School of Medicine, University of Crete, Heraklion, Crete,
Greece.
110.
Circulating epithelial tumor cells a new tool for therapy
monitoring in breast cancer: a more than tenfold increase
in numbers during systemic therapy is highly predictive of
relapse.
Pachmann K, Camara O, Cavallaris A, Krauspe S, Malarski N,
Gajda M, Kroll T, Runnebaum I, Hoeffken K. Friedrich SchillerUniversität Jena, Jena, Germany.
2:45
3:00
3:15
3:30
3:45-5:00
28. Effect of anastrozole on bone mineral density after
one year of treatment: results from bone sub-study of the
International Breast Cancer Intervention Study (IBIS-II).
Singh S, Cuzick J, Edwards R, Blake G, Truscott J, Coleman J,
Eastell R, Howell A. Wolfson Institute of Preventive Medicine,
London, United Kingdom; Kings College School of Medicine,
London, United Kingdom; University of Leeds, United Kingdom;
University of Newcastle, Australia; Christie Hospital, Manchester,
United Kingdom; Northern General Hospital, Sheffield, United
Kingdom.
29. Risk stratification based on the CYP2D6 tamoxifen
metabolizing gene within the Italian tamoxifen prevention
trial.
Bonanni B, Maisonneuve P, Johansson H, Macis D, Serrano D,
Guerrieri-Gonzaga A, Basso D, Zambon C, Plebani M, Nicoloff
M, Fontecha M, Hillman G, Wieczorek L, Rotmensz N, Decensi
A. European Institute of Oncology (EIO); EIO, Milan, Italy;
University-Hospital of Padova, Padova, Italy; Roche Molecular
Diagnostics, Pleasanton, CA; E.O. Ospedali Galliera, Genova, Italy.
SUSAN G. KOMEN FOR THE CURE
BRINKER AWARDS FOR SCIENTIFIC
DISTINCTION LECTURES – Exhibit Hall D
POSTER DISCUSSION 1 & RECEPTION –
Ballroom B
Circulating Tumor Cells 101-110
1014
Are the MRI characteristics of malignant breast lesions
different for African American women?
Jansen SA, Abe H, Shimauchi A, Karczmar GS, Olopade O,
Newstead GM. University of Chicago, Chicago, IL.
1015
Pushing the limits: very high spatial resolution spectroscopic
MR imaging of human breast.
Medved M, Newstead GM, Abe H, Wood AM, Olopade OI,
Shimauchi A, Fischer S, Karczmar GS. University of Chicago,
Chicago, IL; Philips Medical Systems, Cleveland, OH.
1016
The effect of computer-aided detection on the
interpretation of screening mammograms at Intermountain
Healthcare facilities.
Parkinson B, Belnap T, Rowley B, Blaney S, Kerry A, Pinto K, Nkoy
F. Intermountain Healthcare, Salt Lake City, UT.
1017
A new approach to studying the progression of mammary
gland carcinoma in mice: high resolution MRI of early cancer
and DCIS.
Jansen SA, Conzen S, Zamora M, Krausz T, Newstead GM,
Karczmar GS. University of Chicago.
Telemammography in a rural community.
Lopez AM, Deasy S, Carroll M, Krupinski E, Kreykes L, Weinstein
R. University of Arizona, Tucson, AZ; Tuba City Reginal Health
Care Corporation, Tuba City, AZ.
1018
Magnetic resonance imaging in predicting pathologic
residual disease after primary induction chemotherapy.
Anderson CM, Patrick RJ, Rybicki LA, Chellman-Jeffers M, Obi B,
Crowe JP. Cleveland Clinic, Cleveland, OH.
Mammography screening and other preventive care among
African American and native American women with access
to health care.
Bachman SI, Shim V. Kaiser Permanente, Oakland, CA.
1019
Initial clinical evaluation of laser optoacoustic imaging
system for diagnostic imaging of breast cancer.
Oraevsky AA, Ermilov SA, Conjusteau A, Miller T, Gharieb RR,
Lacewell R, Mehta K, Radulescu EG, Herzog D, Thompson S,
Stein A, McCorvey M, Otto P, Khamapirad T. Fairway Medical
Technologies, Houston, TX; Seno Medical Instruments, San
Antonio, TX; University of Texas Medical Branch, Galveston, TX;
University of Texas Health Science Center, San Antonio, TX.
1020
Sonobreast: a novel predictive model for the risk of
malignancy in solid breast nodules with echographic
expression.
Paulinelli RR, Freitas-Junior R, Lucena CEM, Moreira MAR, Moraes
VA, Ruiz AN, Bernardes-Junior JRM, Vidal CSR, Lucato MT, Costa
NGS, Teixeira DA. Federal University of Goias, Goiania, Goias,
Brazil; Santa Casa de Misericordia, Belo Horizonte, Minas Gerais,
Brazil.
1021
High resolution positron emission mammography in breast
cancer management.
Schilling KJ. Boca Raton Community Hospital, Boca Raton, FL.
1022
A comparison study between multidetector-row CT
and histopathological findings in terms of the extension
diagnosis of breast cancer.
Sumiyoshi K, Kani H, Nohara T, Iwamoto M, Harada T, Tanaka S,
Kimura K, Takahashi Y, Shibayama Y, Tsuji M, Kurisu Y, Tanigawa
N. Osaka Medical College, Takatsuki, Osaka, Japan.
1023
Correlation of Ki67 expression with FDG-PET positivity in
triple negative breast cancer.
Tchou J, John T, Basu S, Rosen M, Schnall M, Alavi A. University of
Pennsylvania, Philadelphia, PA.
1024
Breast optical tomography: sensitivities and specificities for
the detection of cancer.
Sharma A, Enfield L, Gibson AP, Everdell NL, Schweiger M,
Arridge S, Delpy DT, Hebden JC, Keshtgar M, Sainsbury RS,
Douek M. University College London Hospital, London, United
Kingdom; University College London, Malet Place, London,
United Kingdom.
1025
Mammographic features of triple-negative versus HER2+ and
ER+ breast cancers.
Yang WT, Dryden M, Broglio K, Dawood S, Valero V, Hortobagyi
G, Atchley D, Arun B. M. D. Anderson Cancer Center, Houston,
TX.
5:00-7:00
POSTER SESSION 1 & RECEPTION Exhibit Hall B
(#1001-1119)
Detection and Diagnosis: Mammography / Imaging 1001-1033
1001
1002
1003
1004
Effect of magnetic resonance imaging on the clinical
management of women with newly diagnosed breast cancer.
Newstead GM, Abe H, Jansen SA, Shimauchi A, Sennett CA,
Schmidt RA, Zak L, Olopade O, Jaskowiak N. University of
Chicago, Chicago, IL.
Deconvolution-based dynamic contrast enhanced MRI
of breast cancer: correlation of tumor blood flow with
pathologic and molecular markers.
Makkat S, Fontaine C, Stadnik T, Luypaert R, Bourgain C, De
Greve J, De Mey J. UZ Brussel, Vrije Universiteit Brussel, Brussels,
Belgium.
1005
How does ER/PR and Her2/Neu status affect the MR
characteristics of invasive ductal carcinoma?
Jansen SA, Abe H, Shimauchi A, Karczmar GS, Newstead GM.
University of Chicago, Chicago, IL.
1006
Breast density assessment using magnetic tesonance imaging
and diffuse optical spectroscopy.
Klifa CS, Shah NS, Watkins M, Li A, Hattangadi J, Tromberg B,
Hylton N. University of California, San Francisco, CA; University of
California, Irvine, CA.
1007
MR imaging of tumor response in breast cancer patients
following neoadjuvant chemotherapy: correlated with
pathological findings.
Chen J-H, Agrawal G, Yu H, Carpenter P, Mehta R, Nalcioglu O,
Su M-Y. University of California Irvine, Irvine, CA.
1008
The utility of MRI in preoperative planning for breastconserving therapy.
Kaufman G, Guth AA, Singh B, Axelrod D, Moy L. NYU School of
Medicine, New York, NY.
1009
Does MRI improve chances of obtaining negative surgical
margins after localized excision? A retrospective study.
Kulkarni K, Newstead GM, Jansen SA, Abe H, Shimauchi A,
Schmidt RA, Jaskowiak N. University of Chicago, Chicago, IL.
1010
The role of breast MRI in the preoperative evaluation of
patients with newly diagnosed breast cancer.
Schell AM, Kaufman PA, Lewis PJ. Dartmouth-Hitchcock Medical
Center, Lebanon, NH.
1011
Comparative accuracy of MRI and ultrasound for predicting
breast cancer extent after neoadjuvant chemotherapy.
Karuna ST, Wechter DG. Virginia Mason Medical Center, Seattle,
WA.
1012
Accuracy of preoperative evaluation of the axilla with MRI in
breast cancer.
Kaufman G, Guth AA, Axelrod D, Moy L. NYU School of
1013
Model selection for analysis of dynamic contrast enhanced
MRI (DCE-MRI) data.
Yankeelov T, Welch EB, Chakravarthy B, Lee R, Freehardt D,
Mayer I, Meszoely I, Kelley M, Means-Powell J, Gore J. Vanderbilt
University, Nashville, TN; Philips Medical Systems, Cleveland, OH.
1026
1027
Effects of the steroidal aromatase inhibitor exemestane
on mammographic breast density and other end-organ
functions.
Cigler T, Fabian CF, Yaffe MJ, Johnston D, Ingle JN, Nassif E,
Brunner R, Wadden N, Pater JL, Richardson H, Tu D, Shangle
Q, Goss PE. Massachusetts General Hospital, Boston, MA;
Sunnybrook Health Sciences Centre, Toronto, ON, Canada;
Kansas University Medical Center, Kansas City, KS; Mayo Clinic,
Rochester, MN; Notre Dame Hospital, Montreal, QC, Canada;
University of Nevada School of Medicine, Reno, NV; Memorial
University of Newfoundland, St. John’s, NL, Canada; National
Cancer Institute of Canada Clinical Trials Group, Kingston, ON,
Canada; (NCIC CTG) MAP.2.
Influence of bilateral breast magnetic resonance imaging in
treatment planning for patients with stage I/II breast cancer.
Figueredo ND, Carruthers CL, Frazier TG. Lankenau Hospital,
Wynnewood, PA; Comprehensive Breast Center, Bryn Mawr
Hospital, Bryn Mawr, PA.
1028
Follow-up rather than excision for benign papillary lesions of
the breast.
Copit DS, Vaidynathan S, Chaudhri Y. Albert Einstein Medical
Center, Philadelphia, PA.
1029
Using three-parameter empirical mathematical model to
analyze breast DCEMRI data; comparison with conventional
BI-RADS classification.
Fan X, Arkani S, Karczmar GS, Abe H, Schmidt RA, Newstead
GM. University of Chicago, Chicago, IL.
1030
A double-blind randomized controlled trial of paracetamol
as a pre-medication for mammography.
Freitas-Junior R, Nascente CM, Carvalho AA, Ximenes C, Silva MF,
Leite Filho AR, Freitas PF. Goias Federal University, Goiania, GO,
Brazil.
1032
Accuracy of clinical evaluation of locally advanced breast
cancer in patients receiving neoadjuvant chemotherapy.
Prati R, Minami CA, Gornbein JA, DeBruhl N, Chung D, Chang
HR. University of California, Los Angeles, CA.
1033
Breast specific gamma imaging and managment of breast
cancer.
Stern L, Rosenberg AL, Brill KL. Methodist Hospital, Philadelphia,
PA; Jefferson Medical College, Kimmel Cancer Center,
Philadelphia, PA.
1038
Concordance of contralateral breast cancer for steroid
receptor and tumour characteristics.
Absar MS, Martin C, Howe M, Zeiton A, Cramer A, Morris
J, Bundred NJ. University Hospital of South Manchester,
Manchester, United Kingdom.
1039
Breast cancer in the elderly: benefits of screening
mammography in the diagnosis.
Hines NL, Leibman AJ. Jacobi Medical Center, Albert Einstein
College of Medicine, Bronx, NY.
1040
Utility of echocardiographic screening for late-onset
cardiomyopathy in breast cancer survivors treated with
cardiotoxic chemotherapy.
Wazir S, Budd GT, Moore HCF, LeGrand S, Andresen S, Tang
WH. Cleveland Clinic, Cleveland, OH.
Prognosis and Response Predictions: Prognostic Factors I
1041-1074
1041
Does HER-2 status influence locoregional failure rates after
mastectomy in patients with pT1-3pN0 early stage breast
cancer?
Kwan W, Al-Tourah AJ, Speers C, Kennecke H, Norris B, Olivotto
I. BC Cancer Agency, Fraser Valley Centre, Surrey, BC, Canada; BC
Cancer Agency, Vancouver Centre, Vancouver, BC, Canada; BC
Cancer Agency, Vancouver Island Centre, Victoria, BC, Canada.
1042
Elevated JAG1 mRNA expression, associated with the basal
phenotype, is a poor-prognosis indicator in lymph nodenegative breast cancer.
Reedijk M, Dickson BC, Pinnaduwage D, Mulligan AM, Zhang
H, Bull SB, O’Malley F, Egan SE, Andrulis IL. University Health
Network, Toronto, ON, Canada; Mount Sinai Hospital, Toronto,
ON, Canada; Hospital for Sick Children, The Toronto Medical
Discovery Tower, Toronto, ON, Canada.
1043
Recurrence score by oncotype DX evaluated on the primary
breast tumor predicts the 2-year survival after first relapse.
Bianchini G, Zambetti M, Mariani P, Moliterni A, Bianchi G,
Mariani G, Fasolo A, Carcangiu ML, Valagussa P, Gianni L.
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
1044
Intracystic papillary carcinoma: a review of 917 cases.
Grabowski JE, Saltzstein SL, Sadler GR, Blair SL. UCSD, San Diego,
CA; UCSD, La Jolla, CA.
1045
Short term prognostic index for breast cancer: NPI or Lpi.
Decock J, Hendrickx W, Van Belle V, Brouckaert O, Pintens S, Van
Huffel S, Paridaens R, Amant F, Leunen K, Smeets A, Berteloot
P, Van Limbergen E, Weltens C, Van den Bogaert W, Vanden
Bempt I, Drijkoningen M, Wildiers H, Vergote I, Christiaens M-R,
Neven P. UZ Leuven, Leuven, Belgium.
1046
The microstaging of sentinel lymph node biopsies is not
associated with disease-free survival in breast cancer.
Pugliese MS, Arthurs ZM, Tickman RJ, Allison KH, Beatty JD.
Swedish Cancer Institute, Seattle, WA.
1047
Meta-analysis of gene-expression profiles in breast cancer:
towards a unified understanding of breast cancer sub-typing
and prognosis signatures.
Sotiriou C, Wirapati P, Kunkel S, Farmer P, Pradervand S,
Haibe-Kains B, Desmedt C, Sengstag T, Schütz F, Goldstein DR,
Delorenzi M, Piccart M. Institute Jules Bordet, Brussels, Belgium;
Université Libre de Bruxelles, Brussels, Belgium; University of
Lausanne, Lausanne, Switzerland.
1048
The presence of a fibrotic focus and expansive growth
pattern in breast tumors is associated with gene expression
profiles of aggressive tumor biology.
Van den Eynden GG, Smid M, Van Laere SJ, Colpaert CG, Van
Marck EA, Dirix LY, Vermeulen PB, Foekens JA. (Lab Pathology
University of Antwerp/University Hospital Antwerp, Wilrijk;
Oncology Center, GH St.-Augustinus, Wilrijk, Belgium), Antwerp,
Belgium; Erasmus MC-Daniel den Hoed, Rotterdam, Netherlands.
Detection and Diagnosis: Screening 1034-1040
1034
The missing exam in clinical breast exam.
Goodson III WH, Moore II DH. California Pacific Medical Center
Research Institute, San Francisco, CA; University of California, San
Francisco, CA.
1035
Comparing performance measures in opportunistic and
organized screening mammography for early breast cancer
detection.
Hofvind S, Vacek P, Skelly J, Geller BM. The Cancer Registry of
Norway, Oslo, Norway; University of Vermont, Burlington, VT.
1036
Cost-effectiveness of breast cancer (BC) screening with
contrast enhanced magnetic resonance imaging (MRI) as an
adjunct to x-ray mammography (XM) in high-risk women.
Taneja C, Edelsberg J, Weycker D, Guo A, Oster G, Weinreb
J. Policy Analysis Inc. (PAI), Brookline, MA; Bayer HealthCare
Pharmaceuticals, Wayne, NJ; Yale University School of Medicine,
New Haven, CT.
1037
High incidence of brain metastases found in patients with
HER2 positive metastatic breast cancer. Should these
patients be followed by regular MR scans?
Langkjer ST, Krøldrup L, Kristiansen C, Enevoldsen K, Edal AL,
Ormstrup TE. Vejle Hospital, Vejle, Denmark.
1049
An inflammatory breast carcinoma signature is associated
with reduced relapse free survival in patients with noninflammatory breast cancer.
Van Laere SJ, Van den Eynden GG, Van der Auwera I, van
Dam P, Van Marck EA, Dirix LY, Vermeulen PB. Lab Pathology
University Antwerp and Oncology Center, General Hospital SintAugustinus, Wilrijk, Antwerp, Belgium.
1050
Plasma and serum levels of tissue inhibitor of
metalloproteinases-1 are associated with prognosis in nodenegative breast cancer – a prospective study.
Würtz SØ, Møller S, Mouridsen H, Hertel PB, Friis E, Brünner
N. University of Copenhagen, Frederiksberg, Denmark;
Rigshospitalet, Copenhagen, Denmark.
1051
Non-proportional breast cancer mortality patterns
according to expression of the HER2 protein, using the
residual tissue repository of the National Cancer Institute’s
Surveillance, Epidemiology, and End Results (SEER) program.
Anderson WF, Luo S, Chatterjee N, Rosenberg PS, Goodman
MT, Hernandez BY, Reichman M, Dolled-Filhart MM, O’Regan
RM, Perou CM, Jatoi I, Cartun RW, Sherman ME. National
Cancer Institute, Rockville, MD; University of Hawaii, Honolulu,
HI; Hartford Hospital, Hartford, CT; Emory University, Atlanta,
GA; University of North Carolina, Chapel Hill, NC; HistoRx, New
Haven, CT; National Naval Medical Center, Bethesda, MD.
1052
Withdrawn
1053
Patterns of metastatic spread in triple negative breast
cancer.
Dent R, Trudeau M, Sun P, Narod S. Sunnybrook Health Sciences
Center, Toronto, ON, Canada; Women’s College Hospital,
University of Toronto, Toronto, ON, Canada.
1060
The prognostic significance of human epidermal growth
factor receptor-2 over-expression for the development of
local recurrence after newly diagnosed breast cancer.
Gabos Z, Thoms J, Hanson J, Ghosh S, Deschenes J, Mackey J,
Abdulkarim B. Cross Cancer Institute, Edmonton, AB, Canada;
University of Alberta, Edmonton, AB, Canada.
1061
Do grade I breast cancers require follow-up after breast
conserving treatment?
Hamed H, Jones G, Allen D, Kontos M. Guy’s Hospital, London,
United Kingdom.
1062
Prognostic factors for BRCA1/2-associated familial breast
cancer from Russian population.
Lyubchenko LN, Pospechova NI, Lushnikova AA, Portnoy SM,
Bryuzgin VV, Karpukhin AV, Garkavtseva RPh. N.Blokhin Cancer
Res., Center RAMS, Moscow, Russian Federation; Research Center
for Medical Genetics, Moscow, Russian Federation.
1063
Restratification of the Nottingham prognostic index using
carcinoembroinic antigen cell adhesion molecule 6.
Maraqa L, Cummings M, Peter MB, Hanby AM, Shaaban AM,
Horgan K, Speirs V. St James’s University Hospital, Leeds, West
Yorkshire, United Kingdom; Leeds General Infirmary, Leeds, West
Yorkshire, United Kingdom.
1064
The Amsterdam 70-gene signature predicts outcome in
breast cancer patients with 1-3 positive axillary lymph
nodes.
Mook S, Rutgers EJT, Peterse JL, Nuyten DSA, Horlings H, van
de Vijver MJ, van ‘t Veer LJ. Netherlands Cancer Institute,
Amsterdam, Netherlands.
1065
Quantitative justification of the change from 10% to 30%
for HER-2 scoring in the ASCO-CAP guidelines: tumor
heterogeneity in breast cancer and its prognostic and
predictive implications.
Moeder CB, Giltnane JM, Harigopal M, Molinaro A, Robinson
A, Gelmon K, Huntsman D, Camp RL, Rimm DL. Yale University
School of Medicine, New Haven, CT; British Columbia Cancer
Agency, Vancouver, BC, Canada.
1054
E-cadherin levels may predeict outcome in inflammatory
breast cancer (IBC).
Levine PH, Ganesan C, Young HA, Portera C, Yang S, Swain SM.
The George Washington University Medical Center, Washington,
DC; National Cancer Institute, Bethesda, MD; Washington
Hospital Center, Washington, DC.
1055
Impact of hormone replacement therapy on breast
cancer: Women’s Healthy Eating and Living (WHEL) study
experience.
Parker BA, Flatt SW, Mortimer JA, Natarajan L, Gold EB, Bardwell
WA, Jones LA, Hollenbach KA, Pierce JP. University of California,
La Jolla, CA; University of California, Davis, CA; The University of
Texas, Houston, TX.
1066
HER2 status adds prognostic, but not tamoxifen treatment
predictive, information in hormone receptor positive
premenopausal primary breast cancer.
Rydén L, Fernö M, Stål O, Landberg G, Bendahl P-O. Clinical
Science, Lund, Sweden; Biomedicine and Surgery, Linköping,
Sweden; Laboratory Medicine, Malmö University Hospital,
Malmö, Sweden.
1056
Survival outcomes in pregnancy-associated breast cancer.
Ali A, Wang Y, Kelly J, Falk J, Sehgal R, Vogel V. University
of Pittsburgh Medical Centre, Pittsburgh, PA; University of
Pittsburgh, Pittsburgh, PA.
1067
1057
Clinicopathological and prognostic relevance of uptake
level revealed by 18F-fluorodeoxyglucose positron emission
tomography/computed tomography fusion imaging (18FFDG PET/CT) in primary breast cancer.
Ueda S, Tsuda H, Asakawa H, Omata J, Fukatsu K. National
Defense Medical College, Tokorozawa, Saitama, Japan.
Prospective prognostic value of proliferation in small, lowgrade, lymph-node negative breast cancers.
Baak JPA, Van Diest PJ, Janssen EAM, Voorhorst F, and Other
MMMCP Collaborators. Stavanger University Hospital, Stavanger,
Norway; The Gade Institute, University of Bergen, Bergen,
Norway; University Medical Center, Utrecht, Netherlands; Free
University Medical Center, Amsterdam, Netherlands.
1068
Identification of IGFBP4 as a marker of tamoxifen failure in
primary breast cancer.
Hadad SM, Robertson KE, Baker L, Bray SE, Purdie CA, Jordan L,
Vendrell JA, Cohen PA, Thompson AM. Ninewells Hospital and
Medical School, Dundee, United Kingdom; Universite Lyon, Lyon,
France.
1069
Genomic copy number alterations as predictive markers of
systemic recurrence in breast cancer.
Hwang K-T, Han W, Lee JW, Cho J, Ko E, Kim EK, Jung S-Y,
Jeong E-M, Kang JJ, Yang S-J, Kim S-W, Noh D-Y. Seoul National
University Boramae Hospital, Seoul, Republic of Korea; College
of Medicine, Seoul National University, Seoul, Republic of Korea;
Cancer Research Institute, College of Medicine, Seoul National
University, Seoul, Republic of Korea; Macrogen, Inc., Seoul,
Republic of Korea.
1058
1059
Prognostic differences of WHO-assessed mitotic activity
index (MAI) and mitotic impression by quick scanning in
invasive ductal breast cancer patients under 55 years of age.
Skaland I, van Diest PJ, Janssen EAM, Gudlaugsson E, Søiland
H, Baak JPA. Stavanger University Hospital, Stavanger, Norway;
University Medical Center, Utrecht, Netherlands; University
of Bergen, Bergen, Norway; Free University, Amsterdam,
Netherlands.
Complementary and alternative therapies among long-term
breast cancer survivors.
Carpenter CL, Ganz PA, Bernstein L. Keck School of Medicine at
USC, Los Angeles, CA; David Geffen School of Medicine at UCLA,
Los Angeles, CA.
1070
Prognostic value of the shed antigen of HER-2/neu in
premenopausal breast cancer patients in the TABLE-study.
Lueftner DI, Pechlivanis K, Geppert R, Possinger K. Charite
Campus Mitte, Berlin, Germany.
1071
Down regulation of EFEMP1 is associated with unfavourable
prognosis in sporadic breast cancer patients.
Ramser J, Harbeck N, Sadr-Nabavi A, Naehrig J, Busch R, KiechleBahat M, Meindl A. Tech. University, Munich, Germany.
1072
Cell cycle proteins add independent prognostic information
to Nottingham Prognostic Index (NPI).
Loddo M, Kingsbury S, Sainsbury R. University College London,
United Kingdom.
1073
The prognostic significance of androgen receptor expression
in breast cancer.
Peter M, Maraqa L, Horgan K, Speirs V, Shaaban A. University of
Leeds, Leeds, W Yorks, United Kingdom; Leeds General Infirmary,
Leeds, W Yorks, United Kingdom.
1074
Comparative analysis of uPA/PAI-1 in core biopsies versus
surgical breast cancer samples.
Vetter M, Lantzsch T, Abraha-Späth RS, Olenik C, Thomssen C,
Dittmer J. Martin-Luther University, Halle/Saale, Germany; St.
Elisabeth & St. Barbara Hospital, Halle/Saale, Germany; University
Hospital Eppendorf, Hamburg, Germany; American Diagnostica
GmbH, Pfungstadt, Germany.
Treatment: Chemotherapy – General 1075-1087
1075
Risk of dementia in older breast cancer survivors:
a population-based cohort study of the effect of
chemotherapy.
Baxter NN, Durham SB, Phillips K-A, Virnig EA, Virnig BA.
University of Toronto, Toronto, ON, Canada; University of
Minnesota, Minneapolis, MN; Peter MacCallum Cancer Centre,
Melbourne, Australia.
1076
Final results of the AGO breast cancer study group
MAMMA-3 trial: first-line capecitabine + paclitaxel vs
epirubicin + paclitaxel for high-risk metastatic breast cancer.
Lück H-J, du Bois A, Schrader I, Huober J, Heilmann V, Fasching
PA, Stähle A, Jackisch C, Marth C, Richter B, von Minckwitz
G. HSK, Klinik für Gynäkologie und Gynäkologische Onkolgie,
Wiesbaden, Germany; Henriettenstiftung, Frauenklinik,
Hannover, Germany; Universitäts-Frauenklinik Tübingen,
Tübingen, Germany; Universitäts-Frauenklinik and Poliklinik
Ulm, Ulm, Germany; Universitätsklinikum Erlangen, Frauenklinik,
Erlangen, Germany; St. Vincentius-Krankenhäuser, Frauenklinik,
Karlsruhe, Germany; Klinik für Gynäkologie und Geburtshilfe
Klinikum Offenbach, Offenbach, Germany; Universitätsklinik für
Frauenheilkunde Innsbruck, Innsbruck, Austria; Elbland-Kliniken
Meißen-Radebeul, Standort Radebeul, Frauenklinik, Radebeul,
Germany; Zentrum Frauenheilkunde und Geburtshilfe, Frankfurt,
Germany.
1077
Combined trastuzumab (HER)/docetaxel (TAX) versus
sequential trastuzumab followed by docetaxel at progression
as first line chemotherapy for Her2-positive metastatic
breast cancer: preliminary results (multicenter BOOG-study;
2002-02).
Hamberg P, Bontenbal M, Vernhout RM, Bos MM, Braun HJ,
Erdkamp F, Stouthard JML, van Deijk GA, Schmitz PIM, Seynaeve
C, Klijn JGM. Erasmus University Medical Center, Daniel den
Hoed Cancer Center, Rotterdam, Netherlands; Reinier de Graaf
Hospital, Delft, Netherlands; Vlietland Hospital, Vlaardingen,
Netherlands; Maasland Hospital, Sittard, Netherlands; Haga
Hospital, Den Haag, Netherlands; Medical Center Rijnmond-Zuid,
Rotterdam, Netherlands; Erasmus University Medical Center,
Rotterdam, Netherlands.
1078
Phase III study of gemcitabine plus docetaxel versus
capecitabine plus docetaxel for anthracycline-pretreated
metastatic breast cancer patients: survival results.
Chan S, Romieu G, Huober J, Tubiana-Hulin M, Schneeweiss A,
Lluch A, Llombart A, du Bois A, Carrasco E, Thareau Vaury A,
Fumoleau P. Nottingham City Hospital, Nottingham, United
Kingdom; CRLC Val d’Aurelle, Montpellier Cedex 5, France;
University of Tuebingen, Tuebingen, Germany; Centre Rene
Huguenin, Saint Cloud, France; University of Heidelberg,
Heidelberg, Germany; Hospital Clinico de Valencia, Valencia,
Spain; Hospital Arnau de Villanova, Lerida, Spain; Dr. HorstSchmidt-Klinik, Wiesbaden, Germany; Eli Lilly Spain, Madrid,
Spain; Eli Lilly France, Suresnes Cedex, France; Centre GeorgesFrancois Leclerc, Dijon, France.
1079
Analysis of chemotherapy-induced amenorrhea by three
different chemotherapy regimens in premenopausal women
with early breast cancer.
Han HS, Lee KS, Kim SY, Ro J. National Cancer Center, Goyang-si,
Korea.
1080
A descriptive study of pharmacokinetic alterations of
epirubicin as a function of body size.
Madarnas Y, Clemons M, Walker S, McLean H, Nakatsu K, Sawka
C. Queen’s University; University of Toronto; Cancer Centre of
Southeastern Ontario; Toronto-Sunnybrook Regional Cancer
Centre; Princess Margaret Hospital.
1081
A multicenter, randomized, double-blind, parallelgroup phase II study of gefitinib (IRESSA) or placebo in
combination with docetaxel, as first-line treatment in
patients with metastatic breast cancer.
Tubiana-Hulin M, Spielmann M, Dieras V, Fumoleau P, Delaloge
S, Mefti F, Girre V. Centre Rene Huguenin, Saint Cloud, France;
Institut Gustave Roussy, Villejuif, France; Institut Curie, Paris,
France; Centre G.F. Leclerc, Dijon, France.
1082
Vinflunine in combination with trastuzumab: an active
combination in the treatment of HER2 positive metastatic
breast cancer.
Paridaens R, Wildiers H, Dalenc F, Rixe O, Roche H, Cadic
V, Delgado F-M. UZ Gasthuisberg, Leuven, Belgium; Institut
Claudius Regaud, Toulouse, France; Hopital Pitie-Salpetriere, Paris,
France; Institut de Recherche Pierre Fabre, Boulogne-Billancourt,
France.
1083
A phase III study on the efficacy and safety of docetaxel,
every three weeks or as a weekly regimen in patients with
Willemse PH, Munck L, Creemers GJ, Graaf H, Smit W, Erjavec
Z, Stouthard JM, Deijk G, Bochove A, Vader W, Westermann
AM. UMC, Groningen, Netherlands; Comprehensive Cancer
Centre North-Netherlands, Groningen, Netherlands; Catharina
Ziekenhuis, Eindhoven, Brabant, Netherlands; MCL Zuid,
Leeuwarden, Friesland, Netherlands; Medisch Spectrum Twente,
Enschede, Overijssel, Netherlands; Delfzigt Ziekenhuis, Delfzijl,
Groningen, Netherlands; MCR-Zuid, Rotterdam, Zuid-Holland,
Netherlands; HAGA Ziekenhuis-Rode Kruis, Den Haag, ZuidHolland, Netherlands; ZaansMC, Zaandam, Noord-Holland,
Netherlands; Sanofi-Aventis, Gouda, Zuid-Holland, Netherlands;
AMC, Amsterdam, Noord-Holland, Netherlands.
1084
Benchmarking quality oncology care in the community
setting.
Schwartzberg LS, Tauer K, Blakely J, Johnson R, Reed J, Somer B,
Wheeler B, Walker MS, Stepanski EJ, Fortner BV. The West Clinic,
Memphis, TN; Accelerated Community Oncology Research
Network, Memphis, TN.
1085
Age and prognosis – how did adjuvant therapies influence
the real prognosis?
Morishita M, Thomas G, Leonard R. South West Wales Cancer
Institute, Swansea, United Kingdom; Velindre Hospital, Cardiff,
United Kingdom; Imperial College School of Medicine, London,
United Kingdom.
1086
Dexamethasone, metoclopropamide and omperazole
combination is simple, safe and effective for delayed nausea
and vomiting control in adjuvant chemotheray for early
breast cancer.
Sanchetee SC. Sanchetee Hospital and Cancer Insitute, Jodhpur,
Rajasthan, India.
1087
N0332 phase II trial of weekly irinotecan and docetaxel in
refractory metastatic breast cancer: a North Central Cancer
Treatment Group trial.
Tan WW, Hillman D, Salim M, Northfelt DW, Anderseon DM,
Stella PJ, Niedringhaus R, Bernath AM, Gamini SS, Frances P,
Perez PA. Mayo Clinic, Jacksonville, FL; Mayo Clinic, Rochester,
MN; Allan Blair Cancer Center, Saskatchewan, Canada; Mayo
Clinic Scottsdale, Scottsdale, AZ; Abbott Northwestern Hospital,
Minneapolis, MN; Michigan Cancer Research Consortium,
Ann Arbor, MI; Duluth CCOP, Duluth, MN; Geisinger Clinic &
Medical Center, Danville, PA; Missouri Valley Cancer Consortium,
Omaha, NE.
1093
Predictors of weight gain in patients with early stage breast
cancer.
Mills JB, Gui J, Mulrooney TJ, Schwartz GN. DartmouthHitchcock Medical Center, Lebanon, NH; Dartmouth Medical
School, Hanover, NH.
1094
Memory loss after adjuvant chemotherapy for breast cancer:
a preliminary analysis of mediating variables utilizing crosssectional correlations and multilevel longitudinal analysis.
Beadle G, Rolfe M, Vearncombe K, Andrew B, Mengersen K,
Wright M. Queensland Institute of Medical Research, Brisbane,
Queensland, Australia; Southern Cross University, Lismore, New
South Wales, Australia; University of Queensland, Brisbane,
Queensland, Australia; Queensland University of Technology,
Brisbane, Queensland, Australia.
1095
Research on optimal recovery practices in breast cancer: the
RESTORE trial.
Kimmick GG, McCoy TP, Milhalko SL, Ribisl PM, Anderson RT.
Wake Forest University School of Medicine, Winston-Salem, NC;
Wake Forest University, Winston-Salem, NC; Duke University
Medical Center, Durham, NC.
1096
Breaking bad news: experiences receiving breast cancer
diagnosis in a specialty breast center versus community
practice.
Smith RL, Crawford BJ, Petersen LR, Johnson RE, Mandrekar J, Cha
S, Rhodes DJ, Hartmann LC. Mayo Clinic, Rochester, MN.
1097
Appraisals, coping and distress among couples dealing with
breast cancer.
Hernandez AM, Bigatti SM. Indiana University Purdue University
Indianapolis, Indianapolis, IN.
1098
The psychosocial issues for women diagnosed with breast
cancer who have a concurrent pregnancy or want the option
of a subsequent pregnancy.
Ives A, Longman G, Saunders C, White K. The University of
Western Australia, Perth, WA, Australia; University of Sydney,
Sydney, NSW, Australia.
1099
Prevalence of cognitive complaints is not higher in
postmenopausal breast cancer patients before adjuvant
hormonal therapy compared to healthy controls.
Schilder CM, van Dam F, Boogerd WS, Seynaeve C, van de
Velde CJ, Nortier HW, Linn SC, Schagen SB. Netherlands Cancer
Institute, Amsterdam; Erasmus Medical Center, Rotterdam;
University Medical Center, Leiden, Netherlands.
1100
Unexpected effects of reassurance in women with low-risk
breast cancer.
Griggs JJ, Corbin K, Weiss M, Shields CG. University of Michigan,
Ann Arbor, MI; University of Rochester School of Medicine and
Dentistry, Rochester, NY; breastcancer.org, Narberth, PA.
1101
Breast reconstruction in a university-based public hospital.
Levine SM, Vaksman A, Hiotis K, Levine JP. New York University
Medical Center, New York, NY.
Treatment: Chemotherapy – Support 1088-1090
1088
1089
1090
Reduced incidence of febrile neutropenia and related
complications in elderly breast cancer patients receiving
chemotherapy with pegfilgrastim primary prophylaxis versus
current practice neutropenia management – results from an
integrated analysis.
Aapro M, Schwenkglenks M, Lyman G, Lopez Pousa A, Easton
V, Skacel T, Bacon P, Von Minckwitz G. Clinique de Genolier,
Genolier, Switzerland; University of Basel, Basel, Switzerland;
University of Rochester, Rochester; Hospital Sant Pau, Barcelona,
Spain; Amgen Ltd, Cambridge, United Kingdom; Amgen
(Europe) GmbH, Zug, Switzerland; University of Frankfurt,
Frankfurt, Germany.
Pegfilgrastim promotes neutrophil recovery in elderly
breast cancer patients following anthracycline-containing
chemotherapy.
Brugger W, Bacon P, Lawrinson S, Romieu G. Schwarzwald-Baar
Clinic, University of Freiburg, Villingen-Schwenningen, Germany;
Amgen (Europe) GmbH, Zug, Switzerland; Amgen Ltd, Uxbridge,
United Kingdom; CRLC Val d’Aurelle, Montpellier, France.
Pre-treatment differential white blood cell counts can be
used to identify patients who are at increased risk of severe
myelosuppression following adjuvant chemotherapy.
Jenkins P, Benstead K, Owen R, Elyan S, Ingledew I, Bristol J,
Chan C, Freeman S. Cheltenham General Hospital, Cheltenham,
Gloucestershire, United Kingdom; University of Birmingham,
Birmingham, Edgbaston, United Kingdom.
Treatment: Psychosocial Aspects 1091-1101
Tumor Cell Biology: Angiogenesis 1102-1109
1091
Quality of life in the Intergroup Exemestane Study (IES) 5
years post-randomisation.
Fallowfield LJ, Langridge CI, Kilburn LS, Jones SE, Snowdon CF,
Bliss JM, Coombes C. Brighton & Sussex Medical School, Falmer,
United Kingdom; Institute of Cancer Research, Sutton, United
Kingdom; US Oncology Research, TX; Imperial College London,
United Kingdom; on behalf of the IES Group.
1102
Anti-tumor activity of motesanib diphosphate alone and
in combination with docetaxel or tamoxifen in xenograft
models of human breast carcinoma.
Coxon A, Bush T, Belmontes B, Saffran D, Ona V, Rex K,
Caenepeel S, Hughes P, Kaufman S, Radinsky R, Kendall R, Price J,
Polverino A. Amgen Inc, Thousand Oaks, CA; UT MD Anderson
Cancer Center, Houston, TX.
1092
Prospective multi-center study of the impact of the 21-gene
recurrence score assay on patient satisfaction, anxiety and
decisional conflict for adjuvant breast cancer treatment
selection.
Mumby PB, Lo SS, Norton J, Smerage J, Joseph K, Chew HK,
Hayes D, Albain KS. Loyola University Medical Center, Maywood,
IL; University of Michigan, Ann Arbor, MI; Edward Hospital,
Naperville, IL; University of California, Sacramento, CA.
1103
Non-invasive in vivo subcellular multicolor imaging of the
tumor microenvironment and drug response in real time.
Yang M, Jiang P, Al-Zaid M, Hoffman RM. AntiCancer, Inc., San
Diego, CA; University of California, San Diego, CA.
1104
Anti-angiogenic potential of coenzyme Q10, riboflavin
and niacin in breast cancer patients undergoing tamoxifen
therapy.
Panchanatham S. DR. A.L.M.P-G.I.B.M.S., University of Madras,
Tarmani Campus, Chennai, Tamilnadu, India.
1105
Molecular imaging in the mouse model of breast cancer
based on optical illumination and ultrasonic detection.
Oraevsky AA, Ermilov SA, Eghtedari MA, Conjusteau A, Miller T,
Radulescu EG, Herzog D, Gharieb RR, Lacewell R, Thompson S,
Mehta K, Stein A, Motamedi M. Fairway Medical Technologies,
Houston, TX; Seno Medical Instruments, Houston, TX; University
of Texas Medical Branch, Galveston, TX.
1116
Combination therapy with tetramethoxystilbene and
phosphatidylinositol 3-kinase inhibitor is effective for killing
hormone-resistant breast cancer.
Park H, Aiyar SE, Kim S, Lee Y, Fan P, Santen RJ. Kyungpook
National University Hospital, Daegu, Republic of Korea; University
of Virginia, Charlottesville, VA; Seoul National University, Seoul,
Republic of Korea.
1106
Variation of circulating angiogenic factor level and its
potential value during chemotherapy in patients with
Tang J, Zhao J, Qin J, Pan L, Xu Z. Jiangsu Tumor Hospital,
Nanjing, Jiangsu, China; Nanjing University of Traditional Chinese
Medicine, Nanjing, Jiangsu, China.
1117
Inhibition of breast cancer growth with the combination of
lapatinib and an ADAM protease inhibitor.
Witters LM, Scherle PA, Friedman SM, Redman J, Fridman JS,
Caulder E, Lipton A. Pennsylvania State University College of
Medicine, Hershey, PA; Incyte Corporation, Wilmington, DE.
1118
1107
Association of genetic polymorphisms of VEGF and VEGFR-2
with outcome in E2100.
Schneider B, Wang M, Radovich M, Sledge G, Badve S, Thor A,
Flockhart D, Hancock B, Davidson N, Miller K. Indiana University
School of Medicine, Indianapolis, IN; Harvard, Boston, MA;
University of Colorado Health Sciences Center, Denver, CO;
Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD.
uPAR gene amplification in breast cancer tissue: a rare event.
Pintens S, Vanden Bempt I, Drijkoningen M, Van Belle V,
Brouckaert O, Christiaens M-R, Neven P, Peeters C. UZ Leuven,
Leuven, Belgium; ESAT KULeuven, Leuven, Belgium.
1119
Targeting of mTOR is associated with decreased VEGF
expression and secretion in cancer cells.
Lackner EM, Krauth MT, Kondo R, Rebuzzi L, Eigenberger K,
Vales A, Kornek GV, Zielinski CC, Valent P. Medical University
Vienna, Internal Medicine I, Division of Oncology, Vienna,
Austria; Medical University Vienna, Internal Medicine I, Division
of Hematology and Hemostaseology, Vienna, Austria; Clinic for
Int. Medicine and Infectious Disease, Vienna, Austria; Hanusch
Krankenhaus, Vienna, Austria.
1108
A novel assay to assess the antiangiogenic potential of
cytotoxic drugs in human breast cancer.
Lyons, III JM, Anthony CT, Woltering EA. Louisiana State
University Health Science Center, New Orleans, LA.
1109
Comparing serum levels of vascular endothelial growth
factor in premenopausic women with breast cancer
according to menstrual cycle phase.
Rios Zaragoza S, Martinez Chequer J, Mainero Ratchelous F.
Hospital “Luis Castelazo Ayala” IMSS, Mexico, DF, Mexico.
7:00-10:00
Tumor Cell Biology: Antigens and Markers 1110-1112
1110
Labeling pattern of breast cancer stem phenotype in invasive
breast carcinomas: an immunohistochemical analysis.
Shaye AN, Sahin AA, Huo L, Woodward WA. UT M.D. Anderson
Cancer Center, Houston, TX.
1112
Differential proteomic profiles observed in FFPE breast
tissue specimens of several pathologic states.
Izbicka E, Streeper R, West FB, Yeh I-T. CTRC, San Antonio, TX;
UTHSCSA, San Antonio, TX.
Tumor Cell Biology: Growth Factors / Inhibitors 1113-1119
1113
1114
1115
Susan G. Komen for the Cure proudly presents the 2007 Brinker
Awards for Scientific Distinction featuring special guest and
keynote speaker Ambassador Nancy G. Brinker.
Nuclear FoxO3a expression is associated with lymph node
negative, ER+ invasive ductal carcinomas.
Turashvili G, Fridman E, Romanska H, Lam E, Skarda J, Murray P,
Kolar Z, Lalani E-N. Institute of Pathology, University Olomouc,
Palacky, Czech Republic; Tel Aviv University, Chaim Sheba
Medical Center and Sackler School of Medicine, Tel Aviv,
Israel; Division of Cancer Studies, University of Birmingham,
Birmingham, United Kingdom; Imperial College, London, United
Kingdom.
1111
Insulin-like growth factor I activates gene transcription
programs strongly associated with ER – breast cancer and
poor patient prognosis.
Creighton CJ, Casa A, Lazard ZW, Tsimelzon A, Hilsenbeck SG,
Lee AV. Baylor College of Medicine, Houston, TX.
HER-1 overexpression is found only in oestrogen receptor
negative breast cancer and is rarely associated with HER-1
gene amplification.
Pintens S, Vanden Bempt I, Drijkoningen M, Van Belle V,
Brouckaert O, Christiaens M-R, Neven P, De Wolf-Peeters C. UZ
Leuven, Leuven, Belgium; ESAT, Leuven, Belgium.
Effectiveness of RAD001 (everolimus) in combination with
endocrine therapy varies with cell phenotype.
Farmer I, Pancholi S, Thornhill A, Evans DB, Lane HA, Dowsett
M, Martin L-A. Institute of Cancer Research, London, United
Kingdom; Novartis Institute for BioMedical Research-Basel, Basel,
Switzerland.
SUSAN G. KOMEN FOR THE CURE BRINKER
AWARDS FOR SCIENTIFIC DISTINCTION
DINNER - Henry B. Gonzalez Convention Center Ballroom C
“Towards a Culture of Discovery: Progress and Passion in the
Search for the Cures” will be an evening to remember as we
celebrate Susan G. Komen for the Cure’s 25th anniversary,
congratulate the 2007 Brinker Award Recipients, Joe W. Gray,
PhD and Leslie Bernstein, PhD and honor the great achievements
of our past Brinker Laureates – Henry B. Gonzalez Convention
Center – Ballroom C. Please purchase your tickets to the 2007
Brinker Dinner when registering at www.sabcs.org. You may also
purchase your tickets onsite at the Susan G. Komen for the Cure
booth. Tickets will be awarded on a first-come, first-served basis.
If you have additional questions, please contact sdeland@komen.
org.
Friday, December 
7:00-9:00
POSTER DISCUSSION 2 & CONTINENTAL
BREAKFAST – Ballroom B
Metastasis 201-210
201
A unique model of estrogen receptor (ER) Ĝ-positive breast
cancer metastasis.
Fuqua SA, Beyer A, Selever J, Hilsenbeck SG, Tsimelzon A, Cui Y.
Baylor College of Medicine, Houston, TX.
202
Primary tumor heterogeneity and sentinel lymph node
metastases: understanding molecular processes of breast
cancer metastasis.
Ellsworth DL, Ellsworth RE, Patney HL, Becker TE, Deyarmin B,
Jordan RM, Hooke JA, Shriver CD. Windber Research Institute,
Windber, PA; Walter Reed Army Medical Center, Washington, DC.
203
Identification of genetic predisposition to development of
lymph node metastasis in breast cancer patients.
Callaghan KA, Weyandt JD, Ellsworth RE, Shriver CD. Windber
Research Institute, Windber, PA; Walter Reed Army Medical
Center, Washington, DC.
204
Identification of new candidate breast cancer metastasis
genes.
Geradts J, Desouki MM, Liao S. Duke University Medical Center,
Durham, NC; Medical University of South Carolina, Charleston,
SC.
205
ALDH1 positive stem cells in inflammatory breast cancer
mediate metastasis and are associated with a poor clinical
outcome.
Charafe-Jauffret E, Ginestier C, Tarpin C, Iovino F, Esterni
B, Jacquemier J, Xerri L, Merajver S, Dontu G, Birnbaum D,
Wicha M, Viens P. Institut Paoli-Calmettes, Marseille, France;
Comprehensive Cancer Center, University of Michigan Medical
Center, Ann Arbor, MI.
206
Programmed cell death 4, a novel inhibitor of breast cancer
invasion.
Nieves-Alicea R, Simeone AM, Colburn NH, Tari AM. The
University of Texas M.D. Anderson Cancer Center, Houston, TX;
National Cancer Institute, Frederick, MD.
207
TROP2 is a novel, major determinant in breast cancer
growth and metastatization.
Alberti S, Trerotola M, Vacca G, Zappacosta R, Rossi C, Guerra
E, Bonasera V, Lasorda R, Lattanzio R, Piantelli M. Foundation
University of Chieti, Chieti Scalo, Chieti, Italy.
208
Osteoblasts and their progenitors stimulate breast cancer
cell migration through chemokine secretion.
Molloy AP, Dwyer RM, Kerin MJ. National University of Ireland,
Galway, Ireland.
209
Significance of PELP1/MNAR-mediated ER-nongenotropic
actions in cytoskeleton signaling.
Chakravarty D, Chandrasekharan Nair B, Rajhans R, Cortez V,
Nair SS, Tekmal RR, deGraffenried LA, Sun LZ, Vadlamudi RK.
210
2003
17ß-hydroxysteroid dehydrogenase type 1 is a predictive
factor in premenopausal hormone receptor positive breast
cancer treated with tamoxifen.
Kallstrom A-C, Salme R, Ryden L, Gunnarsson C, Nordenskjold
B, Stal O. Helsingborg Hospital, Helsingborg, Sweden; University
Hospital, Linkoping, Sweden; University Hospital, Lund, Sweden.
2004
A high ratio of 17HSD1/17HSD2 protein expression predicts
the outcome of tamoxifen treatment in postmenopausal
breast cancer.
Jansson A, Gunnarsson C, Persson L, Fornander T, Skoog L,
Nordenskjöld B, Stål O. Linköping University, Linköping, Sweden;
Karolinska University Hospital, Stockholm, Sweden.
2005
TOP2A gene amplification and response to adriamycin based
therapy.
Tubbs R, Barlow W, Budd GT, Swain E, Porter P, Yeh I-T, Sledge
G, Shapiro C, Ingle J, Haskell C, Albain K, Livingston R, Hayes
D. Cleveland Clinic, Cleveland, OH; Fred Hutchinson Cancer
Research Center, Seattle, WA; University of Texas Health Science
Center at San Antonio, San Antonio, TX; Indiana University
Medical Center, Indianapolis, IN; Arthur James Cancer Center
Hospital, Columbus, OH; Mayo Clinic, Rochester, MN; UCLA
Medical Center, Santa Monica, CA; Loyola University Medical
Center, Maywood, IL; Arizona Cancer Center, Tucson, AZ;
University of Michigan Medical Center, Ann Arbor, MI.
2006
Double staining chromogenic in situ hybridization is a
useful alternative to fluorescent in situ hybridization: first
comparative study of HER2 and TOP2A gene amplification
in breast cancer.
Lacroix-Triki M, Mounie E, Charafe-Jauffret E, Jacquemier J.
Institut Claudius Regaud, Toulouse, France; Institut PaoliCalmettes, Marseille, France.
2007
Quantitative measurements of HER2 expression and
HER2:HER2 dimerization identify subgroups of HER2 positive
metastatic breast cancer patients with different probabilities
of response to trastuzumab treatment.
Huang W, Lipton A, Leitzel K, Ali SM, Fuchs EM, Weidler
J, Chappey C, Sperinde J, Tan Y, Jin X, Paquet A, Winslow J,
Petropoulos C, Kostler WJ, Bates M. Monogram Biosciences,
Inc., So San Francisco, CA; Penn State/Hershey Medical Center,
Hershey, PA; Medical University of Vienna, Vienna, Austria.
2008
Inter-observer interpretative reproducibility of HER2
genotyping of a consecutive series of primary breast
carcinomas by Silver In Situ Hybridization (SISH).
Tubbs R, Myles J, Papouchado B, Lloyd R, Oliveira A, McElhinny
A, Vladich F, Pestic-Dragovich L, Downs-Kelly E, Prescott N,
Pettay J, Loftus M, Roberts C, Grogan T, Roche P. Cleveland Clinic
and the Cleveland Clinic Lerner College of Medicine, Cleveland,
OH; Mayo Clinic, Rochester, MN; Ventana Medical Systems
International, Tucson, AZ.
2009
HER2 tumors are heterogeneous, clinically, molecularly,
and in response to preoperative trastuzumab: pathway
analysis of gene expression profiles from three breast cancer
datasets.
Harris LN, Eklund AC, Carter S, Li X, Winer EP, Hilsenbeck
S, Esteva FJ, Symmans WF, Pusztai L, Szallasi Z, Chang J. Yale
University, New Haven, CT; Childrens Informatics Program,
Boston, MA; Dana Farber Cancer Institute, Boston, MA; Baylor
University, Houston, TX; MD Anderson Cancer Center, Houston,
TX.
2010
Comparison of ERBB2 evaluation by immuno-histochemistry
and a quantitative RT-PCR method in primary breast
cancers.
Giacchetti S, Lehmann-Che J, De Roquancourt A, Cuvier C,
Hocini H, Bertheau P, De The H, Espié M, Turpin E. Hopital
Saint-Louis, Assistance Publique-Hopitaux de Paris, Paris, France;
Hopital Saint-Louis, APHP, Paris, France.
Lapatinib prevents the metastatic colonization of EGFR+
and Her-2+ breast cancer cells in the brain.
Palmieri D, Gril BM, Herring J, Vega-Valle E, Hua EK, Leiwehr
D, Steinberg SM, Gilmer TM, Rubin SD, Steeg PS. National
Cancer Institute, Bethesda, MD; SAIC-NCI, Fredrick, MD;
GlaxoSmithKline, Collegeville, PA.
7:00-9:00
POSTER SESSION 2 & CONTINENTAL
BREAKFAST - Exhibit Hall B
(#2001-2121)
Prognosis and Response Predictions: Predictive
Factors I 2001-2026
2001
2002
Elevated serum TIMP-1/HER-2 predicts decreased response
and survival in metastatic breast cancer.
Lipton A, Leitzel K, Chaudri-Ross HA, Evans DB, Ali SM, Demers
L, Hamer P, Brown-Shimer S, Pierce K, Guar V, Carney W. Penn
State University/Hershey Medical Center, Hershey, PA; Novartis
Pharma AG, Basel, Switzerland; Novartis Institutes for BioMedical
Research Basel, Basel, Switzerland; Penn State/Hershey Medical
Center; Lebanon VAMC, Lebanon, PA; Oncogene Science
Biomarker Group/Siemens Medical Solutions Diagnostics,
Cambridge, MA.
Plasminogen activator inhibitor-1 and tissue inhibitor of
metalloproteinases-1 are additive in predicting response to
chemotherapy in metastatic breast cancer.
Schrohl Rasmussen A-S, Meijer-van Gelder ME, Holten-Andersen
MN, Christensen IJ, Look MP, Mouridsen HT, Foekens JA,
Brünner N. University of Copenhagen, Faculty of Life Sciences,
Copenhagen, Denmark; Erasmus MC, Josephine Nefkens
Institute, Rotterdam, Netherlands; Hvidovre Hospital, Hvidovre,
Denmark; Rigshospitalet, Copenhagen, Denmark.
2011
Development of novel proximity-based immunoassays for
the detection of HER heterodimerization in breast cancer
cell line lysates and formalin-fixed, paraffin-embedded
tissue.
Eli* L, Shi* Y, Dao-Pick T, Bose J, Frankson K, Penuel E, Weston J,
Pidaprthi S, Mukherjee A, Nguyen X-T, Williams S, Goodman L,
Winslow J. Monogram Biosciences, South San Francisco, CA.
2019
Adding the estimation of cyclin D1 gene amplification to
the standard panel of predictors in breast carcinoma can
significantly improve identification of tumors resistant to
tamoxifen.
Petrakova K, Nenutil R, Vyskocil J, Fabian P, Palacova M,
Hanzelkova Z, Knoflickova D. Masaryk Memorial Cancer Institute,
Brno, Czech Republic.
2012
Characterization of a novel proximity immunoassay for
the quantitative determination of HER2 protein expression
and HER2 homodimerization in formalin-fixed, paraffinembedded breast cancer tissue.
Winslow J, Shi Y, Tan Y, Jin X, Dua R, Penuel E, Mukherjee A,
Sperinde J, Pannu H, Chenna A, DeFazio-Eli L, Pidiparthi S, Chen
L, Williams S, Larson J, Goodman L, Whitcomb J, Petropoulos C,
Huang W. Monogram Biosciences, Inc., South San Francisco, CA.
2020
Single agent in vitro drug sensitivity of molecular breast
cancer subtypes defined by gene expression analysis.
Brase J, Schmidt M, Hengstler J, von Törne C, Kölbl H, Gehrmann
M. University of Luebeck, Luebeck, Germany; University of Mainz,
Mainz, Germany; University of Dortmund, Dortmund, Germany.
2021
Tumour volume analysis. A better way than RECIST?
Gordon AB, Stebbing J, Coombes C. Charing Cross Hospital,
London, United Kingdom.
2022
Association of an extracellular matrix gene cluster with
breast cancer prognosis and response to tamoxifen.
Helleman J, Jansen MPHM, Sieuwerts AM, van Staveren IL, Ritstier
K, Look MP, Meijer-van Gelder ME, Klijn JGM, Foekens JA, Berns
EMJJ. Erasmus MC, Rotterdam, Netherlands.
2023
Increased b1 integrin expression is a predictor of
trastuzumab resistance in HER-2 overexpressing metastatic
breast cancer patients.
Thoms J, Sabri S, Lesniak D, Lai R, Deschennes J, Mackey J, Murray
D, Abdulkarim B. University of Alberta, Edmonton, AB, Canada.
2024
Preliminary results from I-SPY trial: tumor patterns on
pre-treatment MRI predict breast conservation therapy
eligibility.
Gomez R, Hylton N, Madhavan S, Leung E, Broadwater G,
Herman B, Esserman L, ISPY Radiology, Clinical & Pathology
Investigators. UCSF, San Francisco, CA; NCI, Bethesda, MD;
CALGB, Durham, NC; ACRIN, Providence, RI.
2025
Molecular markers as predictors of breast cancer response to
adjuvant epirubicin-CMF chemotherapy in the BR9601 trial.
Bartlett JM, Munro AF, Cameron DA, Thomas J, Prescott R,
Twelves C. University of Edinburgh, Edinburgh, United Kingdom;
Western General Hospital, Edinburgh, United Kingdom;
University of Bradford, Bradford, United Kingdom.
2026
Identification of molecular predictors of response of
advanced breast cancer patients to aromatase inhibition.
Haynes B, Ghazoui Z, Anderson H, Dunbier A, Dexter T, Mackay
A, Smith IE, Dowsett M. Royal Marsden Hospital, London, United
Kingdom; The Breakthrough Toby Robins Breast Cancer Research
Centre, London, United Kingdom.
2013
HER2 and SPARC status in tumors play an important role
in the relative effectiveness of nanoparticle albumin-bound
(nab) paclitaxel versus polysorbate-based docetaxel.
Desai N, Trieu V, Hwang L, Wu R, Hawkins M, Soon-Shiong
P, Gradishar W. Abraxis BioScience, Inc., Los Angeles, CA;
Northwestern University, Chicago, IL.
2014
HER2 immunohistochemistry: comparison of image analysis
based interpretation of CB11 and 4B5 clones using reference
fluorescence in-situ hybridization.
Fine JL, Bhargava R, Surti U, Dabbs DJ. Magee-Womens Hospital
of UPMC, Pittsburgh, PA.
2015
Expression of the microtubule-associated protein, tau,
predicts improved survival, but not response, to a
combination of docetaxel and vinorelbine in HER-2 negative
Gralow JR, Barlow WE, Gown AM, Goldstein LC, Porter PL, Yeh
I-T, Livingston RB, Hayes DF. University of Washington, Seattle,
WA; Fred Hutchinson Cancer Research Center, Seattle, WA;
Phenopath, Seattle, WA; UT San Antonio, San Antonio, TX;
Arizona Cancer Center, Tucson, AZ; University of Michigan, Ann
Arbor, MI.
2016
2017
2018
Microtubule-associated protein tau is a marker of
pathological complete response in Her-2/neu positive
neoadjuvant treated breast cancer patients.
Rueckert S, Wirtz R, Lenhard M, Hasmueller S, Ditsch N, Ruehl
I, Kahlert S, Bauerfeind I, Untch M. LMU, Universtity of Munich,
Munich, Germany; Siemens Medical Solutions Diagnostics
GmbH, Leverkusen, Germany; Helios Klinikum Berlin-Buch, Berlin,
Germany.
Cyclin-dependent kinase 2 to 1 specific activity ratio
predicts response to epirubicin and paclitaxel in human
breast cancer.
Kim SJ, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S, Tsukamoto
F, Akazawa K, Nakayama S, Matsushima T, Torikoshi Y, Ishihara
H. Graduate School of Medicine, Osaka University, Suita, Osaka,
Japan; Osaka Koseinenkin Hospital, Osaka, Japan; Sysmex
Corporation, Kobe, Hyogo, Japan.
High pretreatment cyclin E levels may define a higher
risk subset of basal-like breast cancers: in depth
immunohistochemical analysis and clinical outcome of
neoadjuvantly treated basal-like breast cancers.
Osborne CR, Tripathy D, Allada N, Bian A, Xie X-J, Ashfaq R.
UT Southwestern Medical Center, Dallas, TX; Baylor University
Medical Center, Dallas, TX.
Risk and Prevention: Diet and Nutrition 2027-2031
2027
Diet, lifestyle, and BRCA-related breast cancer risk among
French-Canadian.
Ghadirian P, Nkondjock A, Robidoux A, Narod S. University
of Montreal, Epidemiology Research Unit, Research Centre
CHUM, Hôtel-Dieu, Montreal, QC, Canada; CHUM, Hôtel-Dieu,
Montreal, QC, Canada; Women’s College Hospital - University of
Toronto, Toronto, ON, Canada.
2028
Milk products are a source of dietary progesterone.
Goodson III WH, Handagama P, Moore II DH, Dairkee S.
California Pacific Medical Center Research Institute, San
Francisco, CA.
2029
Cardioprotective effects of oral dietary glutamine in tumorbearing rats treated with doxorubicin.
Todorova VK, Kaufmann Y, Klimberg VS. University of Arkansas
for Medical Sciences, Little Rock, AR; Central Arkansas Veterans
Healthcare System, Little Rock, AR.
2030
Effects of Korean red ginseng on the concentration of
blood estrogen, leptin and urinary excretion of estrogen
metabolites in postmenopausal women.
Kang SH, Lee SJ, Baek NW, Kim EM. Yeungnam University
Medical Center, Daegu, Korea.
2031
Breast cancer survivors who use selected herbal supplements
have lower circulating estradiol and free estradiol: the
Health, Eating, Activity and Lifestyle study.
Wayne SJ, Koprowski C, Neuhouser ML, Ulrich CM, Bernstein L,
Gilliland F, Wiggins C, Baumgartner K, Baumgartner R, McTiernan
A, Ballard-Barbash R. University of New Mexico, Albuquerque,
NM; University of Southern California, Los Angeles, CA; Fred
Hutchinson Cancer Research Center, Seattle, WA; National
Cancer Institute, Bethesda, MD.
Risk and Prevention: Familial Breast Cancer / Genetic Testing
2032-2051
2032
2033
2034
Toward individualized risk prediction: the clinical benefit
of risk reduction mastectomy and oophorectomy in BRCA
carriers with breast cancer.
Burke HB, Hoang A, Metcalfe K, Culver JO, MacDonald DJ,
Grant M, Thornton A, Robson M, Narod S, Weitzel JN. George
Washington University, Washington, DC; University of Toronto,
Toronto, ON, Canada; Memorial Sloan Kettering CA Ctr, New
York, NY; City of Hope, Duarte, CA.
A BRCA1 or BRCA2 mutation and young age predict fast
breast cancer growth. Implications for screening?
Tilanus-Linthorst MM, Obdeijn I-M, Hop WC, Causer P, Leach
MO, Warner E, Pointon L, Hill K, Klijn JG, Warren RM, Gilbert FJ.
Erasmus University MC, Rotterdam, Netherlands; Sunnnybrook &
Women’s Health Sciences Centre, Toronto, Canada; Institute of
Cancer Research and Royal Marsden NHS, Sutton, Surrey, United
Kingdom; Addenbrooke’s Hospital and University, Cambridge,
United Kingdom; University of Aberdeen, Aberdeen, United
Kingdom.
Breast carcinoma in situ and the prevalence of BRCA1 and
BRCA2 mutations in a large commercial database.
Hall MJ, Reid JE, Noll WW, Frye CA, Burbidge LA, Wenstrup RJ.
Herbert Irving Comprehensive Cancer Center, New York, NY;
Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
2035
Lifetime risk for breast and ovarian cancer in
postmenopausal BRCA carriers: cause for concern?
Tice JA, Crawford B, Ziegler J, McLennan J, Beattie M. UCSF, San
Francisco, CA.
2036
BRCA1- and BRCA2-associated breast cancer is more
sensitive to standard chemotherapy for metastatic disease in
comparison with sporadic breast cancer.
Kriege M, Seynaeve C, Meijers-Heijboer H, Collee M, MenkePluymers MBE, Bartels CCM, van den Ouweland A, van Geel B,
Hooning M, Brekelmans CTM, Klijn JGM. ErasmusMC-Daniel den
Hoed Cancer Center, Rotterdam, Netherlands.
2037
BRCA mutation in Chinese population: preliminary results
from the Hong Kong hereditary and high risk breast cancer
programme.
Kwong A, Wong CLP, Ma E, Ford JM. The University of Hong
Kong; Hong Kong Santorium and Hospital, Hong Kong; Stanford
University, CA.
2038
The CHEK2*1100delC variant: present in the west of Ireland
breast cancer population.
Colleran GC, Rowan A, Miller N, Sawyer E, Curran C, Kerin M,
Tomlinson I. National University of Ireland Galway, Galway,
Ireland; London Research Institute, Cancer Research UK, London,
England, United Kingdom.
2039
Addressing the needs of men in BRCA1/2 families.
Daly MB. Fox Chase Cancer Center, Philadelphia, PA.
2040
Identification of a recurring BRCA1 mutation in Bahamian
women with breast cancer.
Donenberg T, Turnquest T, Lunn J, Curling D, Krill-Jackson E,
Hurley J. University of Miami/Jackson Memorial Hospital, Miami,
FL; Doctor’s Hospital, Nassau, Bahamas; Princess Margaret
Hospital, Nassau, Bahamas; Mount Sinai Comprehensive Cancer
Center, Miami Beach, FL.
2041
BRCA1 and BRCA2 mutation carrier predictions using the
BRCAPRO model in clinic-based minority families.
Huo D, Senie RT, Terry MB, Daly MB, Buys SS, Ogutha J, Hope
K, Olopade OI. University of Chicago, Chicago, IL; Columbia
University, New York, NY; Fox Chase Cancer Center, Philadelphia,
PA; University of Utah Health Sciences Center, Salt Lake City, UT.
2042
Outcome in BRCA2 mutation carriers is superior to that of
high-risk women with sporadic breast cancer.
McLennan JL, Hwang ES, Moore DH, Crawford BB, Esserman LJ,
Ziegler JL. University of California, San Francisco, CA.
2043
BRCA mutations among women with bilateral breast cancer:
mutation carrier rate and sensitivity of the BRCAPRO model
based on age at first diagnosis.
Ready K, Vogel K, Atchley D, Amos C, Solomon K, Lu K, Arun B.
The University of Texas M.D. Anderson Cancer Center, Houston,
TX.
2044
Large genomic alterations in BRCA1 in young women with
breast cancer participating in the breast cancer family
registry.
Smith LD. Genetic Epidemiology Laboratory, The University of
Melbourne, Parkville, VIC, Australia.
2045
Clinical characteristics and choices regarding prophylactic
surgery in BRCA mutation carriers.
Stuckey A, Dizon D, Legare R, Wilbur J, Kent J, Tejada-Berges T,
Gass J. Women and Infants’ Hospital/Warren Alpert Medical
School of Brown University, Providence, RI.
2046
Cancer-predictive methylation patterns in hereditary breast
cancer.
Suijkerbuijk KP, Fackler MJ, Sukumar S, van Gils CH, van Laar T,
Vooijs M, van der Wall E, van Diest PJ. University Medical Center
Utrecht, Utrecht, Netherlands; Johns Hopkins, Baltimore, MD.
2047
BRCA testing in underserved women: 5 years of follow-up.
Wilcox C, Lee R, Chan S, Crawford B, Luce J, Ziegler J, Beattie MS.
San Francisco General Hospital, San Francisco, CA; University of
California, San Francisco, San Francisco, CA.
2048
Prophylactic surgeries among BRCA1/2 mutation carriers in
the Netherlands.
Hooning MJ. The Collaborative Group on Hereditary Breast and
Ovarian Cancer in the Netherlands (HEBON).
2049
Breast cancer outcomes in an ethnically diverse clinic-based
cohort of high-risk individuals.
Nanda R, Spyrka S, Huo D, Cook M, Chen L, Hope K, Cummings
S, Olopade O. University of Chicago, Chicago, IL.
2050
Different rate of BRCA1/BRCA2 predisposing mutations
according to family history and clinical criteria of breast/
ovarian cancer risk.
Sidoni T, De Marchis L, Midulla C, Capalbo C, Giusti R, Paris
I, Assalone P, Rocchi A, Ronzino G, Di seri M, Scambia G,
Ficorella C, Marchetti P, Cortesi E, Frati L, Gulino A, Giannini
G, Ricevuto E. University of L’Aquila, Medical Oncology,
L’Aquila, Italy; University “La Sapienza”, Service of Molecular and
Ultrastructural Pathology, Rome, Italy; University “La Sapienza”,
Medical Oncology, Rome, Italy; UCSC, Campobasso, Italy; S. Carlo
Hospital, Rome, Italy; S. Andrea Hospital, Rome, Italy.
2051
Endogenous sex hormones and family history of breast
cancer in Chinese women.
Zhou L, Yin W, Lu J, Di G, Wu J. Cancer Hospital, Shanghai, China.
2061
A retrospective analysis of the impact of oncotype DX low
recurrence score results on treatment decisions in a single
academic breast cancer center.
Liang H, Brufsky AM, Lembersky BB, Rastogi P, Vogel VG.
University of Pittsburgh Cancer Institute, Pittsburgh, PA.
2062
A cohort study of the total health care costs for modern
treatment of disseminated breast cancer.
Dahlberg L, Lindman H, Lundkvist J. Uppsala University, Uppsala,
Sweden; European Health Economics, Stockholm, Sweden.
2063
Halved pegfilgrastim doses in adjuvant breast cancer
patients associated with similar efficacy but reduced
toxicity.
Bartelt ME, Harman S, Lower EE. University of Cincinnati,
Cincinnati, OH.
2064
Cost-effectiveness analysis of trastuzumab therapy in
patients with early HER-2 positive breast cancer in Brazil.
Vernaglia PR, Cunha FM, Correa M, Perdicaris MR, Saggia MG,
Santos EAV, Nasciben VD, Pelizon C. Brazilian Institute for
Cancer Control, São Paulo, SP, Brazil; Campinas Medical Center,
Campinas, SP, Brazil; A. C. Camargo Cancer Hospital, São Paulo,
SP, Brazil; Beneficência Portuguesa Hospital, Santos, SP, Brazil;
Roche Pharmaceuticals, São Paulo, SP, Brazil.
2065
Cost comparison of capecitabine in the treatment of
patients with breast cancer: an analysis from a claims
database.
Rugo HS, Schulman KL, Zelt S. University of California San
Francisco, San Francisco, CA; Thomson Healthcare, Cambridge,
MA; Roche Labs Inc., Nutley, NJ.
Treatment: Bone Metastases 2052-2057
2052
2053
Systemic treatment of transforming growth factor-beta
(TGFĝ) antagonists inhibited osteolytic bone metastasis
induced by human breast cancer cells.
Bandyopadhyay A, Wang L, Agyin JJ, Lopez-Casillas F, Tang Y, Sun
LZ. University of Texas Health Science Center, San Antonio, TX;
Universidad Nacional Autónoma de México, Mexico DF, Mexico.
Bone-derived IGF-1 enhances bone pain through activation
of acid-sensing nociceptors in bone metastases of breast
cancer.
Sakurai T, Umemura T, Yono H, Williams P, Farias A, Yoneda T.
Wakayama Medical University Kihoku Hospital, Ito, Wakayama,
Japan; University of Texas Health Center San Antonio, San
Antonio, TX.
2054
Patients’ disease and treatment parameters significantly
affect survival in metastatic breast cancer.
Major P, Cook R. Juravinski Cancer Centre, Hamilton, ON,
Canada; University of Waterloo, Waterloo, ON, Canada.
2055
Natural history of skeletal complications in patients
receiving chemotherapy for breast cancer metastatic to
bone.
Major P, Cook R. Juravinski Cancer Centre, Hamilton, ON,
Canada; University of Waterloo, Waterloo, ON, Canada.
2056
Application of preventive measures minimizes the
occurrence of the osteonecrosis of the jaw (ONJ) in solid
tumors patients (pts) with bone metastases treated with
bisphosphonates (BPs): a single Institution series.
Ripamonti C, Maniezzo M, Cislaghi E, Campa T, Fagnoni E,
Saibene G, Bareggi C, Ascani L, Pigni A, Brunelli C. National
Cancer Institute, IRCCS Foundation, Milano, Italy.
2057
Treatment: Endocrine Therapy 2066-2106
2066
Phase II double-blind randomized trial of daily oral RAD001
(everolimus) plus letrozole (LET) or placebo (P) plus LET as
neoadjuvant therapy for ER+ breast cancer.
Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M,
Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G,
Steinseifer J, Molloy B, Tokaji E, Dixon JM, Jonat W, Rugo HS.
Hospital Vall d’Hebron, Barcelona, Spain; NN Petrov Research
Inst of Oncology, St. Petersburg, Russian Federation; Onc
Centrum St Augustinus, Wilrijk, Belgium; City Oncological
Dispensary, St. Petersburg, Russian Federation; Hospital Clinico
Univ Lozana Blesa, Zaragoza, Spain; Centre Rene Gauducheau,
Nantes, France; General Hospital, Vienna, Austria; Univ Hospital,
Salzburg, Austria; Novartis Pharma AG, Basel, Switzerland; Istituto
Nazionale Tumori, Milan, Italy; Western General Hospital,
Edinburgh, United Kingdom; Univ-Frauenklinik, Kiel, Germany;
Univ of CA SF, San Francisco, CA.
2067
Randomized Phase II study of gefitinib (IRESSA) or placebo
in combination with tamoxifen in patients with hormone
receptor positive metastatic breast cancer.
Osborne K, Neven P, Dirix L, Mackey J, Robert J, Underhill C,
Gutierrez C, Magill P, Hargreaves L. Baylor College of Medicine,
Houston, TX; Gasthuisberg, Leuven, Belgium; Sint Augustinus
Oncologisch, Wilrijk, Belgium; Cross Cancer Institute, Edmonton,
Canada; CHAUQ Hospital du St-Sacrement, Quebec, Canada;
Murray Valley Private Hospital, Wondonga, Australia;
AstraZeneca, Macclesfield, United Kingdom.
2068
Withdrawn.
Bone pain effectiveness and renal safety of ibandronate in
breast cancer patients - are results of controlled clinical
trials consistent with daily clinical practice? Interim analysis
of a non-interventional post marketing surveillance trial in
Germany.
Meden H, Kuehnle H, Seraphin J, Soeling U, Luhn B.
Diakoniekrankenhaus Rotenburg, Germany; Medizinische
Hochschule Hannover, Hannover, Germany; Haematological
and Oncological Practice, Northeim, Germany; Kassel, Germany;
Hamburg, Germany.
Treatment: Cost Effectiveness 2058-2065
2058
Cost-effectiveness of late extended adjuvant letrozole
following a prolonged therapy break from tamoxifen MA-17 post-unblinding analysis.
Karnon J, DiTrapani F, Kaura S. University of Sheffield, Sheffield,
Yorkshire, United Kingdom; Novartis Pharmaceuticals, East
Hanover, NJ.
2059
Comparison of cost of distant disease-free year gained of
aromatase inhibitors letrozole, anastrozole or exemestane
versus tamoxifen for early breast cancer in hormone
receptor-positive postmenopausal women: Canadian
perspective.
El Ouagari K, Karnon J, Kaura S. Novartis, Dorval, QC, Canada;
University of Sheffield, Sheffield, United Kingdom; Novartis, East
Hanover, NJ.
2060
Surgical follow-up for low to average risk breast cancer
patients: too much too soon?
Khokhotva V, George RL, Khokhotva M. Kingston General
Hospital, Queen’s University, Kingston, ON, Canada.
2069
Hot flushes and the risk of recurrence - retrospective,
exploratory results from the ATAC trial.
2080
Increased prevalence of retinal hemorrhages among
anastrozole users.
Eisner A, Falardeau J, Toomey MD, Vetto JT. Oregon Health &
Science University, Beaverton, OR; Oregon Health & Science
University, Portland, OR.
2081
New treatment strategies using aromatase inhibitors: a
preclinical study.
Chen S, Phung S, Masri S. Beckman Research Institute of the City
of Hope, Duarte, CA.
2082
A placebo-controlled trial examining the effects of letrozole
on mammographic breast density and bone and lipid
metabolism.
Cigler T, Yaffe MJ, Johnston D, Verma S, Findlay B, Wadden N,
Pater JL, Richardson H, Tu D, Shangle Q, Goss PE. Massachusetts
General Hospital, Boston, MA; Sunnybrook Health Sciences
Centre, Toronto, ON, Canada; The Ottawa Hospital, Ottawa,
ON, Canada; Niagara Health System, St. Catharines, ON, Canada;
Memorial University of Newfoundland, St. John’s, NL, Canada;
National Cancer Institute of Canada Clinical Trials Group,
Kingston, ON, Canada; (NCIC CTG) MAP.1.
2083
Survival analysis of first-line tamoxifen versus aromatase
inhibitors for estrogen-positive metastatic breast cancer in
postmenopausal women - a BC perspective.
Kyritsis V, De Lemos M, Walker B, Kennecke H, Nakashima L.
BC Cancer Agency, Vancouver, BC, Canada; Queens University
Belfast, Belfast, Ireland.
2084
Impact of CYP2A6 genotype on pharmacokinetics,
safety and efficacy of letrozole treatment in Japanese
postmenopausal women with metastatic breast cancer.
Minami H, Ohsumi S, Nakamura S, Inaji H, Takenoshita S,
Fujiwara Y, Iino Y, Woo M, Tanii H, Tominaga T, Takashima S.
CGS20267 Collaborate Study Group, Tokyo, Japan.
2085
Bone health and anastrozole adverse events in Japan.
Sagara Y, Rai Y. Hakuaikai Sagara Hospital, Kagoshima City,
Kagoshima Prefecture, Japan.
2086
The effects of exemestane, anastrozole and tamoxifen
on bone mineral density and bone turnover markers in
postmenopausal early breast cancer patients: preliminary
results of N-SAS (national surgical adjuvant study) BC04, the
TEAM Japan sub-study.
Aihara T, Hozumi Y, Suemasu K, Takei H, Takehara M, Osumi
S, Saito T, Masuda N, Ohashi Y. Aihara Hospital, Minoo, Osaka,
Japan; Jichi Medical University, Shimono, Tochigi, Japan; Saitama
Cancer Center, Kitaadachi, Saitama, Japan; Hokkaido Cancer
Center, Sapporo, Hokkaido, Japan; Shikoku Cancer Center,
Matsuyama, Ehime, Japan; Saitama Red Cross Hospital, Saitama,
Saitama, Japan; Osaka National Hospital, Osaka, Japan; The
University of Tokyo, Tokyo, Japan.
2087
LET-LOB: preoperative letrozole plus lapatinib or placebo
in hormone-receptor positive HER2 negative operable
breast cancer. Preliminary report of activity and cardiac
tolerability.
Frassoldati A, Guarneri V, Cagossi K, Bottini A, Cavanna L,
Jovic G, Piacentini F, Oliva C, Conte P. University of Modena,
Modena, Italy; Ramazzini Hospital, Carpi, Modena, Italy; Azienda
Ospedaliera, Cremona, Italy; General Hospital, Piacenza, Italy;
Glaxo SmithKline, Greenford, United Kingdom.
Cuzick J. Wolfson Institute of Preventive Medicine, London,
United Kingdom.
2070
Withdrawn.
2071
Risk factors for joint symptoms in the ATAC trial.
Sestak I, on Behalf of the ATAC Trialists’ Group. Wolfson
Institute of Preventive Medicine, London, United Kingdom.
2072
Comparison of joint problems as reported by patients in a
randomised adjuvant trial of anastrozole and letrozole.
Renshaw L, McHugh M, Williams L, Dixon OM, Fallowfield LJ,
Evans DB, Dixon JM. Western General Hospital, Edinburgh,
Scotland, United Kingdom; University of Edinburgh, Edinburgh,
Scotland, United Kingdom; Brighton & Sussex Medical School,
Falmer, Sussex, United Kingdom; Novartis Institutes for
BioMedical Research Basel, Basel, Switzerland.
2073
The effect of anastrozole on bone mineral density: updated
results from the bone subprotocol of the ATAC trial.
Eastell R, Coleman R, Mansel R, Bianco A, Nagykalnai T, Cuzick
J, on Behalf of the ATAC Trialists’ Group. Academic Unit of
Bone Metabolism, Sheffield, United Kingdom; Cancer Research
Centre, Sheffield, United Kingdom; University of Wales College
of Medicine, Cardiff, United Kingdom; Universita Degli Studi
De Napoli Federico II, Naples, Italy; Uzsoki H Hospital, Budapest,
Hungary; Cancer Research UK, London, United Kingdom.
2074
A randomised study of the effects of letrozole and
anastrozole on bone turnover.
McCaig FM, Renshaw L, Williams L, Young O, Murray J,
Macaskill EJ, McHugh M, Hannon R, Dixon JM. Western General
Hospital, Edinburgh, Scotland, United Kingdom; Medical School,
University of Edinburgh, Edinburgh, Scotland, United Kingdom;
Northern General Hospital, Sheffield, England, United Kingdom.
2075
Increased efficacy and combination therapy: targeted
letrozole/estrogen receptor-ĝ specific ligand nanoparticles
homing to mammary tumors in HER-2/aromatase double
transgenic mice.
Nair HB, Santhamma B, Agyin JK, Perla RP, Rossini G, Kirma
NB, Liu Y-G, Evans DB, Tekmal RR. University of Texas Health
Science Center at San Antonio, San Antonio, TX; Southwest
Research Institute, San Antonio, TX; Novartis Pharma AG, Basel,
Switzerland.
2076
Molecular characterization of aromatase inhibitor
resistance: a genome-based approach.
Masri S, Phung S, Wang X, Wu X, Yuan Y-C, Chen S. Beckman
Research Institute of the City of Hope, Duarte, CA.
2077
Therapeutic strategies using aromatase inhibitors and
tamoxifen in a post-menopausal breast cancer model.
Alami N, Li Z, Macedo LF, Brodie A, Leyland-Jones B. VM Institute
of Research, Montreal, QC, Canada; U. of Maryland, Baltimore,
MA; McGill University, Montreal, QC, Canada.
2078
Endometrial status in the Intergroup Exemestane Study (IES)
up to 2 years post-treatment.
Bertelli G, Hall E, Ireland E, Jassem J, Bliss JM, Snowdon CF,
Coombes RC. Singleton Hospital, Swansea, United Kingdom;
Institute of Cancer Research, Sutton, United Kingdom; Medical
University of Gdansk, Poland; Imperial College London, United
Kingdom; on behalf of the IES Group.
2079
Adjuvant aromatase inhibitors in early breast cancer toxicity and adherence. Important observations in clinical
practice.
Dent SF, Hopkins S, Di Valentin T, Verreault J, Vandermeer
L, Verma S. The Ottawa Hospital Regional Cancer Centre
(TOHRCC), Ottawa, ON, Canada.
2088
2089
Health-related quality of life and psychological distress in
Japanese patients with breast cancer treated with tamoxifen,
exemestane or anastrozole for adjuvant therapy: a phase III
randomized study of National Surgical Adjuvant Study of
Breast Cancer (N-SAS BC) 04.
Takehara M, Ohsumi S, Takei H, Shimozuma K, Ohashi Y,
Suemasu K, Hozumi Y. Jichi Medical University, Shimotsuke,
Tochigi, Japan; National Hospital Organization Shikoku Cancer
Center, Matsuyama, Ehime, Japan; Saitama Cancer Center, KitaAdachi, Saitama, Japan; Ritsumeikan University, Kusatsu, Shiga,
Japan; University of Tokyo, Bunkyo, Tokyo, Japan; Arche Clinic
Breast Center, Omiya, Saitama, Japan.
The lipid metabolism of SERMs and AI with primary breast
cancer: combined results of Multi 01 and 02 trial.
Kusama M, Mitsuyama S, Yanagita Y, Doihara H, Komaki K,
Ikeda T, Kimura M, Sano M, Miyauchi K, Anan K. Shinjuku Breast
Center, Tokyo, Japan; Kitakyushu Municipal Medical Center,
Fukuoka, Japan; Gunma Cancer Center, Gunma, Japan; Okayama
University Medical School, Okayama, Japan; Breastopia NAMBA
Hospital, Miyazaki, Japan; Teikyo University School of Medicine,
Tokyo, Japan; Ota General Hospital, Gunma, Japan; Niigata
Association of Occupational Health Inc., Niigata, Japan; Miyauchi
Clinic, Hyogo, Japan.
2090
Estrogen deprivation is crucial for the antitumor effect of
fulvestrant and adding the HER inhibitor gefitinib delays
acquired resistance in a xenograft model of ER-positive
breast cancer.
Massarweh S, Osborne K, Heidi W, Schiff R. University of
Kentucky and Markey Cancer Center, Lexington, KY; Baylor
College of Medicine and Dan L. Duncan Cancer Center, Houston,
TX.
2091
Fulvestrant vs exemestane following non-steroidal
aromatase inhibitor failure: first overall survival data from
the EFECT trial.
Chia S, Piccart M, Gradishar W, on Behalf of the EFECT Writing
Committee. British Columbia Cancer Agency, Vancouver, BC,
Canada; Jules Bordet Institute, Brussels, Belgium; Robert H. Lurie
Comprehensive Cancer Centre of Northwestern University,
Chicago, IL.
2092
Pharmacokinetic profile of the fulvestrant (Fasolodex™)
loading-dose regimen in postmenopausal women with
hormone receptor-positive advanced breast cancer.
McCormack PJ, Sapunar F. AstraZeneca, Macclesfield, Cheshire,
United Kingdom.
2093
Fulvestrant does not stimulate endometrial growth in
postmenopausal breast cancer patients.
Morales L, Neven P, Timmerman D, Wildiers H, Konstantinovic
ML, Tan PN, Christiaens M-R, Paridaens R. University Hospitals
KULeuven; Faculty of Medicine, KULeuven, Belgium.
2094
Fulvestrant in pretreated postmenopausal patients
with metastatic breast cancer: analysis from the French
multicentre compassionate use programme.
Gligorov J, Antoine EC, Dalenc F, Namer M, Chollet P, Spielmann
M, Campone M, Zelek L, Debled M. APHP Tenon, Paris, France;
Clinique Hartmann, Neuilly, France; APHP H Mondor, Creteil,
France; Centre Antoine Lacassagne, Nice, France; Institut
Gustave Roussy, Villejuif, France; Centre Claudius Regaud,
Toulouse, France; Centre Bergonie, Bordeaux, France; Centre
Rene Gauducheau, Nantes, France; Centre Jean Perrin, Clermont
Ferrand, France.
2095
Plasma immunoreactive estradiol is increased during
therapy with fulvestrant in menopausal breast cancer
patients.
Illarramendi JJ, Salgado E, Vera R, Rivero A, Tirapu B, Del Rio L,
Lainez N, Martinez M. Hospital de Navarra, Pamplona, Spain.
2096
HDAC inhibitors sensitize ER negative breast cancer cells to
AIs.
Sabnis GJ, Gediya LK, Njar VCO, Brodie AMH. University of
Maryland, School of Medicine, Baltimore, MD; University of
Maryland Greenebaum Cancer Center, Baltimore, MD.
2097
Phase II trial of the HDAC inhibitor, vorinostat, in
combination with tamoxifen for patients with advanced
breast cancer who have failed prior anti-hormonal therapy.
Lacevic M, Minton SE, Schmitt ML, Bicaku E, Marchion DC,
Munster PN. H. Lee Moffitt Cancer Center & Research Institute,
Tampa, FL.
2098
Tamoxifen resistance and tumor initiation mediated by
Dicer overexpression in breast cancer progenitor cells - role
of BCRP.
Selever J, Lewis MT, Corona-Rodriguez A, Tsimelzon A, Fuqua SA.
Baylor College of Medicine, Houston, TX.
2099
Co-prescription rates of tamoxifen and CYP2D6 inhibitors:
are we compromising breast cancer outcome?
Connolly RM, Barron TI, Feely J, Kennedy MJ. Mater Misericordiae
Hospital, Dublin, Ireland; Trinity College Dublin, Dublin, Ireland;
Trinity College Dublin & St James’s Hospital, Dublin, Ireland.
2100
Association of chemotherapy and estrogen receptor
genotype with change in bone mineral density after one year
of tamoxifen therapy.
Henry NL, Nguyen A, Robarge J, Li L, Hayden J, Lemler S, Schott
A, Skaar TC, Flockhart DA, Hayes DF, Stearns V, Consortium
on Breast Cancer Pharmacogenomics (COBRA) Investigators.
University of Michigan, Ann Arbor, MI; Indiana University,
Indianapolis, IN; Johns Hopkins University, Baltimore, MD.
2101
Late tamoxifen treatment in patients previously operated
for breast cancer without postoperative tamoxifen: interim
analysis.
La Mura N, Magri MD, Scalone S, Da Ronch L, Miolo G, Freschi A,
Veronesi A. Centro di Riferimento Oncologico, Aviano, PN, Italy.
2102
Randomized phase III trial of exemestane or tamoxifen in
first-line hormonal treatment of postmenopausal women
with metastatic breast cancer.
Chernozemsky I, Kalinov K, Tzekov H, Racheva M, Hristova S,
Tomova A, Koynova T, Taskova V, Boideva L, Eniu A, Krasteva
E. National Oncology Centre, Sofia, Bulgaria; New Bulgarian
University, Sofia, Bulgaria; University Hospital “Sv. Marina”, Varna,
Bulgaria; Dispensary of Oncological Diseases, Veliko Tarnovo,
Bulgaria; Dispensary of Oncological Diseases, Plovdiv, Bulgaria;
Dispensary of Oncological Diseases, Sofia, Bulgaria; Dispensary of
Oncological Diseases, Varna, Bulgaria; Dispensary of Oncological
Diseases, Haskovo, Bulgaria; Institute of Oncology, Cluj Napoca,
Romania.
2103
Tamoxifen withdrawal syndrome.
Sedlacek SM, Sedlacek JE. Rocky Mountain Cancer Centers,
Denver, CO; Dartmouth College, Hanover, NH.
2104
Downregulated expression of SIAH2, an ubiquitin E3 ligase,
is associated with endocrine therapy failure.
Jansen MP, Ritstier K, Dorssers LC, van Staveren IL, Helleman J,
Look MP, Meijer-van Gelder ME, Sieuwerts AM, Portengen H,
Klijn JG, Foekens JA, Berns EM. Erasmus MC/Daniel den Hoed
Cancer Center, Rotterdam, Netherlands.
2105
PET FES measures uterine and tumor in vivo
pharmacodynamics of endocrine therapy.
Linden HM, Peterson LM, Schubert EK, Sandarajan L, Mankoff
DA. University of Washington, Seattle, WA.
2106
Adjuvant hormonal therapy choice in women with early
stage breast cancer.
Song X, Nicholas G, Dent S, Verma S. The Ottawa Hospital
Regional Cancer Centre, Ottawa, ON, Canada.
2117
Lentivirus-mediated oncogene delivery to initiate tumors in
mouse mammary epithelial cells.
Siwko S, Lewis B, Gutierrez C, Li Y. Baylor College of Medicine,
Houston, TX; University of Massachusetts Medical Center,
Worcester, MA.
2118
FGFR1 amplification is a breast cancer treatment target and
is associated with endocrine therapy resistance.
Turner NC, Iorns E, Smith A, Lambros MB, Reis-Filho JS, Ashworth
A. The Institute of Cancer Research, London, United Kingdom.
2119
Identification of proline-, glutamic acid-, leucine,
rich protein (PELP1) as a novel CDK4 substrate and
characterizing its role in breast cancer cell proliferation.
Chandrasekharan Nair B, Nair SS, Chakravarty D, Rajhans R,
Cortez V, Yew RP, Tekmal R, Vadlamudi RK. UTHSCSA, San
Antonio, TX.
2120
The regulation of LKB1 by hormones and its implications for
post-menopausal breast cancer.
Brown KA, McInnes KJ, Simpson ER. Prince Henry’s Institute,
Clayton, Victoria, Australia; Monash University, Clayton, Victoria,
Australia.
2121
Androgen receptor CAG repeats, haplotypes, non-random
X chromosome inactivation, and LOH at Xq25 in relation to
breast cancer risk.
Chien H-T, Tsai H-C, Chen S-T, Chien Y-C. National Changhua
University, Changhua, Taiwan, Taiwan; Changhua Christian
Hospital, Changhua, Taiwan, Taiwan.
Tumor Cell Biology: Imunology / Immunotherapy 2107-2114
2107
A systematic review of the role of adjuvant ovarian ablation
in the treatment of women with early stage breast cancer.
Eisen A, Messersmith H, Trudeau M. Cancer Care Ontario, ON,
Canada; McMaster University, Hamilton, ON, Canada.
2108
Trilostane (modrenal) as a hormonal treatment for postmenopausal women with breast cancer.
Sabine VS, Speirs V, Macaskill JE, Shaaban AM, Campbell F,
Renshaw L, Faratian D, Bartlett JM, Dixon MJ. University of
Edinburgh, Edinburgh, United Kingdom; University of Leeds,
Leeds, United Kingdom.
2109
Characterization of anti-MUC1 immune response in patients
with in situ, early and locally-advanced breast cancer.
Geller BA, Lepisto AJ, McKolanis JR, Ahrendt GM, Potter DM,
Finn OJ, Brufsky AM. University of Pittsburgh Cancer Institute,
Pittsburgh, PA; University of Pittsburgh School of Medicine,
Pittsburgh, PA; University of Pittsburgh Cancer Institute; MageeWomens Hosptial of UPMC, Pittsburgh, PA.
2110
2111
Relation of intratumoral B-cells and response to
neoadjuvant chemotherapy.
Lenhard MS, Wirtz RM, Hasmueller S, Rueckert S, Ditsch N, Ruehl
I, Kahlert S, Bauerfeind I, Untch M, on Behalf of the Participating
Centers. Ludwig-Maximilians-University of Munich, Munich,
Germany; Molecular Research, Leverkusen, Germany; Helios
Hospital, Berlin-Buch, Germany.
Decreased accumulation of CD163-positive macrophages
is associated with nodal metastases in patients with breast
cancer.
Mansfield AS, Heikkila P, Vakkila J, von Smitten K, Leidenius M.
Helsinki University Central Hospital, Helsinki, Finland; University
of Helsinki, Helsinki, Finland.
2112
Immunological status of micrometastasis-positive sentinel
nodes in breast cancer patients.
Matsuura K, Osaki A, Saeki T, Ohara M, Murakami S, Arihiro
K. International Medical Center, Saitama Medical University,
Hidaka, Saitama, Japan; Research Institute for Radiation Biology
and Medicine, Hiroshima, Japan; Hiroshima University, Hiroshima,
Japan.
2113
Clinicopathological significance of regulatory T cells in
breast cancer.
Ohara M, Murakami S, Yamaguchi Y, Arihiro K. Radiation Biology
and Medicine, Hiroshima University, Hiroshima, Japan; Kawasaki
Medical School, Kurashiki, Okayama, Japan; Hiroshima University,
Hiroshima, Japan.
2114
Alternatively activated macrophages promote the
invasiveness of breast cancer cells.
Gong C, Zhang X, Liu S, Yu F, Su F, Song E. Sun Yat-Sen Memorial
Hospital, Guangzhou, Guangdong, China.
9:00-9:30
Energy balance, insulin, and breast cancer
Michael Pollak, MD
McGill University
Montreal, CANADA
9:30-11:15
Mechanism of action of herceptin killing of HER-2+ breast
cancer cells under “in vitro” and “in vivo” conditions.
Kute TE, Savage L, Wood J, Vaughn J. Wake Forest University
Medical Center, Winston-Salem, NC; Wake Forest University,
Winston-Salem, NC.
2116
Clinical and immunologic responses of HLA-A3+ breast
cancer patients vaccinated with the HER2/neu-derived
peptide vaccine, E75, in a phase I clinical trial.
Patil R, Holmes JP, Amin A, Carmichael M, Jama YH, McNeill A,
Hueman MT, Craig D, Ponniah S, Peoples GE. Windber Medical
Center, Windber, PA; National Naval Medical Center, Bethesda,
MD; USUHS, Bethesda, MD; Brooke Army Medical Center, Ft.
Sam Houston, TX.
9:30
31. Genomic approaches to breast cancer subset
identification and treatment.
Albertson D, Chin K, Devries S, Feiler H, Pinkel D, Spellman
P, Waldman F, Wang N, Hennessy B, Mills G, Barcellos Hoff
MH, Bissell M, Guan Y, Hu Z, Kuo W-L, McCormick F, Neve R,
Stampfer M, Wooster R, Yaswen P, Das D, Fridlyand J, Correll E,
Jin J, Nordmeyer B, Sudar D, Chew K, Dairkee S, Ljung BM, Hwang
S, Esserman L, Arbushites M, Benz C, Koehler M, Marks JD, Zhou
Y, Park J, Weber B, Gray J. University of California, San Francisco,
CA; Lawrence Berkeley National Laboratory, Berkeley, CA; MD
Anderson Cancer Center, Houston, TX; GlaxoSmithKline, King of
Prussia, PA; California Pacific Medical Center, San Francisco, CA;
Buck Institute for Age Research, Novato, CA; Genentech, South
San Francisco, CA.
9:45
32. Genome-wide analysis of DNA copy number alterations
in conjunction with gene expression profiling identifies DNA
amplification loci that predict distant recurrence in lymph
node-negative (LNN) primary breast cancer patients.
Zhang Y, Klijn J, Yu J, Jiang J, Jatkoe T, Sieuwerts A, Martens J,
Wang Y, Foekens J. Johnson & Johnson, San Diego, CA; Erasmus
MC, Rotterdam, Netherlands.
10:00
33. Gene expression profiles of ER+/PR-breast cancer
are associated with genomic instability and Akt/mTOR
signaling, and predict poor patient outcome better than
clinically assigned PR status.
Creighton CJ, Osborne CK, van de Vijver M, Foekens JA, Wang
Y, Zhang Y, Klijn JGM, Horlings HM, Hilsenbeck SG, Lee AV,
Schiff R. Baylor College of Medicine, Houston, TX; Netherlands
Cancer Institute, Amsterdam, Netherlands; Erasmus MC-Daniel
den Hoed, Rotterdam, Netherlands; Veridex LLC, a Johnson &
Johnson Company, San Diego, CA.
Tumor Cell Biology: Oncogenes/Tumor Suppressor Genes
2115-2121
2115
10:15
10:30
10:45
11:00
34. Expression of alphavbeta6 supersedes Her2 and triplenegative/basal classification of breast cancer and defines
novel subgroups with poor survival: implications for breast
cancer classification and treatment.
Jones JL, Thomas GJ, Duffy SW, Chou P, Gabe R, Ellis I, Green
A, Saha A, Mulligan KT, Ryder K, Gillet C, Violette S, Weinreb
P, Hart IR, Marshall JF. Bart’s and the London, Queen Mary’s
School of Medicine and Dentistry, London, United Kingdom;
Nottingham City Hospital, Nottingham, United Kingdom; Guy’s
Hospital, London, United Kingdom; Biogen Idec, Cambridge, MA.
35. A stroma-related gene signature predicts resistance to
epirubicin-containing neoadjuvant chemotherapy in breast
cancer.
Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P,
Becette V, André S, Piccart M, Campone M, Tubiana-Hulin M,
MacGrogan G, Petit T, Jassem J, Rouanet P, Blot E, Bogaerts J,
Bergh J, Iggo R, Delorenzi M. National Centre of Competence
in Research (NCCR) Molecular Oncology, Swiss Institute for
Experimental Cancer Research (ISREC), Epalinges, Switzerland;
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland;
European Organisation for Research and Treatment of Cancer
(EORTC), Breast Cancer Group, Brussels, Belgium; The Swiss
Group for Clinical Cancer Research (SAKK), Bern, Switzerland;
The Anglo-Celtic Cooperative Oncology Group (ACCOG),
Edinburgh University, Edinburgh, United Kingdom; The Swedish
Breast Cancer Group (SweBCG), Karolinska Institute, Stockholm,
Sweden.
36. The clinical significance of polysomy 17 in the HER2+
N9831 intergroup adjuvant trastuzumab trial.
Reinholz MM, Jenkins RB, Hillman D, Lingle WL, Davidson N,
Martino S, Kaufman P, Kutteh L, Perez EA. Mayo Clinic College
of Medicine, Rochester, MN; John Hopkins, Baltimore, MD;
The Angeles Clinic and Research Institute, Santa Monica, CA;
Dartmouth Hitchcock Medical Center, Lebanon, NH; Oncology
Associates of Cedar Rapids, Cedar Rapids, IA; Mayo Clinic College
of Medicine, Jacksonville, FL.
2:00
The women’s health initiative randomized trials of
menopausal hormone therapy: Results and impact on
clinical practice
Rowan Chlebowski, MD, PhD
LA Biomedical Research Institute
Torrance, CA
2:30
A review of HRT and breast cancer in other epidemiologic
studies
Jack Cuzick, PhD
Wolfson Institute of Preventive Medicine
London, UNITED KINGDOM
3:00
Understanding changes in breast cancer incidence.
Interactions between epidemiological and clinical trial
evidence.
Peter Ravdin, MD, PhD
MD Anderson Cancer Center
Houston, TX
3:30-5:00
3:30
41. ATAC: 100 month median follow-up (FU) shows
continued superior efficacy and no excess fracture risk
for anastrozole (A) compared with tamoxifen (T) after
treatment completion.
Forbes JF, Cuzick J, Buzdar A, Howell A, Baum M on behalf of
the ATAC Trialists’ Group. University of Newcastle, Calgary
Mater Hospital, NSW, Australia; Cancer Research UK, UK; M.D.
Anderson Cancer Center, USA; Christie Hospital, UK; Portland
Hospital, UK.
3:45
42. Mid-term efficacy of a breast cancer screening program
for women with a familial or genetic susceptibility: update of
the Dutch MRI screening study (MRISC).
Rijnsburger AJ, Obdeijn I-M, Kriege M, Boetes C, Oosterwijk JC,
Tollenaar RAEM, Peterse H, Bergers E, Tilanus-Linthorst MMA, de
Koning HJ, Rutgers EJT, Klijn JGM, on behalf of the MRISC Study
Group. Erasmus MC, University Medical Center Rotterdam,
Rotterdam, Netherlands; University Medical Center Nijmegen,
Nijmegen, Netherlands; Groningen University Medical Center,
Groningen, Netherlands; Leiden University Medical Center,
Leiden, Netherlands; Netherlands Cancer Institute, Amsterdam,
Netherlands; Free University Medical Center, Amsterdam,
Netherlands.
4:00
43. Detection of enhancing lesions on contrast-enhanced
MRI of the breast using real-time virtual sonography: fusion
of MRI and sonography data.
Nakano S, Yorozuya K, Takasugi M, Mouri Y, Fukutomi T, Arai
O, Mitake T. Aichi Medical University, Aichi-gun, Aichi, Japan;
Hitachi Medical Corporation, Kashiwa-city, Chiba, Japan.
4:15
44. MRI for diagnosing pure ductal carcinoma in-situ.
Kuhl CK, Schrading S, Wardelmann E, Braun M, Kuhn W, Schild
HH. University of Bonn, Bonn, Germany.
4:30
45. Noninvasive monitoring of neoadjuvant chemotherapy
using optical tomography with ultrasound localization:
initial experience.
Tannenbaum S, Hegde P, Kane M, Xu C, Kurtzman S, Baccaro N,
Iyer M, Wilson L, Deckers P, Zhu Q. University of Connecticut,
Farmington, CT; University of Connecticut, Storrs, CT.
4:45
46. Tomosynthesis for the detection of breast cancer in a
clinical setting.
Ikeda DM, Ruschin M, Timberg P, Svahn T, Zackrisson S,
Andersson I. Radiology, Lund University, Malmoe University
Hospital, Malmoe, Sweden; Radiology, Stanford University School
of Medicine, Stanford, CA.
37. Multidrug resistance and breast cancer: a meta-analysis
of MDR1 and its clinical significance.
Trock B, Leonessa F, Clarke R. Johns Hopkins, Baltimore, MD;
Uniformed Services University of Health Sciences, Bethesda, MD;
Georgetown University, Washington, DC.
11:15-12:00
WILLIAM L. MCGUIRE MEMORIAL LECTURE –
Exhibit Hall D
Sponsored by GlaxoSmithKline.
Biomarking the oestrogen dependence of breast
cancer
Mitchell Dowsett, PhD
Institute of Cancer Research/Royal Marsden NHS Trust
London, UNITED KINGDOM
12:00-1:00
12:30-1:45
CASE DISCUSSION 1 – Ballroom A
2:00-3:30 MINI-SYMPOSIUM 2 – Exhibit Hall D
WOMEN’S HEALTH INITIATIVE: HRT AND OTHER
ISSUES
Peter Ravdin, MD, PhD, Moderator
MD Anderson Cancer Center
Houston, TX
2:00
Introduction
5:00-7:00
POSTER DISCUSSION 3 & RECEPTION –
Ballroom B
309
Evaluation of trastuzumab, docetaxel and capecitabine
as first-line therapy for HER2-positive locally advanced or
Wardley A, Antón-Torres A, Pivot X, Morales-Vasquez F, Zetina
L, Dias Gaui M, Otero Reyes D, Jassem J, Button P, Bell R. Christie
Hospital NHS Foundation Trust, Manchester, United Kingdom;
Hospital Universitario Miguel Servet, Zaragoza, Spain; CHU Jean
Minjoz, Besançon, France; Instituto Nacional de Cancerología,
Mexico City, Mexico; Hospital Roosevelt, Guatemala City,
Guatemala; Instituto Nacional do Câncer, Rio de Janeiro, Brazil;
Hospital CIMA, San José, Costa Rica; Akademia Medyczna,
Gdansk, Poland; Roche Products Pty Ltd, Dee Why, New South
Wales, Australia; Andrew Love Cancer Centre, Geelong Hospital,
Geelong, Victoria, Australia.
310
A phase I study of trastuzumab-DM1, a first-in-class HER2
antibody-drug conjugate, in patients with advanced HER2+
breast cancer.
Krop IE, Beeram M, Modi S, Rabbee N, Girish S, Tibbitts J, Holden
SN, Lutzker SG, Burris HA. Dana-Farber Cancer Institute, Boston,
MA; Institute for Drug Development, San Antonio, TX; Memorial
Sloan-Kettering Cancer Center, New York, NY; Genentech, South
San Francisco, CA; Sarah Cannon Research Institute, Nashville,
TN.
Antibodies and Immunotherapy 301-310
301
Optimal dose and schedule of a HER2/neu peptide (E75)
vaccine in disease-free breast cancer patients: results from
two phase I/II clinical trials.
Holmes JP, Patil R, Amin A, Jama YH, McNeill A, Hueman MT,
Craig D, Ponniah S, Peoples GE. National Naval Medical Center,
Bethesda, MD; Windber Medical Center, Windber, PA; USUHS,
Bethesda, MD; Brooke Army Medical Center, Ft. Sam Houston,
TX.
302
Clinical results of a phase I trial of a HER2/neu-derived
peptide (GP2) vaccine in disease-free, node-negative breast
cancer patients.
Carmichael M, Holmes JP, Mittendorf EA, Amin A, Hueman MT,
Ponniah S, Peoples GE. USUHS, Bethesda, MD; National Naval
Medical Center, Bethesda, MD; UTMD Anderson Cancer Center,
Houston, TX; Brooke Army Medical Center, Ft. Sam Houston, TX.
303
Immunotherapy against metastatic breast cancer with a
twist.
Demaria S, Wang B, Yang AM, Santori F, Kawashima N,
Matsumura S. New York University School of Medicine, New
York, NY.
304
10 years follow up of pilot phase III immunotherapy study
in early stage breast cancer patients using oxidized mannanMUC1.
Vassilaros S, Tsibanis A, Tsikkinhs A, McKenzie IF, Apostolopoulos
V. PROLIPSIS – Diagnostic Breast Center, Athens, Greece; Burnet
Institute at Austin, Heidelberg, Victoria, Australia.
POSTER SESSION 3 & RECEPTION –
Exhibit Hall B
(#3001-3120)
Detection and Diagnosis: Axillary/Sentinel Nodes 3001-3027
3001
Is intraoperative cytology of sentinel nodes useful and
predictive for non-sentinel axillary nodes? NSABP B-32.
Julian TB, Anderson SJ, Fourchotte V, Brown AM, Boudros E,
Mamounas EP, Costantino JP, Wolmark N. NSABP Medical
Affairs, NSABP Investigators & NSABP Operation & Biostatistical
Centers, Pittsburgh, PA.
Targeting of the chemokine receptor CXCR4 in acquired
trastuzumab resistance.
Tripathy D, Mukhopadhyay P, Verma U, Mukhopadhyay C,
Shelton J, Story M, Ding L. University of Texas Southwestern
Medical Center, Dallas, TX.
3002
First clinical results on the potential of intraoperative
imaging for sentinel lymph node biopsy in breast cancer.
Barranger E, Kerrou K, Pitre S, Duval M-A, Charon Y, Uzan S.
Tenon Hospital, Paris, France; Lariboisiere Hospital, Paris, France;
CNRS Paris 7- Paris 11, Orsay, France.
TBCRC 001: EGFR inhibition with cetuximab in metastatic
triple negative (basal-like) breast cancer.
Carey LA, Mayer E, Marcom PK, Rugo H, Liu M, Ma C, Rimawi M,
Storniolo A, Forero A, Esteva F, Wolff A, Ingle J, Ferraro M, Sawyer
L, Davidson N, Perou CM, Winer EP. University of North Carolina;
Dana Farber; Duke; UCSF; Georgetown; Washington University;
Baylor; Indiana University; University of Alabama-Birmingham;
M.D. Anderson; Johns Hopkins; Mayo.
3003
Optical biopsy scanner utilising elastic scattering
spectroscopy for rapid intra-operative diagnosis of sentinel
node metastases in breast cancer.
Somasundaram SK, Chicken DW, Austwick MR, Bown SG,
Keshtgar MR. University College London, London, United
Kingdom.
3004
Sentinel lymph node biopsy for advanced breast cancer
after neoadjuvant chemotherapy: results of the French
multicenter prospective trial GANEA.
Classe J-M, Giard S, Mignotte H, Rodier J-F, Leveque J, Ferron G,
Marchal F, Alran S, Ladonne J-M, Cuisenier J, Dupre P-F, Body
G, Andrieux N, Campion L. Cancer Center, Nantes, France;
Cancer Center, Lille, France; Cancer Center, Lyon, France; Cancer
Center, Strasbourg, France; University Hospital, Rennes, France;
Cancer Center, Toulouse, France; Cancer Center, Nancy, France;
Cancer Center, Paris, France; Cancer Center, Rouen, France;
Cancer Center, Dijon, France; University Hospital, Brest, France;
University Hospital, Tours, France.
3005
The basal breast cancer molecular subtype predicts for
a lower incidence of axillary lymph node involvement in
primary breast cancer.
Crabb SJ, Immonen T, Bajdik CD, Cheang MC, Leung S, Speers
CH, Huntsman D, Nielsen TO, Chia SK. BC Cancer Agency,
Vancouver, BC, Canada.
305
Circulating immature myeloid cells in breast cancer patients
correlate with clinical cancer stage and cyclophosphamide
treatment: implications for cancer immunotherapy.
Montero AJ, Dewaay DJ, Salem M, Cole DJ, Diaz-Montero CM.
Medical University of South Carolina, Charleston, SC.
306
307
308
5:00-7:00
Preliminary results of a randomized phase II study of weekly
irinotecan/carboplatin with or without cetuximab in
O’Shaughnessy J, Weckstein DJ, Vukelja SJ, McIntyre K, Krekow
L, Holmes FA, Asmar L, Blum JL. US Oncology Research, Inc.,
Houston, TX; Baylor-Charles A. Sammons Cancer Center, Dallas,
TX; Texas Oncology, P.A. – Dallas Presbyterian, Dallas, TX; New
Hampshire Oncology-Hematology, Hookset, NH; Tyler Cancer
Center, Tyler, TX; The Breast Care Center of North Texas,
Bedford, TX; Texas Oncology, P.A., Houston, TX.
3006
Axillary staging is more accurate today than ever before: no
increase in the false negative rate with wide-spread adoption
of sentinel node technique.
Helyer LK, Coburn NG, Law CH, McCready DR. Princess Margaret
Hospital, Toronto, ON, Canada; Sunnybrook Health Sciences
Centre, Toronto, ON, Canada.
3007
Rapid detection of lymph node metastasis in breast cancer
patients by “One-step Nucleic Acid Amplification (OSNA)”:
results from a multi-institutional clinical study.
Kaneko T, Akiyama F, Tsujimoto M, Noguchi S, Inaji H,
Nakamura S, Otomo Y, Kato Y, Matsuura N. The Cancer
Institute Ariake Hospital of the Japanese Foundation for Cancer
Research, Tokyo, Japan; Osaka Police Hospital, Osaka, Japan;
Osaka University, Osaka, Japan; Osaka Medical Center of Cancer
and Cardiovascular Diseases, Osaka, Japan; St Luke’s International
Hospital, Tokyo, Japan; SYSMEX Corp, Kobe, Japan.
3008
Clinical significance of occult axillary lymph node metastases
in breast cancer patients without adjuvant systemic therapy:
a long-term retrospective study.
Kelten C, Mittendorf EA, Broglio K, Vo T, Middleton LP, Ueno N,
Hunt KK, Sahin AA. UT M.D. Anderson Cancer Center, Houston,
TX.
3009
Dual-labeled trastuzumab-based imaging agent for the
detection of human epidermal growth factor receptor-2
(HER2) overexpression in breast cancer.
Sevick-Muraca EM, Sampath L, Kwon S, Ke S, Schiff R, Mawad
ME. Baylor College of Medicine, Houston, TX.
3010
Peripheral blood microarray data may aid in predicting
lymph node status of breast cancer patients.
Jordan RM, Hu H, Heckman CM, Kvecher L, Shriver CD, Mural R,
Yang Y-C. Windber Research Institute, Windber, PA; Walter Reed
Army Medical Center, Washington, DC.
3011
Magnetic nanoparticles for detecting cancer spread.
Joshi T, Pankhurst QA, Hattersley S, Brazdeikis A, Hall-Craggs M,
De Vita E, Bainbridge A, Sainsbury R, Sharma A, Douek M. Royal
Free and University College Medical School, London, United
Kingdom; London Centre for Nanotechnology, London, United
Kingdom; Texas Center for Superconductivity, Houston, TX;
University College London Hospital, London, United Kingdom.
3012
Intra-operative assessment of sentinel lymph node using real
time quantitative PCR versus delayed assessment of sentinel
lymph node: a cost-effectiveness model.
Goyal A, Douglas-Jones A, Woods V, Jasani B, Mansel RE. School
of Medicine, Cardiff University, Cardiff, United Kingdom.
3013
Discriminating between sentinel node micrometastases and
sub micrometastases is not contributive to omit axillary
lymph node dissection.
Gilles HG, Sylvia GS, Herve MH, Max BM, Jean Marc CJM,
Monique CM, Claude NC, GCFCC. Institut Paoli Calmettes,
Marseille, Bouches du Rhone, France; Centre Oscar Lambret,
Lille, France; Centre Leon Berard, Lyon, France; Centre Rene
Gauducheau, Nantes, France; Casamance, Marseille, France;
Hopital G Pompidou, Paris, France; Groupe des Chirurgiens de
Federation des CLCC, France.
3014
3015
Scoring system to predict non-sentinel lymph node status in
breast cancer patients with metastatic sentinel lymph nodes:
comparison with other scoring systems and nomogram.
Cho J, Han W, Ko E, Lee JW, Chung SY, Kim E-K, Hwang K-T, Kim
S-W, Noh D-Y. Seoul National University College of Medicine,
Seoul, Korea.
Detailed pathologic evaluation of non-sentinel axillary
lymph nodes following identification of sentinel lymph node
metastases by cytokeratin immunohistochemistry and/or
permanent section H&E levels.
Lillemoe TJ, Dunn D, Bretzke M, Johnson E, O’Leary J, Stoller
D, Fraki S, Pearson S, Diaz LK. Abbott Northwestern Hospital,
Minneapolis, MN.
3016
“One Step Nucleic Acid Amplification” for rapid molecular
analysis of breast cancer lymph nodes: the way towards one
stop sentinel node surgery?
Snook KL, Kissin MW, Layer GT, Jackson P, de Vries CS, Shousha
S, Sinnett HD, Nigar E, Singhal H, Chia Y, Cunnick G. Royal
Surrey Hospital, Guildford, Surrey, United Kingdom; The
University of Surrey, Guildford, Surrey, United Kingdom; Charing
Cross Hospital & Imperial College, London, United Kingdom;
Northwick Park Hospital, Harrow, Middlesex, United Kingdom;
Wycombe General Hospital, High Wycombe, Buckinghamshire,
United Kingdom.
3017
Rapid detection of sentinel lymph node metastasis in breast
cancer by OSNA assay.
Beitsch P, Taylor W, Jordan J, Garcia M, Kocian L. Dallas Surgical
Group, Dallas, TX.
3018
Preoperative axillary ultrasound and fine needle aspiration
cytology of the axillary nodes in the diagnosis of axillary
nodal involvement in breast cancer.
Swinson C, Ravichandran D, Nayagam M, McLaggan S, Wilkie J,
Wright D, Yanny L, Allen S. Luton & Dunstable NHS Foundation
Trust, Luton, United Kingdom.
3019
Metastatic pattern of axillary lymph nodes after sentinel
lymph node on 3D-CT lymphography.
Yamashita K, Shimizu K. Musashikosugi Hospital, Nippon
Medical School, Kawasaki, Kanagawa, Japan; Nippon Medical
School, Bunkyo-ku, Tokyo, Japan.
3020
The necessity of two gene markers for accurate detection of
lymph node micrometastasis using an investigational real
time RT-PCR assay confirmed by 0.2 mm interval frozen
section analysis in breast cancer.
Kurosumi M, Kobayashi Y, Takei H, Kitsugi K, Ueno M, Green
G, Vargo J. Saitama Cancer Center, Saitama, Japan; Veridex LLC,
Japan; Veridex LLC, NJ.
3021
Navigation surgery using a dye and fluorescence for
detecting sentinel lymph nodes in breast cancer.
Hojo T, Kinoshita T, Yoshida M, Shien T, Iwamoto E, AkashiTakana S. National Canver Center Hospital, Tokyo, Japan.
3022
Real time reverse transcriptase-polymerase chain reaction
assay as an adjuvant tool in evaluation of breast cancer
sentinel lymph nodes.
Tafe LJ, Schwab MC, Rizzo EJ, Joel LA, Wells WA, Tsongalis GJ.
Dartmouth Medical School, Dartmouth Hitchcock Medical
Center and Norris Cotton Cancer Center, Lebanon, NH.
3023
Sentinel node excision after neoadjuvant chemotherapy - a
multicentric analysis.
Bauerfeind IGP, Kuehn T, Himsl I, Ruehl IM, Kahlert S, Lebeau A,
Untch M, Hoess C. Ludwig-Maximilians-University of Munich,
Grosshadern, Munich, Germany; Klinikum Esslingen, Esslingen,
Germany; University Eppendorf, Hamburg, Germany; Klinikum
Berlin Buch, Berlin, Germany; Krankenhaus, Ebersberg, Germany.
3024
Clinicopathologic factors associated with microinvasion in
ductal carcinoma in situ: possible utility in planning sentinel
lymph node biopsy.
Mahtani R, Ying B, Rescigno J, Aziz M, Bernik S, Klein P. St.
Vincents Cancer Care Center, New York, NY.
3025
Utility of internal mammary lymph node biopsy in breast
cancer.
Ozmen V, Cabioglu N, Ozcinar B, Ozgen G, Tihan D, Mudun A,
Ozmen T, Igci A, Muslumanoglu M, Kecer M, Dagoglu T. Istanbul
Medical Faculty, University of Istanbul, Istanbul, Capa Fatih,
Turkey.
3026
3027
Long term follow up after 664 sentinel node biopsies: local
axillary failure and overall survival.
Soler C, Bouteille C, Chol R, Reynaud R, Gremillet E, Bousserolles
AM. Centre Hospitalier Privé de la Loire, Saint-Etienne, France;
Centre Hospitalier Universitaire, Saint-Etienne, France; Centre
Hospitalier General, Firminy, France; Centre Hospitalier General,
Le Puy en Velay, France.
Patterns of cellular distribution within the sentinel node
positive for breast cancer.
Tsiapali E, Dizon D, Steinhoff M, Gass J. Women and Infants
Hospital, Providence, RI; Brown University Medical School,
Providence, RI.
3037
Fine needle aspiration cytology material is highly suitable
for mRNA extraction and subsequent molecular analysis of
breast cancer.
Uzan C, Andre F, Veronique S, Suzette D, Philippe V. Institut
Gustave Roussy, Villejuif, France; UPRESS EA 3535, France.
3038
The borderline amplified HER2 FISH result on breast core
biopsy: indications for further sampling do affect patient
management.
Striebel JM, Bhargava R, Surti U, Brufsky A, Dabbs DJ. Magee
Womens Hospital, University of Pittsburgh Medical Center,
Pittsburgh, PA.
3039
Core biopsy following neoadjuvant chemotherapy in breast
cancer - a tool to predict both residual disease and plan
axillary treatment.
Balasubramanian R, Aref F, Sivagurunathan S, Riddle P, Ahmad R,
Vashisht R. West Middlesex University Hospital, London, United
Kingdom.
3040
Medico-economic evaluation of the rapid diagnosis of breast
lesions using fine-needle aspiration in a one stop breast
clinic.
Delaloge S, Noel E, Andre F, Benhamou E, Larue C, Balleyguier
C, Vielh P, de Pouvourville G. Institut Gustave Roussy, Villejuif,
France; ESSEC Business School, Cergy Pontoise, France.
3041
Equivocal triple assessment summary scores - do they mean
anything?
Parmeshwar R, Harland RN. Royal Albert Edward Infirmary,
Wigan, Lancashire, United Kingdom.
Detection and Diagnosis: Diagnostic Pathology 3028-3041
3028
3029
3030
Gene expression by standardized quantitative RT-PCR in
the special histologic subtypes of estrogen receptor positive
invasive breast cancer.
Baehner FL, Watson D, Ballard JT, Palmer G, Shak S. Genomic
Health, Inc., Redwood City, CA.
One-step nucleic acid amplification for intra-operative
detection of lymph node metastases in breast cancer
patients.
Schem C, Maass N, Bauerschlag DO, Jonat W, Carstensen M,
Löning T, Tiemann K. University Clinic of Schleswig-Holstein,
Campus Kiel, Kiel, Germany; Albertinen Krankenhaus, Hamburg,
Germany; University Clinic of Hamburg Eppendorf, Hamburg,
Germany.
Discrepancy between triple negative phenotype and basallike tumor: an immunohistochemical analysis based on 150
“triple-negative” breast cancers.
Conforti R, Bidard F-C, Michiels S, Boulet T, Tomasic G, Mathieu
M-C, Delaloge S, Andre F. Institut Gustave Roussy; Breast Cancer
Business Unit; Institut Gustave Roussy, Villejuif, France.
3031
Prophylactic mastectomy - trends in pathology findings.
Wen YH, Roses DF, Axelrod DM, Guth AA, Shapiro RL,
Cangiarella J, Ziguridis N, Darvishian F, Singh B. New York
University School of Medicine, New York, NY.
3032
Multiplexed immunohistochemical quantitative molecular
phenotyping via multispectral imaging and automated
segmentation.
Hoyt CC, Gossage K, Levenson RM, Bandaru R, Gardner H.
Cambridge Research and Instrumentation, Inc., Woburn, MA;
Novartis Institutes for BioMedical Research Inc., Cambridge, MA.
3033
3034
3035
3036
Assessment of ErbB2 gene amplification with quantitative
real time PCR.
Gunnarsson C, Olsson H, Nilsson J, Holmlund B, Jansson A.
Linkoping University Hospital, Linkoping, Sweden; Faculty of
Health Science Linkoping, Linkoping, Sweden.
Scoring system to predict malignancy in patients diagnosed
as atypical ductal or lobular hyperplasia on ultrasoundguided core needle biopsy.
Ko E, Han W, Lee JW, Cho J, Kim E, Jung S-Y, Moon WK, Park IAe,
Kim S-W, Lee ES, Noh D-Y. Seoul National University Hospital,
Seoul, Korea; Bundang Seoul National University Hospital,
Sungnam-si, Korea; National Cancer Center, Goyang-si, Korea.
Identification of commonly aberrant genomic regions using
high-resolution array CGH on paraffin-embedded breast
cancer samples.
Davis R, Poirier B, De Witte A, Lin E, Borowsky A, Gosh J, Gao J,
Giles S, LeProust E, Amorese D, Roberts D, Shams S, Carmack C,
Gregg JP. UC Davis, Sacramento, CA; Agilent Technologies, Santa
Clara, CA; BioDisovery, Manhattan Beach, CA.
Correlation between breast core biopsies of uncertain
malignant potential and subsequent excision biopsies.
Fazel MZ, Rothnie ND, Payne S. Southend University Hospital,
Southend-on-Sea, Essex, United Kingdom.
Detection and Diagnosis: Biopsy Techniques 3042-3044
3042
Is diathermy excision of gynaecomastia superior to saline
adrenaline and sharp dissection technique?
Parmeshwar R, Harland RNL, Prasad R. Royal Albert Edward
Infirmary, Wigan, Lancashire, United Kingdom.
3043
The accuracy of preoperative core biopsy in patients with
ductal carcinoma in situ.
Halliday M, Bruce E, Marshall, Thompson C, Shokuhi S, Jones L,
Harries S, Clarke D. Warwick Hospital, Warwick, Warwickshire,
United Kingdom.
3044
Breast biopsy for mammographically detected
nonpalpable lesions using a vacuum-assisted biopsy
device (Mammotome) and an upright-type stereotactic
mammography unit.
Ohsumi S, Taira N, Aogi K, Takashima S, Nishimura R. National
Hospital Organization Shikoku Cancer Center, Matsuyama,
Ehime, Japan.
Epidemiology and Outreach: Racial Aspects 3045-3052
3045
Racial differences in frequency and spectrum of BRCA1/2
mutations in young women with breast cancer.
Haffty BG, Choi DH, Moran MS, Silber A, Matloff E, Lee MH,
Ranieri K, Toppmeyer D. UMDNJ-RWJMS and Cancer Institute of
New Jersey, New Brunswick, NJ; Soonchunhyang Hospital, Seoul,
Korea; Yale University, New Haven, CT.
3046
A transcription factor-centric computational analysis of
genes differentially expressed in healthy breast tissues from
African American and Caucasian women.
Hu H, Stegmaier P, Field LA, Kel A, Shriver CD, Liebman MN,
Mural RJ. Windber Research Institute, Windber, PA; BIOBASE
GmbH, Wolfenbüttel, Germany; Walter Reed Army Medical
3047
Identification of protein expression differences in invasive
breast tumors from African American compared to
Caucasian women.
Ellsworth RE, Seeley EH, Ellsworth DL, Sanders M, Hooke JA,
Caprioli RM, Shriver CD. Windber Research Institute, Windber,
PA; Vanderbilt University, Nashville, TN; Walter Reed Army
Medical Center, Washington, DC.
3048
NCIC CTG MAP.3: enrollment and study drug adherence of
ethnic minority women in a breast cancer prevention trial.
Moy B, Richardson H, Johnston D, Pater JL, Chlebowski R, AlésMartínez JE, Ingle J, Goss PE. Massachusetts General Hospital,
Boston, MA; Queen’s University, Kingston, ON, Canada; HarborUCLA, Torrance, CA; Hospital Ruber Internacional, Madrid, Spain;
Mayo Clinic, Rochester, MN.
3049
Ethnicity and breast cancer: risk and predictors in a pre-paid
health plan.
Shim VC, Li Y, Baer D, Udaltsova N, Klatsky AL. Kaiser
Permanente Medical Center, Oakland, CA; Kaiser Permanente
Medical Care Program, Oakland, CA.
3050
Identification of trends in large breast cancers in an
ethnically diverse population.
Bailey L, Mendelsohn MA, Bishop S. Alta Bates Summit Medical
Center, Berkeley-Oakland, CA.
3051
Patterns of therapy and adherence to established treatment
guidelines in caucasian versus African-American newepisode breast cancer patients.
Short L, Fisher M, Wahl P, White S, Rodriguez N, Kelly M.
HealthCore, Inc., Wilmington, DE; Blue Cross Blue Shield
of Georgia, Atlanta, GA; University of Pittsburgh School of
Medicine, Pittsburgh, PA.
3052
Multiethnic comparisons of genome-wide alterations in
breast cancer using paraffin embedded samples.
Baumbach LL, Ahearn ME, Jorda M, Gomez C, Halsey TA, Ellison
K, Farragher SM, Jellema GL, Gluck S. Miller School of Medicine,
Univ of Miami, Miami, FL; Almac Diagnostics, Durham, NC.
3056
Multicenter phase II randomized trial evaluating toxicities
of concurrent and sequential radiotherapy and letrozole
(COHORT) as adjuvant therapy after conservative surgery
in postmenopausal women with hormone receptor positive
tumors: preliminary results.
Azria D, Ozsahin M, Rosenstein B, Romieu G, Gutowski M,
Zaman K, Llacer Moscardo C, Lemanski C, Jeanneret-Sozzi
W, Gligorov J, Gourgou S, Larbouret C, Pelegrin A, Dubois J-B,
Belkacemi Y. CRLC Val d’Aurelle, Montpellier, France; Centre
Hospitalier Universitaire Vaudois, Lausanne, Switzerland; NYU
School of Medicine, New York, NY; AP-HP CancerEst Tenon,
Paris, France; CLCC Oscar Lambret, Lille, France.
3057
Distant metastasis: the most common type of early
recurrence with adjuvant tamoxifen therapy.
Doughty JC, Wilson CR, Monypenny IJ, Skene AI, Abram P,
Gattuso J, Carpenter R, Angerson WJ, Mansell J. Western
Infirmary, Glasgow, Scotland, United Kingdom; University of
Wales College of Medicine, Cardiff, United Kingdom; Royal
Bournemouth Hospital, Bournemouth, United Kingdom;
Northern Ireland Cancer Centre, Ulster, United Kingdom; St.
Bartholomew’s Hospital, London, United Kingdom.
3058
Acceptance of extended hormonal therapy with letrozole
after 5 years of adjuvant tamoxifen in post menopausal
breast cancer patients in Calgary, Alberta.
Trotter T, Railton C, Webster M, Paterson AHG. Tom Baker
Cancer Centre, Calgary, AB, Canada.
3059
Chronological changes of side effect profile of anastrozole
compared with tamoxifen in Japanese women: findings
from N-SAS BC03 trial every 3 months after one year of the
randomization.
Hozumi Y, Aihara T, Takatsuka Y, Osumi S, Aogi K, Imoto S,
Iwata H, Watanabe T, Nakagami K, Ohashi Y. Jichi Medical
University, Shimotsuke, Tochigi, Japan; Kansai Rosai Hospital,
Amagasaki, Hyogo, Japan; Shikoku Cancer Center, Matsuyama,
Ehime, Japan; National Cancer Center East, Kashiwa, Chiba, Japan;
Aichi Cancer Center Central, Nagoya, Aichi, Japan; Hamamatsu
Oncology Center, Hamamatsu, Shizuoka, Japan; Shizuoka General
Hospital, Shizuoka, Japan; Tokyo University, Bunkyo-ku, Tokyo,
Japan.
3060
First results of the prospective Hospital del Mar Bone Health
Breast Cancer study (HMBHBC) in postmenopausal women
receiving adjuvant aromatase inhibitors for early breast
cancer.
Nogues X, Servitja S, Velat M, Nadal R, Garces JM, Pena
MJ, Albanell J, Diez-Perez A, Tusquets I. Hospital del Mar,
Autonomous University Barcelona, Barcelona, Spain.
3061
Compliance with tamoxifen and arimidex in the adjuvant
treatment of women with breast cancer.
Hadji P, Ziller V, Holzhauer W, Ziller M, Kalder M, Wagner U.
Philipps-University of Marburg, Marburg, Germany.
3062
Risk of contralateral breast cancer in patients receiving
adjuvant aromatase inhibitor - the rate of positive biopsies
for cancer.
Castaner MC, Elledge R, Tham YL. Baylor College of Medicine,
Houston, TX.
3063
Phase II feasibility trial incorporating bevacizumab into
dose dense doxorubicin and cyclophosphamide followed
by paclitaxel in patients with lymph node positive breast
cancer: a trial of the Eastern Cooperative Oncology Group
(E2104).
Miller KD, O’Neill A, Perez EA, Seidman AD, Sledge GW. Indiana
University Cancer Center, Indianapolis, IN; Dana Farber Cancer
Institute; Mayo Clinic; Memorial Sloan Kettering Cancer Center.
Treatment: Adjuvant Therapy 3053-3082
3053
A prospective study comparing clinical rheumatological
findings and tenosynovial and synovial changes on magnetic
resonance imaging of breast cancer patients receiving
adjuvant aromatase inhibitors or tamoxifen.
Morales L, Pans S, Verschueren K, Paridaens R, Westhovens R,
Timmerman D, Desmet L, Marie-Rose C, Neven P. University
Hospitals KULeuven, Belgium.
3054
A study of associations between estrogen and tamoxifen
metabolism, cytochrome 2D6 and sulfotransferase 1A1
polymorphisms, and sulfotransferase 1A1 gene copy number
during steady state tamoxifen treatment.
Gjerde J, Geisler J, Lundgren S, Ekse D, Breilid H, Hauglid M,
Varhaug JE, Mellgren G, Steen VM, Lonning PE, Lien EA. Section
for Endocrinology, Institute of Medicine, University of Bergen,
Norway; Section of Oncology, University of Bergen, Norway;
Norwegian University of Science and Technology, Department
of Cancer Research and Molecular Medicine, Norway; Haukeland
University Hospital, Norway; Center for Medical Genetics and
Molecular Medicine, Haukeland University Hospital, Norway;
Institute of Medicine, University of Bergen, Norway; University
of Bergen, Norway; Section of Oncology, University of Bergen,
Bergen, Norway; Section for Endocrinology, University of Bergen,
Norway.
3055
How compliant are patients with oral hormonal therapies?
Data from a randomized, placebo controlled study of
tamoxifen after adjuvant chemotherapy in premenopausal
women with early breast cancer (NCIC CTG MA.12).
Bramwell VHC, Pritchard KI, Tu D, Tonkin K, Vachhrajani H,
Robert J, Arnold A, Vandenberg TA, O’Reilly SE, Graham B,
Shepeherd LE. National Cancer Institute of Canada Clinical Trials
Group, Queen’s University, Kingston, ON, Canada.
3064
BCIRG 006: quality of life (QoL) of patients (pts) treated
with docetaxel and trastuzumab-based regimens in node
positive and high risk node negative HER2 positive early
breast cancer.
Au H-J, Robert N, Eiermann W, Pienkowski T, Crown J, Martin M,
Pawlicki M, Chan A, Bee V, Slamon D. Breast Cancer International
Research Group (BCIRG), Edmonton, AB, Canada.
3065
Cardiac safety of adjuvant bevacizumab plus dose-dense
doxorubicin/cyclophosphamide followed by nanoparticle
albumin-bound paclitaxel in patients with early stage breast
cancer.
McArthur HL, Rugo H, Paulson M, Rourke M, Traina T, Panageas
K, Steingart R, Dang C, Fornier M, Park J, Moasser M, Melisko M,
Sugarman S, Norton L, Hudis CA, Dickler MN. Memorial SloanKettering Cancer Center, New York, NY; UCSF Comprehensive
Cancer Center, San Francisco, CA.
3066
3067
Preliminary results of a multicenter study of bevacizumab
with 3 docetaxel-based adjuvant breast cancer regimens.
Yardley DA, Hart L, Badarinath S, Waterhouse DM, Daniel
B, Childs BH, Burris III HA. Tennessee Oncology, Nashville,
TN; Florida Cancer Specialists, Fort Meyers, FL; Integrated
Community Oncology Network, Jacksonville, FL; Oncology
Hematology Care, Cincinnati, OH; Chattanooga Oncology
& Hematology Associates, Chattanooga, TN; Sanofi-Aventis,
Bridgewater, NJ.
Pre-anthracycline and herceptin cardiac scanning for
adjuvant breast carcinoma: a retrospective analysis of results
in Scotland’s biggest cancer centre.
Lindsay CR, McIlroy P, Stirling L, Canney PA. Gartnavel General
Hospital, Glasgow, Scotland, United Kingdom.
3068
Adjuvant trastuzumab uptake outside of clinical trials.
Snow SL, Rayson D, Barnes PJ, Sellon M, Skedgel C, Dewar R,
Weber A, Younis T. Queen Elizabeth II Health Sciences Centre,
Halifax, NS, Canada; Cancer Care Nova Scotia, Halifax, NS,
Canada.
3069
Final toxicity analysis of the ADEBAR phase III study
evaluating the role of docetaxel in the adjuvant therapy
of breast cancer patients with extensive lymph node
involvement.
Janni W, Harbeck N, Sommer H, Rack B, Augustin D, Simon W,
Jueckstock J, Wischnik A, Annecke K, Friese K, Kiechle-Bahat M.
LMU, Munich, Germany; Frauenklinik, Deggendorf, Germany;
Frauenklinik, Stuttgart, Germany; Frauenklinik, Augsburg,
Germany; Klinikum Rechts der Isar TU, Munich, Germany.
3070
T1N0 triple negative breast cancer: adjuvant chemotherapy
treatment and risk of recurrence.
Kaplan HG, Malmgren JA, Atwood MK. Swedish Cancer Institute,
Seattle, WA; HealthSTAT Consulting, Inc, Seattle, WA.
3071
The incidence of thromboembolism in patients receiving
adjuvant anthracycline based chemotherapy for early stage
breast cancer.
Nolan L, Boleti E, Darby A, Simmonds PD. Southampton
University Hospitals NHS Trust, Southampton, United Kingdom.
3072
Chemotherapy dose delays and dose reductions in breast
cancer patients receiving dose-dense FEC and docetaxel results of a randomized, open-label phase II study.
Wildiers H, Dirix L, Neven P, Prové A, Clement P, Amant F, Skacel
T, Paridaens R. University Hospital Gasthuisberg, Leuven, Belgium;
St-Augustinus Hospital, Wilrijk, Belgium; Amgen (Europe) GmbH,
Zug, Switzerland.
3073
A feasibility study of capecitabine monotherapy for elderly
patients with high risk early breast cancer.
Bernard-Marty C, Widakowich C, Demonty G, Personeni N,
Lebrun F, Paesmans M, Veys I, Lieutenant F, Kabanga E, Biganzoli
L, Nogaret J-M, Piccart MJ, Cardoso F. Jules Bordet Institute,
Brussels, Belgium; Prato Hospital, Prato, Italy.
3074
Delivery of adjuvant dose dense doxorubicin+cyclophosph amide¢paclitaxel to early stage breast cancer patients with
pegfilgrastim and darbepoetin alfa support - interim results
from an Australian phase II study.
De Boer RH, Patterson W, Beith J, Rocchi L, Beer F, Lewis C.
Royal Melbourne Hospital, Melbourne, Victoria, Australia;
Queen Elizabeth Hospital, Woodville, South Australia, Australia;
Royal Prince Alfred Hospital, Camperdown, New South Wales,
Australia; Amgen Australia Pty Ltd, Hawthorn, Victoria, Australia;
Prince of Wales Hospital, Randwick, New South Wales, Australia.
3075
A pilot study to investigate the feasibility and cardiac effects
of pegylated liposomal doxorubicin (PL-DOX) as adjuvant
therapy in elderly breast cancer patients.
Wildiers H, Jurcut R, Denys H, de Backer J, Ganame J, Herbots
L, Neven P, Cocquyt V, Rademakers F, Voigt J-u, Paridaens R.
University Hospital Gasthuisberg, Leuven, Belgium; University
Hospital Gent, Gent, Belgium.
3076
Adjuvant chemotherapy in breast cancer patients older than
70 years.
Garg P, Rana F, Guthrie TH. University of Florida, Jacksonville, FL;
Baptist Cancer Center, Jacksonville, FL.
3077
Annual hazard rates of recurrence for early breast cancer.
What has changed in the last 10 years? Results from the
NORA study.
Cazzaniga ME, Mustacchi G, Pronzato P, De Matteis A, Di
Costanzo F, Nardi M, Barberis G, D’Aprile M, Rulli E, Floriani I. Az
Osp Treviglio-Caravaggio, Treviglio, Bergamo, Italy.
3078
Do patients with infiltrating lobular carcinoma (ILC) have an
increased risk of contralateral, local, or distant recurrences
compared with patients with infiltrating ductal carcinoma
(IDC)?
Pestalozzi BC, Zahrieh D, Mallon E, Gusterson B, Gelber R, Price
K, Castiglione-Gertsch M, Coates A, Goldhirsch A. International
Breast Cancer Study Group, Berne, Switzerland.
3079
Prognostic effect of amenorrhea and return of menses after
adjuvant treatment of premenopausal patients with nodepositive breast cancer.
Jonat W, Sauerbrei W, Kaufmann M, Schumacher M. UKSH
Schleswig Holstein, Kiel, Germany; Universitätsklinikum Freiburg,
Freiburg, Germany; University of Frankfurt, Frankfurt, Germany.
3080
Detection of minimal residual disease (MRD) in peripheral
blood of primary breast cancer patients - translational
research in the SUCCESS-study.
Jueckstock JK, Rack B, Thurner-Hermanns E, Forstbauer H, Pantel
K, Ulmer H-U, Beckmann MW, Lichtenegger W, Janni WJ, Friese
K, Sommer HL. Frauenklinik, Klinikum Innenstadt, Munich
University, Munich, Bavaria, Germany; Klinikum Rosenheim,
Rosenheim, Bavaria, Germany; Oncologic Practice Dr. Forstbauer/
Dr. Ziske, Troisdorf, Nordrhein-Westfalen, Germany; University
Hamburg-Eppendorf, Hamburg, Germany; Klinikum Karlsruhe,
Karlsruhe, Baden-Wuerttemberg, Germany; Frauenklinik,
University of Erlangen, Erlangen, Bavaria, Germany; Charite
Universitaetsmedizin, Berlin, Germany.
3081
Biological risk assessment based on snap frozen tissue
samples. Feasibility, qualitiy assuance and study progress of
the multicenter trial NNBC 3-Europe.
Thomssen C, Vetter M, Geurts-Moespot A, Persing M, Paepke
D, Schmidt M, Meisner C, von Minckwitz G, Sweep F, Harbeck
N. Martin-Luther Universitaet, Halle/Saale, Germany; Radboud
Universiteit, Nijmegen, Netherlands; Technische Universitaet
Muenchen, Muenchen, Germany; Johannes-Gutenberg
Universitaet, Mainz, Germany; Eberhard-Karls Universitaet,
Tuebingen, Germany; German Breast Group, Neu-Isenburg,
Germany.
3082
Evaluation of practice patterns in the treatment of nodenegative, hormone-receptor positive breast cancer patients
with the use of the oncotype DX assay at the University of
Pennsylvania.
Erb C, Fox KR, Patel M, Hook K, DeMichele A, Kaplan C,
Domchek S. University of Pennsylvania, Philadelphia, PA.
3094
Targeting up-regulated notch signaling in the CD133+ stem
cells within the protected niche of the lymphovascular
embolus of inflammatory breast cancer.
Barsky SH, Xiao Y, Ye Y. The Ohio State University College of
Medicine, Columbus, OH.
3095
The overexpression of ERBB receptor tyrosine kinases
and ABC transporters is associated with an increased side
population in hormone resistant breast cancer cells.
Chumsri S, Nakanishi T, Phatak P, Macedo LF, Sabnis G,
Hamburger AW, Brodie AH, Burger AM. University of Maryland
Greenebaum Cancer Center, Baltimore, MD; University of
Maryland School of Medicine, Baltimore, MD.
3096
CTEN and LKB1: novel tumor biomarkers for breast cancer
implications of resistance and response to tyrosine kinase
inhibitor (TKI)-based therapies in breast cancer.
Yarden Y, Shell SA, Spector NL, Bacus SS. Targeted Molecular
Diagnostics, Westmont, IL; Duke University Medical Center,
Durham, NC; Weizmann Institute of Science, Rehovot, Israel.
3097
HER2 increases the translational rates of acetyl-CoA
carboxylase alpha and fatty acid synthase in breast cancer
cells.
Lee MJ, Park B-W, Yoon S, Lee M-Y, Kim K-S, Kim J-H, Park S-H.
Yonsei University, College of Medicine, Seoul, Korea; Yonsei
University, College of Medicine, Korea.
3098
The identification of proteins associated with radiotherapy
resistance in breast cancer cells: screening 725 antibodies
simultaneously using novel microarray technology.
Smith L, Qutob O, Watson MB, Beavis AW, Lind MJ, Drew
PJ, Cawkwell L. University of Hull, Hull, East Yorkshire, United
Kingdom.
3099
A combined proteomic and microarray screening
approach for the identification of proteins associated with
radiotherapy resistance in breast cancer cells.
Smith L, Qutob O, Watson MB, Beavis AW, Jameel JK, Welham
KJ, Drew PJ, Lind MJ, Cawkwell L. University of Hull, Hull, East
Yorkshire, United Kingdom.
3100
Genomic signature of invasive lobular cancer by DNA array
hybridization.
Hwang ES, Devries S, Roydasgupta R, Fridlyand J, Chin K, Chen
Y-Y, Korkola J, Waldman FM. University of California, San
Francisco, CA; Memorial Sloan Kettering Cancer Center, New
York, NY.
3101
The genomic relationship between breast carcinomas and
their paired lymph node metastases.
Desouki MM, Gaile DP, Conroy J, McQuaid D, Nowak NJ,
Shepherd L, Liao S, Geradts J. Medical University of South
Carolina (MUSC), Charleston, SC; State University of New York,
Buffalo, NY; Roswell Park Cancer Institute, Buffalo, NY; Duke
University Medical Center, Durham, NC.
3102
A Q-RT PCR profile for the cytological diagnosis of early
breast lesions.
Delaloge S, Laurent I, Scott V, Dessen P, Andre F, Suciu V,
Saghatchian M, Lazar V, Lidereau R, Michiels S, Vielh P. Institut
Gustave Roussy, Villejuif, France; Centre Rene Huguenin, Saint
Cloud, France.
3103
Breast cancer classication according to “stem cell-like”
features and its relevance for systemic adjuvant treatment
decision.
Rody A, Holtrich U, Gätje R, Engels K, von Minckwitz G, Loibl
S, Gehrmann M, Ruckhäberle E, Ahr A, Solbach C, Karn T,
Kaufmann M. J.W. Goethe-University, Frankfurt, Germany;
German Breast Group, Neu-Isenburg, Germany; Siemens Medical
Solutions Diagnostics GmbH, Leverkusen, Germany.
Treatment: Hormone Replacement Therapy 3083-3087
3083
Reduced use of HRT by women in Victoria Australia in 2002
was not followed by a fall in breast cancer incidence.
Bell R, Chappell G, Stagoll O, Maljevac S, Wilkinson J, Giles
GG. The Geelong Hospital, Barwon Health, Geelong, Victoria,
Australia; BreastScreen Victoria, Melbourne, Victoria, Australia;
Victorian Cancer Registry, Melbourne, Victoria, Australia.
3085
The effects of vaginal estrogens on plasma estradiol levels in
women taking aromatase inhibitors.
Howard G, Wills S, Kresge C, McConnell D, Balasubramaniam M,
Decker D. William Beaumont Hospital, Royal Oak, MI; School of
Public Health, University of Michigan, Ann Arbor, MI.
3086
Use of hormonal therapies before and after diagnosis
of a high risk breast lesion among 1,198 women in the
community setting.
Habel LA, Puligandla B, Jiang SF, Callahan ME, Kutner S, Shim
V. Kaiser Permanente, Oakland, CA; Kaiser Permanente, Santa
Teresa, CA.
3087
The multidisciplinary management of menopause symptoms
after breast cancer.
Saunders CM, Hickey M, Stuckey B. University of Western
Australia, Perth, WA, Australia; Sir Charles Gairdner Hospital,
Perth, WA, Australia.
Tumor Cell Biology: Apoptosis 3088-3089
3088
Protein kinase C-epsilon and -eta confers TRAIL resistance in
breast cancer cells via distinct mechanisms.
Persaud SD, Jain K, Shankar E, Basu A. University of North Texas
Health Science Center, Fort Worth, TX.
3089
Naphthaquinones - Promising anticancer agents against
breast and ovarian cancers.
Thasni AK, Nair RS, Rojini G, Ratheeshkumar T, Gopal S, Banergji
A, Srinivas P. Rajiv Gandhi Centre for Biotechnology, Trivandrum,
Kerala, India.
Tumor Cell Biology: Carcinogenesis 3090-3092
3090
Contribution of chromosomal alterations to the
development of poorly-differentiated invasive breast
carcinomas.
Ellsworth RE, Hooke JA, Ellsworth DL, Shriver CD. Windber
Research Institute, Windber, PA; Walter Reed Army Medical
3091
Mouse mammary tumor virus-related sequence expression
in the patients with breast phyllodes tumors.
Luschnikova AA, Parokonnaya AA, Lyubchenko LN, Polevaya EB,
Peredereeva EV, Smirnova EG. N.Blochin Cancer Research Center
RAMS, Moscow, Russian Federation.
3092
Interactions between breast cancer cells and their stromal
component: an analysis of alterations in gene expression.
Sotiriou C, El Ouriaghli F, Majjaj S, Haibe-Kains B, Desmedt
C, Lallemand F, Larsimont D, Piccart M. Institut Jules Bordet,
Brussels, Belgium; Université Libre de Bruxelles (U.L.B.), Brussels,
Belgium.
Tumor Cell Biology: Tumor Biology 3093-3112
3093
Insulin sensitivity gene expression and efficacy of systemic
adjuvant therapy in women with early breast cancer.
Gennari A, Sormani M, Bruzzi P, Pronzato P, Mirisola V, Ravera
G, Pfeffer U. National Cancer Rsearch Institute, Genoa, Italy;
University of Genoa, Genoa, Italy.
3104
DNA hypermethylation profile of inflammatory breast
cancer.
Van der Auwera I, Van den Bosch S, Van Laere SJ, Van den
Eynden GG, van Dam P, Colpaert CC, van Engeland M, Van
Marck EA, Vermeulen PB, Dirix LY. Translational Cancer Research
Group (Laboratory of Pathology University of Antwerp/
University Hospital Antwerp, Edegem; Oncology Centre, General
Hospital St-Augustinus, Wilrijk), Wilrijk, Antwerp, Belgium;
Research Institute GROW, Maastricht, Netherlands.
3105
Changes of stromal protein expression after preoperative
systemic therapy in breast cancer.
Szasz AM, Tokes A-M, Toth AI, Farkas A, Dank M, Molnar IA,
Harsanyi L, Kulka J. Semmelweis University, Budapest, Hungary.
3106
3107
Vitronectin in the tumor microenvironment promotes
breast cancer cell proliferation and elevated protein
synthesis despite hypoxia by integrin Ĝvĝ3 activation of the
mTOR/4E-BP1 pathway.
Pola C, Formenti SC, Schneider RJ. New York University School of
Caveolin-1 enhances the growth inhibitory effects of
gefitinib in MCF-7 breast cancer cell line.
Agelaki S, Spiliotaki M, Markomanolaki Ch, Kallergi G, Stournaras
Ch, Georgoulias V. University General Hospital of Heraklion,
Heraklion, Crete, Greece; School of Medicine, University of Crete,
Heraklion, Crete, Greece.
6054
The breast cancer surveillance consortium: a platform for
collaborative research stemming from breast cancer risk
through survivorship research.
Geller BM, Ballard-Barbash R, Buist DSM, Carney PA, Kerlikowske
K, Miglioretti DL, Rosenberg RD, Taplin SH, Yankaskas B, Weaver
DL. University of Vermont, Burlington, VT; National Cancer
Institute, Bethesda, MD; Group Health Cooperative Center
for Health Studies, Seattle, WA; Dartmouth College, Lebanon,
NH; UCSF, San Francisco, CA; University of New Mexico,
Albuquerque, NM; University of North Carolina, Chapel Hill, NC.
6093
Second nonbreast malignancies following breast cancer in
the Japanese female population.
Sato N, Kanbayashi C, Sano M. Niigata Cancer Center Hospital,
Niigata, Japan; Niigata Breast Examination Center, Niigata, Japan.
Saturday, December 
7:00-9:00
POSTER DISCUSSION 4 & CONTINENTAL
BREAKFAST – Ballroom B
Estrogen Receptors 401-409
401
Patterns of estrogen receptor alpha (ER) protein expression
and ESR1 gene amplification in primary and metastatic
breast cancer.
Holst F, Haas H, Nottbohm AK, Sauter G, Simon R. University
Medical Center Hamburg-Eppendorf, Hamburg, Germany.
402
Amplification of ESR1 may predict resistance to adjuvant
tamoxifen in postmenopausal patients with hormone
receptor positive breast cancer.
Ejlertsen B, Nielsen KV, Rasmussen BB, Balslev E, Müller S, Møller
S, Mouridsen HT. Rigshospitalet, Copenhagen, Denmark; Dako
A/S, Glostrup, Denmark.
403
Relationship between ESR1 copy number and ER expression
in the DBCG 89D trial.
Ejlertsen B, Nielsen KV, Rasmussen BB, Jensen M-B, Møller S,
Balslev E, Müller S, Mouridsen HT. Rigshospitalet, Copenhagen,
Denmark; Dako A/S, Glostrup, Denmark.
404
Gene copy number variability of oestrogen receptor-Ĝ in
breast cancer.
Drury S, Lambros, Marchio, Johnson, Salter J, Levey, Fletcher,
Peto, Reis-Filho J, Dowsett M. The Breakthrough Breast Cancer
Research Centre, London, United Kingdom; CR-UK Epidemiology
& Genetics, LSHTM, London, United Kingdom.
405
Serine118 phosphorylation of estrogen receptor: correlation
with kinase pathways and evolution after preoperative
endocrine therapy.
Zoubir M, Mathieu M-C, Simmans F, Bouaziz J, Geha S, Drusch
F, Liedtke C, Spielmann M, Delaloge S, Andre F. Institut Gustave
Roussy, Paris, France; MD Anderson Cancer Center, Houston, TX.
406
Induction of a novel estrogen receptor (ERĜ) phosphoserine (S154) in human breast cancer cells identified by mass
spectrometry.
Britton D, Scott G, Schilling B, Held J, Atsriku C, Baldwin M,
Gibson B, Benz C. Buck Institute for Age Research, Novato, CA.
Rescheduled Posters
407
Withdrawn
1031
408
Mitogen activated protein kinase (MAPK) regulation of
estrogen receptor (ER) Ĝ and tamoxifen resistance.
Cui Y, Fuqua SAW. Baylor College of Medicine, Houston, TX.
3108
3109
The downregulation of cyclin B1 sensitizes the
antiproliferative effect of chemotherapeutics in breast
cancer cells.
Yuan J, Androic I, Kramer A, Kaufmann M, Strebhardt K. Medical
School, J.W. Goethe-University, Frankfurt, Hessen, Germany.
ER dependent regulation of sphingolipid metabolism in the
context of apoptosis and proliferation in breast cancer.
Ruckhäberle E, Karn T, Schiffmann S, Grösch S, Geisslinger
G, Gätje R, Holtrich U, Rody A, Kaufmann M. J.W. Goethe
University, Frankfurt, Germany.
3110
Studies on the role of nicotinic receptors-mediated cell
proliferative effects in human breast cancer cells.
Wu C-H, Ho Y-S. Taipei Medical University, Taipei, Taiwan.
3111
Osteocalcin as a prognostic indicator in ductal mammary
carcinoma.
Davies SR, Mansel RE, Jiang WG. College of Medicine, Caridiff
University, Cardiff, South Glamorgan, United Kingdom.
3112
Expression and activity of core binding factor (CBF) in
human breast cancer cells.
Yong T, Fowler M, Davis N, Meyers S, Sun A. Louisiana State
University Health Sciences Center, Shreveport, LA.
Prognosis and Response Predictions: Prognostic Factors I 3113
3113
Immunohistochemical expression of YKL-40 is not a
prognostic marker in patients with high-risk primary breast
cancer.
Roslind A, Knoop AS, Jensen M-B, Johansen JS, Nielsen DL, Price
PA, Balslev E. Herlev University Hospital, Copenhagen, Denmark;
Odense University Hospital, Odense, Denmark; Copenhagen,
Denmark; University of California San Diego, La Jolla, CA.
Why women with breast cancer do not return for
surveillance mammography.
Geller B, Skelly J, Muss H. University of Vermont, Burlington, VT;
Vermont Cancer Center, Burlington, VT.
409
Single nucleotide polymorphism 3814 C>T (P1272S) in
steroid receptor coactivator-1 alters its coactivation activity.
Richter AS, Hartmaier RJ, Lee AV, Skaar T, Rae J, Li L, Flockhart D,
Tchatchou S, Hemminki K, Schmutzler RK, Meindl A, Bartram
CR, Burwinkel B, Oesterreich S. Baylor College of Medicine,
Houston, TX; Indiana University, Indianapolis, IN; University
of Michigan, Ann Arbor, MI; DKFZ, Heidelberg, Germany;
University of Cologne, Cologne, Germany; Klinikum Rechts der
Isar TU, Munich, Germany; University of Heidelberg, Heidelberg,
Germany.
7:00-9:00
4007
Risk categorisation of node positive tamoxifen treated breast
cancer patients based on genetically defined subtypes.
Schmidt M, Span P, Müller V, Rody A, von Törne C, Sweep F,
Gehrmann M. University of Mainz, Mainz, Germany; Radboud
University Nijmegen, Nijmegen, Netherlands; University of
Hamburg-Eppendorf, Hamburg, Germany; Goethe-University
Frankfurt, Frankfurt, Germany; Siemens Medical Solutions,
Leverkusen, Germany.
4008
ABCB1 MDR1) inherited polymorphisms in relation to
doxorubicin and docetaxel pharmacokinetics in patients
with breast cancer.
Gligorov J, Selle F, Lévy E, Beerblock K, Saintigny P, Avenin D,
Rezai K, Bernaudin J-F, Uzan S, Antoine M, Lévy P, Lokiec F, Fajac
A. Hôpital Tenon, Paris, France; HEGP, Paris, France; Hôpital
Avicenne, Bobigny, France; Centre René Huguenin, Saint-Cloud,
France.
4009
Breast cancer proteomic profiles of tumor susceptibility to
He J, Shen D, Chung D, Saxton R, Faull KF, Whitelegge JP, Chang
HR. School of Medicine, UCLA, Los Angeles, CA.
4010
47% pathologic complete response rate to anthracyclinesbased associated with high cyclophosphamide doses
neoadjuvant chemotherapy in basal-like and triple negative
Le Tourneau C, Dettwiler S, Laurence V, Alran S, Beuzeboc P,
Pierga J-Y, Frenaux P, Sigal-Zafrani B, Dieras V, Vincent-Salomon
A. Institut Curie, Paris, France.
4011
Pharmacogenetic influences on outcome from AC
chemotherapy in the treatment of breast cancer.
Lee JS, Verrill MW, Sludden J, Griffin MJ, Erb S, Sumpter KA, Cole
M, Calvert AH, Boddy AV. Newcastle University, Newcastle
upon Tyne, Tyne & Wear, United Kingdom; Newcastle General
Hospital, Newcastle upon Tyne, Tyne & Wear, United Kingdom.
4012
COX-2 over-expression and sensitivity to celecoxib and
capecitabine in metastatic breast cancer patients.
Metro G, Melucci E, Sperduti I, Mottolese M, Papaldo P, Milella
M, Carlini P, Ferretti G, Cognetti F, Fabi A. Regina Elena National
Cancer Institute, Rome, Italy.
4013
Thymidine phosphorylase expression is associated with time
to progression in patients receiving docetaxel-modulated
capecitabine for metastatic breast cancer.
Puglisi F, Cardellino GG, Di Loreto C, Lombardi D, Perin T, Puppin
C, Andreetta C, Russo S, Minisini AM, Mansutti M, Pizzolitto
S, Adami G, Dipasquale M, Veronesi A. Azienda OspedalieroUniversitaria, Udine, Italy; CRO di Aviano, Aviano (PN), Italy;
General Hospital, San Daniele del Friuli, Italy.
4014
The presence of the FRA12E/SMRT fragile site in the genome
of breast cancer (BC) patients is a predictor of metastatic
development.
O’Connor T, Houde C, Dolce J, Bundy B, Nesline M, Davis W,
Ambrosone C, Levine E, Edge SB, Coignet LJ. Roswell Park Cancer
Institute, Buffalo, NY.
4015
Correlation of IGF1R gene expression and mutations with
the risk of local recurrence in early breast carcinoma treated
with conservative surgery and radiation therapy.
Adrover E, Peiró G, Benlloch S, Sánchez-Tejada L, Lerma E, Peiró
FM, Aranda FI. Universitary General Hospital, Alicante, Spain;
Sant Paús Hospital, Barcelona, Spain.
4016
A retrospective clinical correlation study of the breast
cancer patients’ responses to anticancer drugs with the
expression level of drug response indicators (DRI) measured
in patient’s archival tumor tissue.
Rak Tkaczuk KH, Tait NS, Rogers WH, Tan M, Ioffe O, Lesko
SA, Deamond S, Lum Z-P, Ts’o PO. University of Maryland
Greenebaum Cancer Center, Baltimore, MD; CCC Diagnostics
LLC, Baltimore, MD.
BREAKFAST– Exhibit Hall B
(#4001-4117)
Prognosis and Response Prediction: Predictive Factors II
4001-4025
4001
4002
4003
4004
4005
4006
Early changes in expression of oestrogen-regulated and
proliferation genes illustrate heterogeneity in primary
resistance to letrozole.
Miller WR, Larionov A, Evans DB, Dixon M. University of
Edinburgh, Edinburgh, United Kingdom; Novartis Institutes for
BioMedical Research, Basel, Switzerland.
Radiation-induced CD8 T-lymphocyte apoptosis yield
predicts toxicities after adjuvant treatment with
concurrent and sequential radiotherapy and letrozole in
postmenopausal women with hormone receptor positive
breast cancers: preliminary results of the multicenter phase
II randomized trial (COHORT).
Ozsahin M, Belkacemi Y, Rosenstein B, Llacer Moscardo C,
Lemanski C, Romieu G, Gutowski M, Zaman K, Jeannerat-Sozzi
W, Gourgou S, Gligorov J, Larbouret C, Pèlegrin A, Dubois J-B,
Azria D. Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland; Centre Oscar Lambret, Lille, France; Mount Sinai
School of Medicine and NYU School of Medicine, NY, NY; CRLC
Val d’Aurelle, Montpellier, France; AP-HP CancerEst Tenon, Paris,
France; Centre de Recherche en Cancérologie de Montpellier,
Montpellier, France.
Signal pathway profiling of primary breast tumors identifies
potential phosphoprotein biomarkers that are predictive for
tamoxifen response following recurrence.
Wulfkuhle J, Umar A, Deng J, Timmermans M, Liotta L, Foekens
J, Petricoin E. George Mason University, Manassas, VA; Erasmus
Medical Center, Rotterdam, Netherlands.
Selective serotonin reuptake inhibitors and modification of
tamoxifen effectiveness in Danish breast cancer patients.
Lash T, Cronin-Fenton D, Pedersen L, Ahern T, Sorensen HT,
Lunetta K, Rosenberg C, Silliman R, Hamilton-Dutoit S, Garner
JP, Ewertz M. Boston University, Boston, MA; Aarhus University
Hospital, Aarhus, Denmark; Aalborg Hospital, Aalborg, Denmark.
Predictive gene expression profile of breast cancer patients
treated with tamoxifen.
Lyng MB, Laenkholm AV, Vach W, Pallisgaard N, Knoop A, Ditzel
HJ. Odense University Hospital (OUH); University of Southern
Denmark (SDU); SDU; OUH, Odense, Denmark.
Biomarker analysis of a phase II double-blind randomized
trial of daily oral RAD001 (everolimus) plus letrozole or
placebo plus letrozole as neoadjuvant therapy for patients
with estrogen receptor positive breast cancer.
Gardner H, Bandaru R, Barrett C, Calcaterra M, Crowell T, Decker
J, Dixon M, Fisch R, Fuchs M, Gelb A, Hanoteau N, Jonat W, Lane
H, Lebwohl D, Liu W-H, Molloy B, Pena C, Phillips P, Rheinhardt
J, Rugo H, Salesky S, Steinseifer J, Stumm M, Tokaji E, Voelker
F, Yarbrough G, Yateman N, Yu Y, Zuber E, Baselga J. Novartis
Institutes for Biomedical Research, Cambridge, MA; Novartis
Pharmaceuticals, East Hanover, NJ; Hospital Vall d’Hebron,
Barcelona, Spain; Novartis Pharma AG, Basel, Switzerland; UnivFrauenklinik, Kiel, Germany; UCSF, San Francisco; Western
General Hospital, Edinburgh, United Kingdom.
4017
4028
Withdrawn
4029
Traditional breast cancer risk factors and common breast
pathologies in post-menopausal women.
Maskery SM, Hu H, Liebman M, Hooke J, Shriver CD, Taioli E.
Windber Research Institute, Windber, PA; Walter Reed Army
Medical Center, Washington, DC; University of Pittsburgh,
Pittsburgh, PA.
4030
Validation of the Gail model for breast cancer risk in
postmenopausal women with osteoporosis.
Goldstein S, Yeo A, Qu Y, Wong M, Mitchell B, Mershon J. NYU,
New York, NY; Eli Lilly and Company, Indianapolis, IN.
4031
A pilot study of known or controversial breast cancer risk
factors using the Clinical Breast Care Project database as a
research environment.
Bekash A, Maskery SM, Kvecher L, Hooke J, Liebman MN, Shriver
CD, Mural RJ, Hu H. Windber Research Institute, Windber, PA;
Walter Reed Army Medical Center, Washington, DC.
4032
Prognostic determinants in patients with breast cancer who
are staged using sentinel lymph node biopsy.
Rosman M, Cheng Z, Sawyer K, Verbanac K, Tafra L. Anne
Arundel Medical Center, Annapolis, MD; East Carolina University,
Greenville, NC.
Absolute breast fibroglandular volume strongly associated
with breast cancer risk.
Shepherd JA, Kerlikowske K, Malkov S, Ma L, Margolin F,
Cummings S. University of California at San Francisco, San
Francisco, CA; California Pacific Medical Center, San Francisco,
CA.
4033
Significance of Akt activation and compartmentalization
for prediction of outcome in Her-2 positive breast cancer
patients treated with trastuzumab.
Svoboda M, Grell P, Fabian P, Radova L, Palacova M, Nenutil
R, Vyzula R. Masaryk Memorial Cancer Institute, Brno, Czech
Republic; Tomas Bata University in Zlin, Zlin, Czech Republic.
Large errors in volumetric fibroglandular density occur if
breast thickness and paddle tilt are not measured.
Shepherd JA, Malkov S, Cummings S. University of California
at San Francisco, San Francisco, CA; California Pacific Medical
Center, San Francisco, CA.
4034
The ratio of the estradiol metabolites 2-hydroxyestrone
(2OHE1) and 16a-hydroxyestrone (16aOHE1) predicts breast
cancer risk in postmenopausal but not in premenopausal
women - a case-control study.
Huober J, Zimmermann B, Brunner S, Mueck AO, Wallwiener
D, Seeger H. Kantonsspital St. Gallen, St. Gallen, Switzerland;
University Womens Hospital, Tuebingen, Germany.
4035
Type II diabetes and breast cancer; a potentially modifiable
risk factor?
Jones K, George RL. Kingston General Hospital, Queen’s
University, Kingston, ON, Canada.
4036
Reproductive risk factors and breast tumor characteristics
in African American and non-Hispanic White women with
early onset breast cancer.
Ogutha J, Huo D, Olopade OI. The University of Chicago Medical
Center, Chicago, IL.
4037
Sub epithelial impedance: a new biomarker of breast cancer
risk.
Greene T, Brumfield MK, Pierce M, Davies RJ. Hackensack
University Medical Center, Hackensack, NJ.
4038
The OncoVue® model for predicting breast cancer risk.
Jupe ER, Ralph DA, Manjeshwar S, Knowlton NS, Pugh TW,
DeFreese DC, Gramling BA, Shimasaki CD. InterGenetics
Incorporated, Oklahoma City, OK; NSK Statistical Solutions, LLC,
Choctaw, OK.
Estrogen receptor status: a prognostic predictor of outcome
in HER-2 positive breast cancer with brain metastases.
Vallow L, Hines S, Jain A, Tan W, Buskirk S, Perez EA. Mayo Clinic,
Jacksonville, FL.
4018
The potential prognostic value of osteoprotegrin in ductal
carcinoma of the breast.
Davies SR, Mansel RE, Jiang WG. College of Medicine, Cardiff
University, Cardiff, South Glamorgan, United Kingdom.
4019
The initial response of circulating epithelial tumor cells to
primary systemic chemotherapy in breast cancer is highly
predictive for final tumor reduction and outcome.
Camara O, Kavallaris A, Rengsberger M, Koch A, Schneider U,
Egbe A, Untch M, Pachmann K. Friedrich Schiller-Universität
Jena, Jena, Germany; Helios Klinikum Berlin-Buch, Berlin,
Germany; Transfusionsmedizinisches Zentrum Bayreuth,
Bayreuth, Germany.
4020
4021
4022
Predictors of response to neoadjuvant chemotherapy in
women with locally advanced breast cancer.
Parmar V, Nadkarni MS, Hawaldar R, Shet T, Nair R, Gupta
S, Chinoy R, Badwe R. Tata Memorial Hospital, Mumbai,
Maharashtra, India.
4023
Use of flow cytometry to identify breast cancer patients
likely to benefit from specific targeted therapies.
Visram H, Sangrar W, George R, Greer P. Queen’s University,
Kingston, ON, Canada.
4024
Is pathologic complete response related to level of
hormonal receptor positivity in hormonal-sensitive breast
cancer treated with anthracycline-based neo-adjuvant
chemotherapy?
Petit T, Wilt M, Velten M, Rodier J-F, Fricker J-P, Dufour P,
Ghnassia J-P. CLCC Paul Strauss, Strasbourg, France.
4025
Serum markers predictive of chemotherapy-induced
premature ovarian failure among premenopausal women
with early stage breast cancer.
Anders CK, Snyder SA, Gu L, Unruhe SP, Welch RA, Lyons PS,
Kimmick GG, Marcom KP, Shaw HS, Antenos M, Woodruff
TK, Blackwell KL. Duke University, Durham, NC; Northwestern
University, Chicago, IL.
Risk and Prevention: Risk Factors 4026-4038
4026
4027
Women with elevated body mass index at increased risk of
breast cancer with a poor prognosis.
Kerlikowske K, Desai A, Miglioretti DL, Walker R, Ballard-Barbash
RSM, Buist DSM. UCSF, San Francisco, CA; John Hopkins,
Baltimore, MD; Group Health, Seattle, WA; National Cancer
Institute, Bethesda, MD.
Risk factors for developing breast cancer following benign
breast disease: a 25-year follow-up of a nationwide cohort.
Papa MZ, Chetrit A, Oberman B, Feldman D, Lubin F, Sadetzki
S. Chaim Sheba Medical Center, Ramat-Gan, Israel; Gertner
Institute for Epidemiology and Health Policy Research, RamatGan, Israel; Tel-Aviv University, Tel-Aviv, Israel.
Risk and Prevention: Prevention 4039-4055
4039
A study of relationship between lipophilic statin use and
estrogen receptor negative breast cancers.
Gupta S, Desai A. Albert Einstein Medical Center, Philadelphia,
PA.
4040
4041
4042
Phase II tissue-based biomarker prevention trial of celecoxib
in premenopausal women at high risk for development of
breast cancer.
Fabian CJ, Kimler BF, Mayo MS, Zalles CM, Khan SA, Dooley WC,
Krontiras H, Browne D. University of Kansas Medical Center,
Kansas City, KS; Yale University, New Haven, CT; Northwestern
University Medical Center, Chicago, IL; University of Oklahoma
Health Science Center, Oklahoma City, OK; University of
Alabama Birmingham, Birmingham, AL; National Cancer
Institute, Bethesda, MD.
Immunomodulatory effects of celecoxib in patients at
increased risk for breast cancer.
Arun B, Vuskovic M, Vasiliu D, Xu HY, Atchley D, Chambers J,
Bovin N, Sneige N, Hortobagyi GN, Huflejt M. The University of
Texas M.D. Anderson Cancer Center, Houston, TX; Cellexicon,
Inc, La Jolla, CA; Shemyakin Institute of Bioorganic Chemistry
RAS, Moscow, Russian Federation.
Cumulative effects of raloxifene on the incidence of breast
cancer over 8 years in postmenopausal women with
osteoporosis.
Mershon J, Yeo A, Qu Y, Wong M, Mitchell B, Vogel V. Eli
Lilly and Company, Indianapolis, IN; University of Pittsburgh,
Pittsburgh, PA.
4043
Incidence of breast cancer in postmenopausal women after
discontinuation of long-term raloxifene use.
Vogel V, Qu Y, Wong M, Mitchell B, Mershon J. University of
Pittsburgh, Pittsburgh, PA; Eli Lilly and Company, Indianapolis, IN.
4044
Relative cost-effectiveness of raloxifene and tamoxifen in
chemo-prevention of breast cancer with less thromboembolic events than no chemoprevention.
Bishop JF, Glass P, Taylor PS, Pezzullo ML, Moore PT, Parkinson
BT, Cotter TF, Tracey EA. Cancer Institute NSW, Sydney,
Australia; Access Economics Pty Ltd, Canberra, Australia.
4045
Tamoxifen for the prevention of breast cancer development:
an updated meta-analysis.
Dahabreh IJ, Economopoulos KP. National University of Athens,
Medical School, Athens, Greece.
4046
Prevention of breast cancer using rexinoids: results of a
phase II biomarker modulation trial using bexarotene in
women at high risk of breast cancer.
Brown P, Arun B, Miller A, Isaacs C, Gutierrez C, Huang J, Mohsin
S, Sneige N, Kim H, Sexton K, Weiss H, Hilsenbeck S, Lamph W,
Negro-Vilar A, Johnson K, Elledge R. Baylor College of Medicine,
Houston, TX; MD Anderson Cancer Center, Houston, TX; Cancer
Therapy and Research Center, San Antonio, TX; Georgetown
University, Washington, DC; Ligand Pharmaceuticals, San Diego,
CA; National Cancer Institute, Bethesda, MD.
4047
Chemoprevention in a mouse model for ductal carcinoma in
situ: targeting the mTOR pathway.
Liu SY, Namba R, Enriquez RJ, Tepper CG, Young LJT, Abbey CK,
Borowsky AD, Cardiff RD, Gregg JP. University of California, Davis,
Sacramento, CA; University of California, Davis, CA; University of
California, Santa Barbara, CA.
4048
A strong association between body fat mass and proteomes
of nipple aspirate fluids.
Huang Y, Nagamani M, Anderson KE, Kurosky A, Haag AM, Lu
L-JW. University of Texas Medical Branch, Galveston, TX.
4049
Prophylactic mastectomy: pathological findings in high risk
women.
Sedlacek SM, Sedlacek JE. Rocky Mountain Cancer Centers,
Denver, CO; Dartmouth College, Hanover, NH.
4050
A pilot study to increase physical activity in sedentary
women at risk for breast cancer.
Korde L, Venzon D, Smith AW, Nehrebecky M, Calhoun T,
Sebring N, Drinkard B, Smith M, Prindiville S, Zujewski J, EngWong J. NCI; NIH Clinical Center.
4051
Improving informed consent in clinical trials: a randomised
controlled trial of a decision aid for women invited to
participate in a breast cancer prevention trial (IBIS-II).
Juraskova I, Butow P, Lopez A-L, Seccombe M, Smith B, Coates
A, Boyle F, McCarthy N, Reaby L, Forbes JF. University of Sydney,
NSW, Australia; University of Newcastle, NSW, Australia; Royal
Brisbane Hospital, QLD, Australia.
4052
Effect of green tea extract and tamoxifen on mammary
carcinogenesis of C3H/OuJ mouse.
Sakata M, Ikeda T, Imoto S, Jinno H, Kitagawa Y. Keio University
School of Medicine, Shinjuku, Tokyo, Japan; Teikyo University
School of Medicine, Itabashi, Tokyo, Japan; Kyorin University
School of Medicine, Mitaka, Tokyo, Japan.
4053
Lyophilized aqueous extract of American ginseng (AG)
abrogates induced COX-2 expression in human breast
cancer cells.
Minnis J, Louis S, Peralta E. Southern Illinois University School of
Medicine, Springfield, IL.
4054
Conjugated linoleic acid synergizes with the CYP1B1
inhibitor 2,3’,4,5’-tetramethoxystilbene in suppressing
breast cancer cell growth.
Kirma NB, Nair HB, Liu Y-g, Tekmal RR. University of Texas
Health Science Center @ San Antonio, San Antonio, TX.
4055
Serving the high risk patient in community practice:
development and managment of a high risk clinic.
Prill SJ, Vogel W. Blue Ridge Medical Specialists, Bristol, TN.
Treatment: Antibody-Based Regimens 4056-4064
4056
Trastuzumab treatment beyond progression in patients with
HER-2 positive metastatic breast cancer - the TBP study
(GBG 26/BIG 3-05).
von Minckwitz G, Vogel P, Schmidt M, Eidtmann H, Cufer T,
de Jongh F, Maartense E, Zielinski C, Andersson M, Stein R,
Nekljudova V, Loibl S. University Hospital Frankfurt, Frankfurt,
Germany; German Breast Group, Neu-Isenburg, Germany; Klinik
für Gynäkologie und Gynäkologische Onkologie, Wiesbaden,
Germany; University Hospital Mainz, Mainz, Germany;
Studienzentrale Gynäkologische Onkologie (SGO) Kiel, Kiel,
Germany; Institute of Oncology Ljubljana, Ljubljana, Slovenia;
Ikazia Zickenhuis, Rotterdam, Netherlands; Reinier de Graaf
Gasthuies, Delft, Netherlands; University Hospital and Cancer
Centre, Wien, Austria; Rigshospitalet University Hospital,
Kopenhagen, Denmark; University College London Hospital,
London, United Kingdom.
4057
Retrospective evaluation of clinical outcomes in HER2positive advanced breast cancer patients progressing on
trastuzumab-based therapy in the pre-lapatinib era.
Montemurro F, Viale G, Donadio M, Bottini A, Sanna G, Botti
G, dei Tos AP, Marchiò C, Danese S, Clavarezza M, Del Curto
B, Sapino A, Aglietta M. Institute for Cancer Research and
Treatment, Candiolo, Italy; European Institute of Oncology,
Milano, Italy; Centro Onco Ematologico Subalpino, Torino, Italy;
Breast Unit Istituti Ospitalieri, Cremona, Italy; Istituto Nazionale
Tumori (IST) Fondazione Senatore Pascale, Napoli, Italy; Ospedale
Regionale, Trevisio, Italy; Ospedale S. Anna, Torino, Italy; Istituto
Nazionale per la Ricerca sul Cancro (IST), Genova, Italy; Ospedale
San Giovanni Battista- Molinette, Torino, Italy.
4058
4059
4060
4061
Evaluation of first-line trastuzumab in combination with
epirubicin/cyclophosphamide for patients with HER2positive metastatic breast cancer.
Untch M, Tjulandin S, Jonat W, Meerpohl H, Lichinitser M,
Manikhas GM, Jänicke F, Muscholl M, Pauschinger M, Thomssen
C, Lehle M. Frauenheilkunde mit Geburtshilfe, Berlin, Germany;
Russian Cancer Research Center, Moscow, Russian Federation;
Christian-Albrechts-Universität, Kiel, Germany; Frauenklinik der
St-Vincentius-Krankenhäuser, Karlsruhe, Germany; St Petersburg
City Oncology Hospital, Russian Federation; Universitätsklinikum
Hamburg-Eppendorf, Hamburg, Germany; Ludwig-MaximiliansUniversität, Munich, Germany; Charité - Universitätsmedizin
Benjamin Franklin, Berlin, Germany; Martin-Luther-Universität
Halle-Wittenberg, Halle, Germany; F Hoffmann-La Roche, Basel,
Switzerland.
Clinical use of trastuzumab (Herceptin®) in metastatic breast
cancer (MBC) in Germany from 2001 to 2006.
Jackisch C, Eustermann H, Schoenegg W, Soelling U, Stauch M,
Goehler T, Kuehn W, Krieger G, Reichert D. Klinikum Offenbach,
Offenbach, Germany; Research Institute, Langen, Germany;
Gynaekologische Praxis, Berlin, Germany; Gynaekologische Praxis,
Kassel, Germany; Praxis, Kronach, Germany; Praxis, Dresden,
Germany; Charité, Berlin, Germany; Hegau Klinikum, Singen,
Germany; Klinikum Oldenburg, Germany.
HER-2 positive inflammatory breast cancer: high
pathological response rate with trastuzumab-based
neoadjuvant therapy.
Dawood S, Gonzalez-Angulo AM, Broglio K, Gong Y, Resetkova
E, Yang WT, Barnett CM, Islam R, Ueno NT, Hortobagyi GN,
Cristofanilli M. UT M.D. Anderson Cancer Center, Houston, TX.
Survival gain by trastuzumab therapy after the onset of
intracranial metastasis in metastatic breast cancer.
Nam BH, Kim SY, Han HS, Lee KS, Ro J. National Cancer Center,
Goyang, Korea.
4062
A phase II trial of docetaxel with bevacizumab as first line
therapy for Her2/neu negative metastatic breast carcinoma.
Hurvitz SA, Kabbinavar FF, Allen HJ, Moroose RL, Chan D,
Hagenstad C, Applebaum SH, Patel G, Hu EH, Reese D, Slamon
DJ. UCLA, Los Angeles, CA; Translational Oncology Research
International, Los Angeles, CA.
4063
Bevacizumab combined with chemo-endocrine preoperative
therapy in locally advanced operable breast cancers.
Ferrari B, Scarano E, Pietri E, Dellapasqua S, Colleoni M. European
Institute of Oncology, Milan, Italy.
4064
Capecitabine + docetaxel + bevacizumab as neoadjuvant
therapy for invasive breast cancer: results of a phase II pilot
study.
Greil R, Moik M, Reitsamer R, Ressler S, Stoll M, Namberger K,
Menzel C, Mlineritsch B. Private Medical University Hospital
Salzburg, Salzburg, Austria.
4067
Breast-conserving therapy: balancing surgery and radiation.
Indelicato D, Galloway T, Morris CG, Mendenhall NP. University
of Florida, Gainesville, FL.
4068
Cosmetic effect of breast radiotherapy in older women.
Kunkler IH, Prescott RJ, Williams L, King CC, Jack WJL, Dixon
MJ, van der Pol M. Edinburgh University, Edinburgh, United
Kingdom; Aberdeen University.
4069
Breast conservative therapy results of triple negative breast
cancer.
Tulusan AH, Popovich M, Bühner M, Keilholz L, Volkholz H, Lex
B. Klinikum Bayreuth GmbH, Bayreuth, Germany.
4070
Does surgical closure technique affect early mammographic
detection of tumor recurrence following breast-conserving
therapy?
Newlin HE, Indelicato DJ, Abbitt P, Marshall J, Wymer D,
Grobmyer S, Haigh L, Copeland E, Morris CG, Mendenhall NP.
University of Florida, Gainesville, FL.
4071
Stem cell augmented reconstruction: a new hope for
reconstruction after breast conservation therapy.
Kitamura K, Kajitani K, Hedrick M, Sugimachi K. Kyushu Central
Hospital, Fukuoka, Japan; Cytori Therapeutics, San Diego, CA.
4072
Co-transplantation of adipose tissue-derived regenerative
cells improves long-term retention of fat graft.
Zhu M, Zhou Z, Chen Y, Schreiber R, Fraser JK, Hedrick MH,
Ransom JT, Kuo H-C. Cytori Therapeutics Inc, San Diego, CA;
UCLA, Los Angeles, CA.
4073
Radiofrequency ablation therapy for breast cancer.
Oura S, Tamaki T, Yoshimasu T, Ohta F. Wakayama Medical
University, Wakayama, Japan.
Treatment: Radiation Therapy 4074-4097
4074
Concurrent chemoradiation with capecitabine achieves
meritable response and local control for inoperable and
recurrent neoadjuvant chemotherapy refractory breast
cancer.
Perkins GH, Middleton LP, Tran R, Garcia SM, Cristofanilli M,
Pusztai L, Singletary SE, Strom EA, Woodward WA, Yu T-K, Oh
JL, Tereffe W, Whitman GJ, Huang E, Allen PK, Buchholz TA. The
University of Texas M. D. Anderson Cancer Center, Houston, TX.
4075
The late radiotherapy normal tissue phenotypes of
telangiectasia, fibrosis and atrophy in breast cancer patients
have distinct genotype-dependant causes.
Symonds P, Giotopoulos G, Peat I, Foweraker K, Plumb
M. University of Leicester, Leicester, Leicestershire, United
Kingdom; University Hospitals of Leicester NHS Trust, Leicester,
Leicestershire, United Kingdom.
4076
Increased use of regional radiotherapy is associated with
improved outcome in a population-based cohort of women
with breast cancer and 1-3 positive nodes.
Wai ES, Tyldesley S, Speers CH, Truong PT, Kyle K, Olivotto IA. BC
Cancer Agency - Vancouver Island Centre, Victoria, BC, Canada;
BC Cancer Agency - Vancouver Centre, Vancouver, BC, Canada;
BC Cancer Agency - Vancouver, Vancouver, BC, Canada.
4077
Roles of radiotherapy and chemotherapy in the
development of contralateral breast cancer.
Hooning MJ, Aleman BMP, Hauptmann M, Klijn JGM, Noyon
R, Stovall M, van Leeuwen FE. Netherlands Cancer Institute,
Amsterdam, Netherlands; Erasmus MC, Daniel den Hoed Cancer
Center, Rotterdam, Netherlands; University of Texas, M.D.
Anderson Cancer Center, Houston, TX.
Treatment: Breast Conservation 4065-4073
4065
4066
Increased use of breast-conserving surgery: preferred
treatment or failure to provide adequate local therapy?
Virnig B, Habermann E, Al-Refaie W, Jensen E, Tuttle T. University
of Minnesota, Minneapolis, MN.
Impact of the interval between breast conserving surgery
and adjuvant radiotherapy on clinical outcomes in early
Campbell SAM, Kerr GR, Kunkler IH. Edinburgh Cancer Centre
on Behalf of the Edinburgh Breast Group, Edinburgh, United
Kingdom.
4078
4079
4080
4081
4082
4083
4084
4085
4086
Toxicity and cosmesis from RTOG 95-17: a phase I/II trial
to evaluate brachytherapy as the sole method of radiation
therapy for stage I and II breast carcinoma.
Rabinovitch R, Winter K, Taylor M, Kuske R, Bolton J, Arthur D,
White J, Hanson W, Wilenzick R, McCormick B. U of CO, Aurora,
CO; RTOG, Philadelphia, PA; Washington U, Saint Louis, MO;
AZ Onc Services, Scottsdale, AZ; Ochsner Clinic, New Orleans,
LA; Med Coll VA, Richmond, VA; Med Coll WI, Milwaukee, WI;
MDACC, Houston, TX; MSKCC, New York, NY.
Update of the phase II MammoSite® brachytherapy trial for
DCIS.
Streeter, Jr OE, Benitez P, Vicini F, Mehta V, Quiet C, Kuske R,
Hayes M, Arthur D, Kuerer H, Strom E, Freedman G, Keisch
M, DiPetrillo T, Khan D, Hudes R, Groshen S, Silverstein
MJ. USC/Norris Cancer Center, Los Angeles, CA; William
Beaumont Hospital, Royal Oak, MI; Swedish Cancer Institute,
Seattle, WA; Arizona Oncology Services, Scottsdale, AZ; New
York Presbyterian Hospital, NY, NY; Virgnia Commenwealth
University, Richmond, VA; M.D. Anderson Cancer Center,
Houston, TX; Fox Chase Cancer Center, Philadelphia, PA; Cedars
Medical Center, Miami, FL; Rhode Island Hospital, Providence,
RI; Centinela Freeman Medical Center, Inglewood, CA; St. Agnes
Healthcare, Baltimore, MD.
Partial breast irradiation using the MammoSite® device
for low risk breast carcinoma in patients aged ≥ 60 years:
toxicity, cosmesis and quality of life results of a phase II
study.
Belkacemi Y, Chauvet MP, Giard S, Lacornerie T, Bonodeau F,
Baranzelli MC, Bonneterre J, Lartigau E. Centre Oscar Lambret,
Lille, France.
Intra-fraction motion during tangential treatment of the left
breast: how consistently is the heart actually blocked?
Wang Z, Yin F-F, Maurer J, Wu QJ, Hubbs J, Marks LB. Duke
University Medical Center, Durham, NC.
Prospective trial of individual optimal positioning (prone
versus supine) for whole breast radiotherapy: results of 194
patients.
Formenti SC, Guth AA, Axelrod DM, Goldberg JD, DeWyngaert
JK. New York University School of Medicine, New York, NY.
Relative importance of posterior and upper borders of
tangential radiation portals in axillary lymph node coverage
after breast conserving surgery.
Gross E, Padovani L, Badinand D, George L, Muracciole X, Cowen
D. Hôpital Timone, Marseille, France.
Post-operative radiotherapy does not adversely affect
the outcome of autologous free abdominal flap breast
reconstruction.
Chatterjee J, Lee A, Baker L, Anderson W, Dewar JA, Stevenson
JH, Thompson AM. University of Dundee, Ninewells Hospital and
Medical School, Dundee, Scotland, United Kingdom.
Linear accelerator-based intraoperative radiotherapy in
limited stage breast cancer - results of an ISIORT pooled
analysis in 1131 patients.
Reitsamer R, Fastner G, Merz F, Menzel C, Kopp M, Hager E,
Ciabattoni A, Willich N, Orecchia R, Valentini V, Sedlmayer F.
Paracelsus Private Medical School Salzburg, Salzburg, Austria;
General Hospital Klagenfurt, Klagenfurt, Austria; San Francisco
Neri Hospital, Rome, Italy; University Hospital Münster, Münster,
Germany; European Institute of Oncology, Milan, Italy; Gemelli
University Clinic, Rome, Italy; on behalf of the ISIORT.
The Cambridge breast intensity modulated radiotherapy
trial: dosimetry results for 1089 patients.
Coles CE, Wilkinson JS, Moody AM, Wilson CB, Twyman N,
Hoole ACF, Burnet NG. Cambridge University Hospitals NHS
Foundation Trust, Cambridge, United Kingdom.
4087
Utilization of fiducial markers in accelerated partial breast
irradiation with intensity modulated radiotherapy (IMRT).
Page BR, Gibbons SK. Albany Medical College, Albany, NY;
Albany Medical Center, Albany, NY.
4088
Intervals longer than 20 weeks from breast conserving
surgery to radiation therapy are associated with inferior
outcome for women with early stage breast cancer not
receiving chemotherapy.
Olivotto I, Lesperance M, Berrang T, Speers C, Nichol A, Tyldesley
S, Germain F, Wai E, Holloway C, Kwan W, Truong P. BC Cancer
Agency, Victoria, Vancouver, Kelowna, Surrey, BC, Canada;
University of Victoria, Victoria, BC, Canada; BC Cancer Agency,
Vancouver, BC, Canada.
4089
Are patients with T1-2 breast cancer with 1-3 positive nodes
suitable candidates for partial breast radiotherapy trial
enrolment?
Truong PT, Jones S, Alexander A, Speers C, Kader H, Wai E,
Olivotto IA. BC Cancer Agency, Vancouver Island Centre,
Victoria, BC, Canada.
4090
Lumpectomy and accelerated partial breast irradiation as
an alternative to mastectomy following prior mantle field
radiation or breast irradiation.
Adkison JB, Palazzi-Churas K, Kuske RR, Patel RR. University of
Wisconsin Hospital and Clinics, Madison, WI; Arizona Oncology
Services, Phoenix, AZ.
4091
Surgeon characteristics and receipt of adjuvant radiotherapy
following breast conservation surgery in elderly women with
breast cancer.
Hershman DL, Buono D, Jacobson JS, Tsai WY, Joseph KA, Grann
VR, Neugut AI. Columbia University Medical Center, New York,
NY; Mailman School of Public Health, New York, NY.
4092
Non-invasive imaging techniques quantify radiation induced
vascular changes in the breast.
Klifa CS, Hattangadi J, Hwang J, Watkins M, Sakata T, Tromberg
B, Hylton N, Park C. University of California, San Francisco, CA;
University of California, Irvine, CA.
4093
The identification of patients for postmastectomy
radiotherapy using the Cambridge index: audit of a
prospective series.
Wilson CB, Haba Y, Wishart GC. Addenbrookes Hospital,
Cambridge, United Kingdom.
4094
Postmastectomy locoregional recurrence in Hong Kong: low
risk patients without radiotherapy have more failures than
intermediate risk patients with radiotherapy.
Yau TK, Chang TY, Soong S, Chan K, Sze H, Yeung MW, Lee WM.
Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
4095
Thyroid dysfunction following modern three-dimensional
conformal radiation therapy to low neck in women with
breast cancer — a dosimetric, volumetric, and biochemical
assessment.
Albuquerque K, Beall N, Bova D. Loyola University Medical
Center, Maywood, IL.
4096
Oesophageal carcinoma as second malignancy after
irradiation for breast cancer. From meta-analysis and large
epidemiological studies to patients’ records and dosimetric
questions: where is the truth? Large scale single institutional
experience.
Kirova YM, Asselain B, Fourquet A. Institut Curie, Paris, France.
4097
Patient rated breast symptoms and body image in early
breast cancer: first results of the UK standardisation of
breast radiotherapy (START) trials.
Hopwood P, Haviland J, Sumo G, Mills J, Bliss JM, Yarnold J.
Christie Hospital NHS Foundation Trust, Manchester, United
Kingdom; The Institute of Cancer Research, Sutton, United
Kingdom; Royal Marsden NHS Foundation Trust, Sutton, United
Kingdom; on behalf of the START Trial Management Group.
4108
Profiling HER-family receptor dimerization in HER2
overexpressing cells that coexpress mutated EGFR receptors.
Dua R, Nhonthachit P, Petropoulos C. Monogram Biosciences,
Inc, South San Francisco, CA.
4109
ERBB2 influences the subcellular localization of the estrogen
receptor in tamoxifen resistant MCF-7 cells leading to the
activation of AKT and p90RSK.
Pancholi S, Lykkesfeldt A, Dowsett M, Martin L-A. Institute of
Cancer Research, London, United Kingdom; Danish Institute of
Cancer Research, Copenhagen, Denmark.
4110
Reverse phase protein array analysis of an ER-positive/
HER2-positive breast cancer xenograft model reveals distinct
resistance mechanisms to HER2 targeted therapy.
Wang Y-C, Hennessy B, Huang C, Wiechmann LS, Rimawi M,
Mills GB, Osborne CK, Schiff R. Baylor College of Medicine; M.D.
Anderson, Houston, TX.
4111
Carcinoembryonic antigen cell adhesion molecule 6 has a
functional role in endocrine resistance.
Cummings M, Maraqa L, Speirs V. University of Leeds, Leeds,
West Yorks, United Kingdom.
4112
Distinct chemokines mediate tumourigenicity of breast
cancer cells.
Potter SM, Dwyer RM, Kerin MJ. National University of Ireland,
Galway, Ireland.
The role of amphiregulin in exemestane-resistant breast
cancer cells: evidence of an autocrine loop.
Wang X, Masri S, Phung S, Chen S. City of Hope/Beckman
Research Institute, Duarte, CA.
4113
BRCA1 transcriptionally regulates the genes associated with
the basal phenotype in breast cancer.
James CR, Quinn JE, Gorski JJ, Stewart G, Harkin P. Queen’s
University Belfast, Belfast, Northern Ireland, United Kingdom.
Ĝ6ĝ1 and Ĝ6ĝ4 integrins and their critical role in promoting
resistance to multiple treatment strategies for breast cancer.
Huang C, Osborne CK, Schiff R. Baylor College of Medicine,
Houston, TX.
4114
Kinome survey of molecular pathways lead to tamoxifenresistant breast cancer cell growth.
Gonzalez LG, Park J, Geistlinger TR, Pearlberg J, Endege W,
Degot S, Sawyer J, Hu Y, Harlow E, Labaer J. Harvard Institute
of Proteomics, Cambridge, MA; Dana-Farber Cancer Institute,
Boston, MA.
4115
On the role of calpain in regulation of HER2 and resistance
to trastuzumab in breast cancer cells.
Kulkarni S, Reddy KB, Esteva FJ, Budd TG, Moore HCF, Tubbs RR.
Cleveland Clinic, Cleveland, OH; M.D. Anderson Cancer Center,
Houston, TX.
4116
P450 aromatase regulation by autocrine human growth
hormone confers resistance to aromatase inhibitors in a
human mammary carcinoma cell line.
Perry JK, Yang W-S, Grandison P, Lobie PE. University of
Auckland, Auckland, New Zealand.
4117
Tissue inhibitor of metalloproteinases-1 influences
sensitivity to etoposide in MCF-7 S1 breast cancer cells.
Schrohl Rasmussen A-S, Würtz SØ, Brünner N, Lademann U.
University of Copenhagen, Faculty of Life Sciences, Copenhagen,
Denmark.
Tumor Cell Biology: Cell Biology 4098-4105
4098
4099
4100
4101
4102
4103
4104
4105
Distinct cancer stem cells may mediate heterogeneity
among the human breast premalignant lesions.
Behbod F, Kittrell FS, Allred DC, Eaves C, Kuperwasser C, Perou
CM, Rosen JM, Medina D. Baylor College of Medicine, Houston,
TX; Washington University School of Medicine, St. Louis, MO;
BC Breast Cancer Research Center, Vancouver, Canada; Tufts
Univeristy School of Medicine, Boston, MA; University of North
Carolina at Chapel Hill, Chapel Hill, NC.
Preliminary characterization and in vitro propagation of
putative stem/progenitor cells from human inflammatory
breast cancer.
Woodward WA, Reuben J, Gao H, Krishnamurthy S, Lucci
A, Singh B, Li L, Cristofanilli M. The University of Texas M.D.
Anderson Cancer Center, Houston, TX.
Tumour-associated tenascin-C isoforms promote breast
cancer cell invasion and proliferation through MMPdependant and -independant mechanisms.
Alcock RA, Allen MD, Holliday DL, Edwards DR, Pennington CL,
Shaw JA, Walker RA, Pringle JH, Jones JL. University of Leicester,
Leicester, United Kingdom; Bart’s and the London, Queen Mary’s
School of Medicine and Dentistry, London, United Kingdom;
University of East Anglia, Norwich, United Kingdom.
Development of in vitro models to study
microenvironmental influences on breast cancer
progression.
Holliday DL, Mulligan KT, Jones JL. Barts and the London, Queen
Marys School of Medicine and Dentistry, London, United
Kingdom.
MCF7 and MDA-MB-231 cells cultured on Poly-HEMAcoated dish are more invasive, yet show less tumourigenicity,
than cells cultured on the tissue culture dish.
Kim JB, Lee K-M, Ko E, Han W, Lee JE, Shin I, Lee JW, Cho J, Noh
D-Y. Seoul National University College of Medicine, Seoul, Korea;
College of Natural Sciences, Hanyang University, Seoul, Korea.
The anti-aromatase effect of the natural metabolites
of progesterone: 20Ĝ-dihydroprogesterone and 5Ĝ
dihydroprogesterone in MCF-7aro breast cancer cells.
Pasqualini JR, Chetrite GS. Hormones and Cancer Research Unit,
Paris, France.
Tumor Cell Biology: Drug Resistance 4106-4117
4106
4107
Development of resistance to targeted therapy strategies
transforms the clinically-defined molecular profile subtype
of breast tumors.
Creighton CJ, Massarweh S, Tsimelzon A, Huang S, Hilsenbeck
SG, Osborne CK, Schiff R. Baylor College of Medicine, Houston,
TX; University of Kentucky, Lexington, KY.
The farnesyltransferase inhibitor R115777 (tipifarnib) in
combination with tamoxifen acts synergistically to inhibit
MCF-7 breast cancer cell proliferation and cell-cycle
progression in-vitro and in-vivo.
Martin L-A, Head JE, Pancholi S, Salter J, Quin E, Detre S, Kaye S,
Howes A, Dowsett M, Johnston SR. Institute of Cancer Research,
London, United Kingdom; Johnson & Johnson PRD, High
Wycombe, United Kingdom; Royal Marsden Hospital, London,
United Kingdom.
9:00-9:30
Multidisciplinary guidelines across the continuum of
care: the NCCN experience
Robert Carlson, MD
Stanford University
Stanford, CAS
9:30-10:00
Symptom management in breast cancer survivors
Charles Loprinzi, MD
Mayo Clinic
Rochester, MN
10:00-11:00
10:00
10:15
10:30
10:45
GENERAL SESSION 5– Exhibit Hall D
2:00-3:30
51. Is completion axillary dissection always required after a
positive sentinel node biopsy? NSABP B-32.
Julian TB, Anderson SJ, Fourchotte V, Brown AM, Boudros
E, Mamounas EP, Bear H, Costantino JP, Wolmark N. NSABP
Medical Affairs, NSABP Investigators & NSABP Operation &
Biostatistical Centers, Pittsburgh, PA.
52. The impact of micrometastases in the sentinel nodes of
patients with invasive breast cancer.
Hansen NM, Grube BL, Ye C, Turner R, Brennan M, Brenner J,
Giuliano AE. John Wayne Cancer Institute, Santa Monica, CA;
Saint John’s Hospital and Health Center, Santa Monica, CA.
53. High sensitivity of a molecular assay for breast
metastases in sentinel lymph nodes that are difficult to
detect by frozen section.
Blumencranz P, Deck KB, Whitworth PW, McCue P, Reintgen DS,
Chagpar AS, Beitsch P, Julian TB, Mamounas M, Saha S, Giuliano
A, Simmons R. Morton Plant Mease Healthcare, Clearwater, FL;
Saddleback Memorial Hospital, Laguna Hills, CA; Nashville Breast
Center, Nashville, TN; Jefferson Medical College, Philadelphia, PA;
Lakeland Regional Medical Center, Lakeland, FL; James Brown
Cancer Center, Louisville, KY; Dallas Surgical Group, Dallas, TX;
Allegheny General Hospital, Pittsburgh, PA; Aultman Hospital,
Canton, OH; McLaren Regional Medical Center, Flint, MI; John
Wayne Cancer Institute, Santa Monica, CA; Weill-Cornell Breast
Center, New York, NY.
54. Increased sentinel lymph node lymphangiogenesis
predicts non-sentinel axillary lymph node involvement in
breast cancer patients with a positive sentinel node.
Van den Eynden GG, Vandenberghe MK, van Dam P-JH,
Colpaert CG, van Dam P, van Marck EA, Vermeulen PB, Dirix
LY. (Lab Pathology University of Antwerp/University Hospital
Antwerp, Wilrijk; Oncology Center, GH St-Augustinus, Wilrijk,
Belgium), Antwerp, Belgium.
SYSTEMS BIOLOGY AND TARGETING THE HER
NETWORK IN THE TREATMENT OF BREAST CANCER
C. Kent Osborne, MD, Co-Moderator
and
Rachel Schiff, PhD, Co-Moderator
2:00
Introduction
2:00
HER pathways in the context of systems biology and
integrating networks
Yosef Yarden, PhD
The Weizmann Institute of Science
Rehovat, ISRAEL
2:30
3:00
3:30-5:00
Development of non-invasive optical methods for breast
cancer detection and clinical management
Bruce J. Tromberg, PhD
Beckman Laser Institute
Irvine, CA
11:30
61. The influence of a very high vegetable-fruit-fiber, lowfat diet on prognosis following treatment for breast cancer:
results from the Women’s Healthy Eating and Living (WHEL)
randomized trial.
Pierce JP, Natarajan L, Cann BJ, Parker BA, Greenberg ER, Flatt
SW, Rock CL, Kealey S, Al-Delaimy WK, Bardwell WA, Carlson R,
Emond JA, Faerber S, Gold EB, Hajek RA, Hollenbach K, Jones LA,
Karanja N, Madlensky L, Marshall J, Newman VA, Ritenbaugh C,
Thomson CA, Wasserman L, Stefanick ML. Moores UCSD Cancer
Center, University of California, San Diego, La Jolla, CA; Kaiser
Permanente Northern California, Oakland, CA; Fred Hutchinson
Cancer Research Center, Seattle, WA; Stanford Comprehensive
Cancer Center, Stanford University, Stanford, CA; University of
California, San Diego; University of California, Davis, CA; M.D.
Anderson Cancer Center, The University of Texas, Houston, TX;
Center for Health Research, Portland, OR; Roswell Park Cancer
Institute, Buffalo, NY; University of Arizona, Tucson, AZ; Arizona
Cancer Center, Arizona Prevention Center, University of Arizona,
Tucson, AZ; Stanford Prevention Research Center, Stanford
University, Stanford, CA.
3:45
62. Outcome prediction for Clinical Stage II and III ER+
breast cancer based on treatment response, pathological
stage, tumor grade, Ki67 proliferation index, and estrogen
receptor status after neoadjuvant endocrine therapy.
Ellis MJ, Tao Y, Luo, Evans DB, Bhatnagar, Chaudri-Ross HA, von
Kameke, Miller WR, Eiermann W. Washington University, St
Louis, MO; Novartis Pharma AG, Basel, Switzerland; Edinburgh
University, Scotland; Red Cross Women’s Hospital, Munich,
Germany.
4:00
63. Prognostic utility of the 21-gene assay compared with
Adjuvant! in hormone receptor (HR) positive operable
breast cancer with 0-3 positive axillary nodes treated with
adjuvant chemohormonal therapy (CHT): an analysis of
intergroup trial E2197.
Goldstein L, Ravdin P, Gray R, Yoshizawa C, Childs B, Rowley S,
Shak S, Badve S, Baehner FL, Davidson N, Sledge GW, Sparano
JA. Eastern Cooperative Oncology Group, Brookline, MA; MD
Anderson Cancer Center, Houston, TX; Genomic Health, Inc.,
Redwood City, CA; sanofi aventis, Bridgewater, NJ.
Functional breast imaging: State of the PET
Eric L. Rosen, MD
Seattle Cancer Care Alliance
Seattle, WA
12:00-1:00
12:30-1:45
CASE DISCUSSION 2 – Ballroom A
3:30
Susan Hilsenbeck, PhD, Co-Moderator
and
Eva Sevick-Muraca, PhD, Co-Moderator
Introduction
Novel experimental global approaches in studies of signaling
networks and therapy resistance
René Bernards, PhD
The Netherlands Cancer Institute
Amsterdam, NETHERLANDS
MOLECULAR IMAGING FOR BREAST CANCER
DIAGNOSTICS
11:00
Novel strategies for HER-targeted therapy and mechanisms
of resistance
C. Kent Osborne, MD
Baylor College of Medicine
Houston, TX
11:00-12:00 MINI-SYMPOSIUM 3 – Exhibit Hall D
11:00
MINI-SYMPOSIUM 4 – Exhibit Hall D
4:15
64. Value of centrally-assessed Ki-67 labeling index as a
marker of prognosis and predictor of response to adjuvant
endocrine therapy in the BIG 1-98 trial of postmenopausal
women with estrogen receptor-positive breast cancer.
Viale G, Giobbie-Hurder A. BIG 1-98 Collaborative Group
and International Breast Cancer Study Group (IBCSG), Bern,
Switzerland.
4:30
65. Erythropoietin receptor expression in breast cancer and
correlation to tamoxifen response.
Larsson A-M, Jirstrom K, Rydén L, Landberg G, Pahlman S. Lund
University, University Hospital MAS, Malmo, Sweden.
4:45
66. Inflammatory breast cancer pathogenesis is mediated
in significant part by translation initiation factor eIF4G
amplification and unorthodox protein synthesis.
Silvera D, Arju R, Darvishian F, Levine PH, Formenti SC, Schneider
RJ. New York University School of Medicine, New York, NY;
The George Washington University School of Public Health and
Health Services, Washington, DC.
5:00-7:00
507
Differential effects of doxorubicin and zoledronic acid on
intra-osseous vs extra-osseous breast tumour growth in vivo.
Ottewell PD, Deux B, Monkkonen H, Cross SS, Coleman RE,
Clezardin P, Holen I. University of Sheffield, Sheffield, Yorkshire,
United Kingdom; Faculte de Medicine Laennec, Lyon, France.
508
Survival in breast cancer patients with bone metastases and
reductions in markers of bone resorption during zoledronic
acid treatment.
Lipton A, Cook R, Major P, Smith M, Coleman R. Milton S.
Hershey Medical Center, Hershey, PA; University of Waterloo,
Waterloo, ON, Canada; Juravinski Cancer Centre, Hamilton, ON,
Canada; Massachusetts General Hospital Cancer Center, Boston,
MA; University of Sheffield, Sheffield, United Kingdom.
509
Effects of zoledronic acid on wnt inhibition by dickkopf1 and
frizzled-related protein in patients with bone metastases.
Helsten TL, Mortimer JE, Corr M. Moores UCSD Cancer Center,
La Jolla, CA; University of California, San Diego, CA.
510
Zoledronic acid as adjuvant therapy for women with early
stage breast cancer and occult tumor cells in bone marrow.
Lin A, Park J, Melisko M, Goga A, Moasser M, Moore D, Brissaud
C, Rugo H. University of California-San Francisco, Comprehensive
Cancer Center, San Francisco, CA.
511
Effect of zoledronate on persisting isolated tumor cells in the
bone marrow of patients without recurrence of early breast
cancer.
Rack BK, Jueckstock J, Genss E-M, Schoberth A, Schindlbeck C,
Strobl B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese
K, Janni W. Ludwig-Maximilians-University, Munich, Germany;
Laboratory Drs. Tiller and Partners, Munich, Germany; Estimate
GmbH, Augsburg, Germany.
POSTER DISCUSSION 5 & RECEPTION Ballroom B
Bisphosphonates for Bone Loss and Bone Metastases 501-511
501
502
503
504
505
506
The ZO-FAST trial: zoledronic acid effectively inhibits
aromatase inhibitor associated bone loss in postmenopausal
women with early breast cancer receiving adjuvant letrozole:
24 month BMD results.
De Boer R, Eidtmann H, Lluch A, Pinotti G, Miller J, Schenk N,
Dias R, Coleman R. Royal Melbourne Hospital, Parkville, Victoria,
Australia; Universitaetsklinikum, Kiel, Germany; Hospital Clinico
Universitario de Valencia, Valcenia, Spain; Ospedale di Circolo
Fondazione Macchi, Varese, Italy; Novartis, East Hanover, NJ;
Weston Park Hospital, Sheffield, United Kingdom.
The SABRE (Study of Anastrozole with the Bisphosphonate
RisedronatE) study: 12-month analysis.
Van Poznak C, Hannon RA, Clack G, Campone M, Mackey JR,
Apffelstaedt J, Eastell R. University of Michigan, Ann Arbor, MI;
University of Sheffield, Sheffield, United Kingdom; AstraZeneca,
Macclesfield, Cheshire, United Kingdom; Site Hospitalier Nord
de Nantes, Nantes, France; University of Alberta, Edmonton, AB,
Canada; University of Stellenbosch, Tygerberg, South Africa.
The effect of risedronate on hip structural geometry in
chemotherapy-induced postmenopausal women on SERMS
versus aromatase inhibitors: a 2 year trial.
van Londen G, Perera S, Vujevich K, Sereika S, Bhattacharya R,
Vogel V, Brufsky A, Lembersky B, Greenspan S. University of
Pittsburgh, Pittsburgh, PA; University of Kansas, Kansas City, KS.
Practical guidance for the prevention of aromatase
inhibitor-associated bone loss in women with breast cancer.
Hadji P, Appro M, Brufsky A, Tubiana-Hulin M, Guise T, Body
JJ. Philipps-University of Marburg, Marburg, Germany; Institut
Multidisciplinaire d’Oncology, Genolier, Switzerland; University
of Pittsburgh, Pittsburgh, PA; Centre René Huguenin, St. Cloud,
France; University of Virginia, Charlottesville, Virginia; Université
Libre de Bruxelles, Brussels, Belgium.
Effect of zoledronic acid on bone loss in women undergoing
chemotherapy for breast cancer.
Aft R, Chavez-MacGregor M, Trinkaus K, Naughton M,
Weilbaecher K. Washington University, Siteman Cancer Center,
St. Louis, MO; John Cochran Veterans Administration Hospital,
St. Louis, MO.
Zoledronic acid prevents bone loss in premenopausal
women undergoing adjuvant chemotherapy for early stage
breast cancer.
Hershman DL, McMahon D, Crew K, Cremers S, Irani D,
Cucchiara G, Brafman L, Siarra A, Shane E. Columbia University
Medical Center, New York, NY.
5:00-7:00
POSTER SESSION 5 & RECEPTION Exhibit Hall B
(#5001-5119)
Detection and Diagnosis: Detection 5001-5012
5001
Molecular etiology of breast cancer: potential biomarkers of
risk and for use in prevention.
Cavalieri E, Gaikwad N, Rogan E, Pruthi S, Ingle J. University of
Nebraska Medical Center, Omaha, NE; Mayo Clinic College of
Medicine, Rochester, MN.
5002
Increased detection of breast cancer markers human
epidermal growth factor receptor dimer and downstream
signaling proteins utilizing the VeraTag technology with
dextran modified antibodies.
Wallweber J, Dang T, Gupta S, Winslow J, Petropoulos C.
Monogram Biosciences, Inc., South San Francisco, CA.
5003
Changing pattern of the detection of loco-regional relapse in
breast cancer: the Edinburgh experience.
Montgomery DA, Krupa K, Kerr G, Jack W, Dixon M. Royal
Infirmary, Glasgow, United Kingdom; Royal Alexandra Hospital,
Paisley, United Kingdom; Western General Hospital, Edinburgh,
United Kingdom.
5004
Value of clinical follow-up following breast conserving
treatment for breast cancer.
Hamed H, Kontos M, Jones G, Allen D. Guy’s Hospital, London,
United Kingdom.
5005
Estrogen plus progestin and breast cancer detection with
mammography and breast biopsy.
Chlebowski RT, Anderson G, Pettinger M, Lane D, Langer RD,
Gillian MA, Walsh BW, Chen C, McTiernan A. Los Angeles
Biomedical Research Institute at Harbor-UCLA Medical Center,
Torrance, CA; Fred Hutchinson Cancer Research Center, Seattle,
WA; The State University of New York, Stony Brook, NY;
Geisinger Healthcare, Danville, PA; Medical College of Wisconsin,
Milwaukee, WI; Bringham & Womens Hospital, Boston, MA.
5006
Galactose oxidase Schiff’s reactivity is higher in nipple
aspirate fluid from cancerous breasts than from healthy
patients.
Chagpar AB, Evelegh M. University of Louisville, Louisville, KY;
McMaster University, Hamilton, ON, Canada.
5007
Hormonal attributes of breast ductal lavage fluid in pre- and
post-menopausal women. Effect of tamoxifen.
Chatterton RT, Avram MJ, Helenowski IB, Khan SA.
Northwestern University, Chicago, IL.
5008
Novel impedance device to detect breast cancer in younger
women.
Boolbol SK, Ironstone JS, Feldman SM. Beth Israel Medical Center,
New York, NY.
5009
Intraoperative in vivo reflectance spectroscopy for
discrimination of normal, benign, and malignant breast
tissues.
Brown JQ, Wilke LG, Kennedy S, Palmer GM, Geradts J,
Ramanujam N. Duke University, Durham, NC; Duke University
Medical Center, Durham, NC.
5010
5011
5012
Water state changes in malignant and benign breast tumors
measured by diffuse optical spectroscopy in vivo.
Chung SH, Cerussi AE, Merritt SI, Hsiang D, Mehta R, Tromberg
BJ. University of California, Irvine, CA; Masimo Corporation,
Irvine, CA; UCI Medical Center, Orange.
Sonopheresis and ductal epithelial impedance spectroscopy
as a non-invasive technique for breast cancer diagnosis.
Davies RJ, Brumfield MK, Pierce M, Greene T. Hackensack
University Medical Center, Hackensack, NJ; UMD-New Jersey
Medical School, Newark, NJ.
Combination of mammogram BI-RADS data and serum
mass spectrometry proteomic profiles in improving breast
cancer diagnosis.
Sun M, Sun M, Lokshin AE, Modugno FM, Bigbee WL. University
of Pittsburgh Cancer Institute, Pittsburgh, PA; University of
Pittsburgh, Pittsburgh, PA.
5019
Serum HER2 compared with CA153 for the monitoring of
advanced breast cancer.
Briscoe T, Thompson D, Bosomworth M, Dodwell DJ, Adlard JW.
St James’s University Hospital, Leeds, United Kingdom.
5020
Liquid FISH-like assay for detection of HER-2 gene
amplification in the serum of patients with breast cancer.
Yeh C-H, Whitmire III WA, Albitar M. Quest Diagnostics Nichols
Institute, San Juan Capistrano, CA.
5021
CA 15-3 level at time of metastatic relapse of breast cancer
strongly correlates with hormone receptor but not with
Her2 expression.
Bensouda Y, Andre F, Boulet T, Mathieu MC, Conforti R,
Ponzio-Prion A, de la Motte Rouge T, Zoubir M, El Masmoudi
Y, Spielmann M, Delaloge S. Institut Gustave Roussy, Villejuif,
France.
5022
Differential gene expression in circulating tumor cells
between primary and metastatic breast cancer patients.
Reinholz MM, Kitzmann KK, Hillman D, Lingle WL, Hobday T,
Moreno A, Vivek R, Perez EA. Mayo Clinic College of Medicine,
Rochester, MN; Mayo Clinic College of Medicine, Jacksonville, FL.
5023
Metastasis in blood of breast cancer patients.
Lu J, Zeng W, Zhao Q, Zaslavsky E, Fan T, O’Hea B, Burk M,
Merriam L, Pameijer C, Chen W-T. Stony Brook University
Medical Center, Stony Brook, NY; Vitatex, Inc., Stony Brook, NY.
Detection and Diagnosis: Marrow and Blood Micrometastases
5024-5025
5024
RASSF1A DNA methylation in bone marrow (mRASSF1ABM)
or peripheral blood plasma (mRASSF1APB) of primary breast
cancer (BC) patients.
Braun S, Auer D, Vogl FD, Schneitter A, Egle D, Taucher S,
Daxenbichler G, Marth C. Innsbruck Medical University,
Innsbruck, Austria; Medical Services, Meran, Italy.
5025
Incidence and kinetics of circulating tumor cells in
breast cancer patients treated with primary systemic
therapy including trastuzumab for patients with HER2positive tumors - a translational project within the study
“GeparQuattro”.
Riethdorf S, Loibl S, Komor M, Huober J, Schrader I, Conrad U,
Untch M, von Minckwitz G, Pantel K, Mueller V. University
Medical Center Hamburg-Eppendorf, Hamburg, Germany;
Goethe University Frankfurt, Frankfurt, Germany; German Breast
Group, Neu Isenburg, Germany; University Medical Center
Tuebingen, Tuebingen, Germany; Henriettenstiftung Hannover,
Hannover, Germany; St. Barbara Klinik Hamm Heessen, Hamm
Heessen, Germany; Heliosklinik Berlin-Buch, Berlin, Germany.
Detection and Diagnosis: Circulating Markers 5013-5023
5013
Identification of a metabolic fingerprinting for metastatic
breast cancer by proton nuclear magnetic resonance
spectroscopy-metabolomic analysis.
Claudino WM, Colangiuli D, Biganzoli L, Nepi S, Cappadona
S, Ciarlo A, Luchinat C, Vinci E, Bertini I, Di Leo A. Hospital of
Prato; Istituto Toscano Tumori-Prato, Prato, Italy; Scientific Pole,
University of Florence, Sesto Fiorentino, Florence, Italy; Sesto
Fiorentino, Florence, Italy.
5014
Identification of blood-based biomarkers for the detection
of breast cancer and lymph node status.
Field LA, Love BJ, Hadix JA, Ellsworth RE, Shriver CD. Windber
Research Institute, Windber, PA; Invitrogen Informatics, Carlsbad,
CA; Walter Reed Army Medical Center, Washington, DC.
5016
Discovery of serum biomarkers for breast cancer detection.
Sheta EA, Bryson JK, Meyers GL, Hollingsworth A. Power3
Medical Products, Inc., The Woodlands, TX; Mercy Women’s
Center, Oklahoma City, OK.
5017
Protein markers for the stratification of breast cancer
patients.
Quong JN, Rosenberg AL, Farooqi S, Yeow W-S, Brill KL, Minkeau
A, Sabherwal Y, Quong AA. Thomas Jefferson University and
Hospital, Philadelphia, PA.
5018
Detection of oligometastases in breast cancer by using
tumor markers.
Ertl I, Heinemann V, Bauerfeind I, Laessig D, Nagel D, Seidel D,
Stieber P. Institute of Clinical Chemistry, Munich, Germany;
Medical Department III, Munich, Germany; Gynecological
Department, Munich, Germany.
Prognosis and Response Predictions: Prognostic Factors –
Methods 5026-5040
5026
Web calculators for estimating the risk of breast cancer
death and the impact of adjuvant treatment on that risk.
Michaelson JS, Chen L, Martei Y, Smith B, Younger J.
Massachusetts General Hospital, Boston, MA.
5027
Nodal ratios as an alternative to pN-staging in node-positive
breast cancer: a validation study.
Vinh-Hung V, Vlastos G, Fioretta G, Usel M, Neyroud-Caspar
I, Rapiti E, Verkooijen L, Bouchardy C. Institute for Social and
Preventive Medicine, Geneva University, Geneva, Switzerland;
UZ Brussel, Jette, Brussels, Belgium; International Nodal
Ratio Working Group; Geneva University Hospitals, Geneva,
Switzerland.
5028
Automated image analysis for high-throughput quantitative
detection of ER and PgR expression levels in large-scale
clinical studies: the TEAM trial experience.
Faratian D, Kay C, Campbell F, Robson T, Grant M, Rea D, Bartlett
J. Edinburgh Cancer Research Centre, Edinburgh, Scotland,
United Kingdom; University of Birmingham, Birmingham, United
Kingdom.
5029
Estrogen receptor and breast cancer survival in a Kaiser
permanente population-based study: comparison of
quantitative reverse transcriptase polymerase chain reaction
and immunohistochemistry.
Habel LA, Achacoso N, Maddala T, Alexander C, Baehner
FL, Shak S, Quesenberry C, Gown AM, Goldstein LC. Kaiser
Permanente, Oakland, CA; Genomic Health Inc, Redwood City,
CA; PhenoPath Laboratories, Seattle, CA.
5030
Androgen receptor determination in breast cancer: a
comparison of the dextran-coated charcoal method and
quantitative immunohistochemical analysis.
Søiland H, Skaland I, Van Diermen B, Janssen EAM, Kørner H,
Varhaug JE, Søreide JA, Baak JPA. Stavanger University Hospital,
Stavanger, Norway; Haukeland University Hospital, Bergen,
Norway; University of Bergen, Bergen, Norway; Free University,
Amsterdam, Netherlands.
5031
Human epidermal growth factor receptor 2 (Her-2/Neu),
immunohistochemistry (IHC) and fluorescence in situ
hybridization (FISH) testing at McGill University Health
Centre: a comparison of absolute FISH copies (FISH-ABS abs)
with Her-2 COPY/chromosome 17 ratio (FISH-17 RATIO) in
198 consecutive early breast cancer cases.
Sade S, Momta P, Quenneville L, Mihalcioiu C, Omeroglu A,
Ragaz J. McGill University Health Centre, Montreal, QC, Canada;
McGill University, Montreal, QC, Canada; Jewish General
Hospital, Montreal, QC, Canada.
5032
Quality control procedures are essential in accurate HER2
FISH testing using automated morphometric image analysis.
Barry TS, Tse C, Goldstein LC, Kim PM, Kussick SJ, Kandalaft P,
Gown AM. Phenopath Labs, Seattle, WA.
5033
Impact of ERBB2 on prognosis and microarray data.
Koscielny S. Institut Gustave Roussy, Villejuif, France.
5034
Reproducibility of HER2-analysis in a national survey
performed at 24 routine pathology departments in Sweden.
Ferno M, Haglund M, Bendahl P-O, Hatschek T, Kolaric A, Kovacs
A, Olsson A, Olsson H, Ryden L, Strand C. University Hospital,
Lund, Sweden; University Hospital, Malmo, Sweden; Karolinska
University Hospital, Stockholm, Sweden; University Hospital,
Orebro, Sweden; University Hospital, Gothenburg, Sweden;
University Hospital, Linkoping, Sweden.
5035
Assessing HER-2 status via virtual microscopy.
Bloom KJ, Kyshtoobayeva A, Chen S, Hii A. CLARiENT, Aliso
Viejo, CA.
5036
Intrinsic near-infrared spectroscopic biomarkers applied for
evaluation of final pathological response to neaoadjuvant
chemotherapy.
Kukreti S, Cerussi AE, Tanamai VW, Tromberg BJ, Rita M, David
H, Gratton E. University of California, Irvine, CA; University of
Illinois, Urbana-Champaign, IL.
5037
Prognosis-prediction model using multimarker in lymph
node negative breast cancer by decision tree analysis.
Jung S-Y, Han W, Han M-R, Park IA, Ko E, Kim E, Lee JW, Cho
J, Kim S-W, Hwang K-T, Noh D-Y. Seoul National University
Hospital, Seoul, Republic of Korea.
5038
Bayesian analysis of recurrence in lymph node positive and
lymph node negative breast cancer patients.
Maskery S, Hu H, Liebman M, Shriver C, Verbanac K, Tafra L,
Rosman M. Windber Research Institute, Windber, PA; Walter
Reed Army Medical Center, Washington, DC; East Carolina
University, Greenville, NC; Ann Arundel Medical Center,
Annapolis, MD.
5039
Stage migration of breast cancer using two techniques of
tumor size assessment and its impact on projection for
survival and treatment decision making.
Phillips J, Staszewski H, Schuss A, Buyuk A. Winthrop University
Hospital, Mineola, NY.
5040
Withdrawn
Treatment: DCIS 5041-5047
5041
Sentinel node biopsy in ductal carcinoma in situ of breast - a
meta-analysis.
Ansari B, Ogston SSA, Purdie CCA, Adamson DJA, Brown DC,
Thompson AM. Dundee University, Dundee, Scotland, United
Kingdom.
5042
Pathologic and radiographic response of ER-positive DCIS to
neoadjuvant letrozole therapy.
Hwang ES, Chen Y-Y, Wolverton DE, Lessing JN, Shim V,
Devries S, Anderson J, Johnson LR, Hylton NM, Esserman LJ,
Waldman FM. University of California, San Francisco, CA; Kaiser
Permanente Oakland Medical Center, Oakland, CA; California
Pacific Medical Center, St. Luke’s Hospital, San Francisco, CA;
Emory University School of Medicine, Atlanta, GA; University of
California, San Francisco, CA.
5043
ERISAC trial: evidence exemestane effects oestrogen
receptor (ER) positive ductal carcinoma in situ (DCIS)
proliferation.
Bundred NJ, Cramer A, Cheung KL, Johnson RL, Flint P, Young
O, Grassby S, Turner L, Baildam A, Barr L, Byrne GJ, Dixon JM.
University Hospital of South Manchester, Manchester, United
Kingdom; University of Nottingham, Nottingham, United
Kingdom; Western General Hospital, Edinburgh, United
Kingdom.
5044
Genetic and phenotypic characteristics in pleomorphic
lobular carcinoma in situ.
Chen Y-Y, Roydasgupta R, DeVries S, Anderson J, Wa C,
Fitzgibbons P, Jacobs T, MacGrogan G, Peterse H, VincentSalomon A, Tokuyasu T, Hwang ES, Schnitt S, Waldman FM.
University of California, San Francisco, CA; St Jude Med Ctr,
Fullerton, CA; Virginia Mason Med Ctr, Seattle, WA; Institute
Bergonie, Bordeaux, France; Netherlands Cancer Institute,
Amsterdam, Netherlands; Insititute Curie, Paris, France; Beth
Israel Deaconess Med Ctr, Boston, MA.
5045
Molecular profiling of DCIS: identification of distinct
subgroups of potential prognostic importance.
Clark SE, Marshall JF, Hart IR, Carpenter R, Jones JL. St.
Bartholomew’s Hospital, London, United Kingdom; Institute of
Cancer, QMUL, London, United Kingdom.
5046
Suboptimal local control of ductal carcinoma in situ of
the breast is associated with inferior 10-year breast cancer
specific survival in a population-based cohort of women
treated with breast conserving surgery.
Wai ES, Alexander CS, Culp M, Moccia P, Mackinnon M, Moore
S, Olivotto IA. BC Cancer Agency - Vancouver Island Centre,
Victoria, BC, Canada; University of British Columbia, Victoria, BC,
Canada.
5047
Can subcutaneous mastectomy be considered an alternative
for ductal carcinoma in situ treatment, when breast
conservation is not possible?
Giménez Climent MJ, Merck B, LLopis Martínez F, Sancho Merle
F, Vázquez Albaladejo C. Fundación Instituto Valenciano de
Oncología, Valencia, Spain.
Treatment: Male Breast Cancer 5048-5051
5048
Male breast cancer (MBC): impact of early diagnosis and
adjuvant treatments. Analysis of 983 cases.
Cutuli B, Cohen-Solal-Le-Nir C, Serin D, Kirova Y, Belkacemi
Y, Gaci Z, Lemanski C, De Lafontan B, Zoubir M, Maingon
P, Mignotte H, Tunon de Lara C, Edeline J, Penault-Llorca F,
Romestaing P, Delva C. Polyclinique de Courlancy, Reims, France;
Sylia-Stat, Bourg La Reine, France.
5049
Survivin and COX-2 expression in male breast cancer.
Younis T, Dakin-Hache KA, Rayson D, Dewar R, Gray S, Barnes PJ.
Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada;
Cancer Care Nova Scotia, Halifax, NS, Canada; Dalhousie Medical
School, Halifax, NS, Canada.
5050
Patterns of body size in male breast cancer and impact of
obesity on disease outcome.
Kulkarni S, Franssen E, Madarnas Y. Queen’s University, Kingston,
ON, Canada.
5051
Expression of basal-like markers in male breast cancers.
Flanagan MB, Bhargava R, Dabbs DJ, Thull D, Chivukula M.
Magee-Womens Hospital, Pittsburgh, PA.
5056
Randomized placebo-controlled phase l l trial with
preoperative epirubicin and cyclophosphamide +/- gefitinib
in patients with operable and estrogen receptor negative
breast cancer.
Ejlertsen B, Bentzon N, Jacobsen E, Kromann N, Ottestad L, Ingvar
C. University Hospital of Copenhagen, Copenhagen, Denmark;
Herlev Hospital, Herlev, Denmark; Vejle Hospital, Vejle, Denmark;
University Hosp. of Copenhagen Rigshospitalet, Copenhagen,
Denmark; Norske Radiumhospital, Oslo, Norway; University
Hospital Lund, Lund, Sweden.
5057
Efficacy and safety results from a randomized, phase
II trial of neoadjuvant capecitabine + epirubicin +
cyclophosphamide vs 5-FU + epirubicin + cyclophosphamide
in operable breast cancer.
Roché H, Penault-Llorca F, Berton Rigaud D, Tubiana Mathieu
N, Ferrero J-M, Coudert B, Mousseau M, Monnier A, Orfeuvre H,
Audhuy B, Rotarski M, Homokos H, Fumoleau P. Inst Claudius
Régaud, Toulouse, France; Centre Jean Perrin, Clermont-Ferrand,
France; Centre René Gauducheau, St. Herblain, France; Hôpital
Dupuytren, Limoges, France; Centre Antoine Lacassagne, Nice,
France; Centre Georges François Leclerc, Dijon, France; CHU de
Grenoble, La Tronche, France; CH de Montbeliard, Montbeliard,
France; CH de Fleyriat, Bourg en Bresse, France; Hôpital Pasteur,
Colmar, France; Centre Oncologie Du Pays Basque, Bayonne,
France; Roche, Neuilly sur Seine, France.
Treatment: Neoadjuvant Therapy 5052-5076
5052
Significant improvement in disease free and overall survival
with neoadjuvant, dose intensified two weekly treatment
with anthracycline and taxane in primary breast cancer,
including inflammatory disease. Fifty five months median
follow up results of a multicenter prospective randomised
phase III AGO-trial.
Untch M, Konecny G, Moebus V, Bauerfeind I, Thomssen Ch,
Harbeck N, Kuhn W, Bothmann G, Wallwiener D, Kreienberg R,
Lueck HJ. Helios Klinikum Berlin Buch, Berlin, Germany; Mayo
Clinic, Rochester, MN; Klinikum Frankfurt Hoechst, Frankfurt,
Germany; University of Munich Grosshadern, Munich, Germany;
University of Halle, Halle, Germany; Technical University of
Munich, Munich, Germany; University of Bonn, Bonn, Germany;
Städtisches Klinikum, Wolfsburg, Germany; University of
Tuebingen, Tuebingen, Germany; University of Ulm, Ulm,
Germany; Horst Schmitt Kliniken, Wiesbaden, Germany.
5053
Evaluating the efficacy and safety of trastuzumab given
concomitantly to epirubicin/cyclophosphamide ¢
docetaxel±capecitabine as neoadjuvant treatment of HER2
overexpressing primary breast cancer. First analysis of the
GBG/AGO intergroup-study “GeparQuattro”.
Untch M, Rezai M, Loibl S, Fasching P, Huober J, Tesch H,
Bauerfeind I, Hilfrich J, Mehta K, von Minckwitz G. Frauenklinik,
Berlin, Germany; Senologie, Brustzentrum, Düsseldorf, Germany;
University Hospital Frankfurt, Frankfurt, Germany; Neu-Isenburg,
Germany; Frauenklinik mit Poliklinik, Erlangen, Germany;
Senologiezentrum Ostschweiz SENZO, St. Gallen, Switzerland;
Onkologie Bethanien, Frankfurt, Germany; Frauenklinik,
München, Germany; Frauenklinik, Hannover, Germany.
5058
Sequential epirubicin/cyclophosphamide followed by
docetaxel with or without celecoxib or trastuzumab
according to HER2 status, as primary chemotherapy
for localized invasive breast cancer patients: results of
the planned interim analysis and analysis of predictive
parameters. Supported by PHRC AOM/2OO2/02117, Pfizer
inc., Roche, sanofi-aventis.
Marty M, Guinebretiere J-M, Mathieu M-C, Sigal-Zafrani B, de
Roquancourt A, Spielmann M, Giacchetti S, Extra J-M, Spyratos F,
de The H, Pierga J-y, Salmon R, Mefti-Lacheraf F, Asselain B. Saint
Louis University Hospital, Paris, France; Centre Rene Huguenin,
Saint Cloud, France; Institut Gustave Roussy, Villejuif, France;
Institut Curie, Paris, France.
5054
Development of a genomic tool to predict pathologic
complete remission in a community-based, preoperative,
phase II trial of 5-fluorouracil, epirubicin, cyclophosphamide
followed by docetaxel-capecitabine for stage II, III breast
cancer.
Holmes FA, Hellerstedt B, Pippen J, Vukelja SJ, Kocs D, Collea R,
Blum JL, McIntyre K, Ward FT, Pusztai L, Boehm KA, Asmar L,
O’Shaughnessy J. US Oncology Research, Houston, TX; Texas
Oncology, P.A., Houston, TX; Baylor-Charles A. Sammons Cancer
Center, Dallas, TX; Texas Oncology Cancer Centers, Austin, TX;
Tyler Cancer Center, Tyler, TX; Texas Cancer Center, Round
Rock, TX; New York Hematology and Oncology, Albany, NY;
Texas Oncology, P.A., Dallas, TX; M.D. Anderson Cancer Center,
Houston, TX.
5059
Neoadjuvant capecitabine plus docetaxel ± trastuzumab
therapy for recently diagnosed breast cancer: phase II
results.
Tripathy D, Moisa C, Gluck S. University of Texas Southwestern
Medical Center, Dallas, TX; Roche Laboratories, Inc, Nutley, NJ;
University of Miami, Miami, FL.
5060
Dose-dense docetaxel, carboplatinum and trastuzumab as
neoadjuvant therapy for human epidermal growth factor
receptor-2 - positive stage II and III breast cancer.
Han HS, Doliny P, Blaya M, Gluck S, Slingerland J, Silva O, Welsh
C, Hurley J. Sylvester Comprehensive Cancer Center, University of
Miami, Miami, FL.
5061
High pathologic complete response rate effectively predicted
by proliferation index in HER2-positive localized breast
cancer treated with weekly paclitaxel followed by FEC with
concurrent trastuzumab.
Pernas S, Urruticoechea A, Falo C, Pardo B, Villanueva R, Ortega
R, Garcia A, Moreno A, Perez J, Gil M. Institut Català d’OncologiaH.U. de Bellvitge. IDIBELL, L’Hospitalet-Barcelona, Spain.
5062
The influence of T-cells on the response to a neodjuvant
therapy with docetaxel/epirubicin/cyclophosphamide (TEC).
Kemming D, Bosse U, Vogt U, Schlotter CM, Tidow N, Brandt
BH. University Medical Center Hamburg Eppendorf, Hamburg,
Germany; Institute of Pathology, Osnabrueck, Germany;
European Laboratory Association, Ibbenbueren, Germany; Clinic
Center Ibbenbueren, Ibbenbueren, Germany; Uiniversity of
Muenster, Muenster, Germany.
5055
Primary systemic therapy using docetaxel/
cyclophosphamide/bevacizumab (TCB) followed by
doxorubicin (A) in operable or locally advanced breast
cancer (BC).
Makhoul I, Klimberg S, Henri-Tillmen R, Westbrook K, Hutchins
L. University of Arkansas for Medical Sciences, Little Rock, AR.
5063
Preliminary recurrence and survival analysis of patients
(pts) receiving neoadjuvant q4week carboplatin and weekly
paclitaxel ± weekly trastuzumab in resectable and locally
advanced breast cancer: update of BrUOG BR-95.
Sikov WM, Fenton MA, Strenger R, Dizon DS, Legare RD, Graves
TA, Brown University Oncology Group. Rhode Island Hospital,
Providence, RI; Women and Infants Hospital, Providence, RI; The
Miriam Hospital, Providence, RI.
5064
Pharmacokinetic and pharmacodynamic analysis of
cyclophosphamide, epirubicin and capecitabine vs 5-FU,
epirubicin and cyclophosphamide as neoadjuvant therapy in
Milano G, Deporte R, René N, Etienne-Grimaldi M-C, Berton
Rigaud D, Ferrero J-M, Dalenc F, Piutti M, Homokos H, Fumoleau
P. Centre Antoine Lacassagne, Nice, France; Centre René
Gauducheau, Saint Herblain, France; Institut Claudius Regaud,
Toulouse, France; Roche, Neuilly sur Seine, France; Centre
Georges François Leclerc, Dijon, France.
5071
The farnesyl transferase (FT ase) inhibitor (FTI) tipifarnib
inhibits FT ase in vivo and enhances the efficacy of
neoadjuvant dose-dense doxorubicin-cyclophosphamide
(AC) in patients with locally advanced breast cancer (LABC).
Sparano JA, Coppola D, Kazi A, Merajver S, Vahdat L, Li T,
Pellegrino C, Munster P, Hoschander S, Hopkins U, Hershman
D, Wright JJ, Kleer C, Sebti S. Montefiore-Einstein Cancer Center,
Bronx, NY; H. Lee Moffitt Cancer Center, Tampa, FL; University
of Michigan, Ann Arbor, MI; Weill Medical College of Cornelly
University, NY, NY; Columbia University, NY, NY; National
Cancer Institute, Bethesda, MD.
5072
A phase 2 trial of neoadjuvant letrozole for postmenopausal
patients with stage 2 and 3 ER and/or PgR+ breast cancer endpoint comparisons.
Ellis M, Luo R, Tao Y, Crowder R, Hoog J, Guintoli T, Commean
P, Carey L, Harris L, Fleming G, Esserman L, Budd T, Iversen E,
Olson J. Siteman Cancer Center, MO; UNC-CH, NC; DFCI, MA; U
Chicago, IL; UCSF, CA; Cleveland Clinic, OH; Duke, NC.
5065
Does combination of neoadjuvant and adjuvant
chemotherapy improve outcome in operable breast cancer
patients?
Knauer M, Haid A, de Vries A, Schneider Y, Lang A, Winder T,
Alton R, Wenzl E. University Teaching Hospital, Feldkirch, Austria.
5073
A randomized phase II neoadjuvant trial in patients with
stage II-III and inflammatory breast cancer.
Somlo G, Paz B, Shen J, Garberoglio C, Luu T, Chung C, Hurria A,
Frankel P, Baker N, Wilczynski S, Arnold K, Yeb Y. City of Hope
Comprehensive Cancer Center, Duarte, CA.
5066
Pathologic complete response following paclitaxel
(cremophor or albumin bound) + carboplatin ±
trastuzumab ± bevacizumab sequenced after in vivo
chemosensitivity-adapted dose-dense doxorubicincyclophophamide in inflammatory breast cancer.
Mehta RS, Schubbert T, Jackson D, Hsiang D, John B. University of
California, Irvine, Orange, CA.
5074
Clinical relevance of neoadjuvant chemotherapy in invasive
lobular carcinoma of the breast.
Vrancken Peeters M-JTFD, Linn SC, Loo CE, Peterse HL, Rutgers
EJTh, Rodenhuis S. Netherlands Cancer Institute, Amsterdam,
Netherlands.
5075
Tumor and normal interstitial fluid proteomic
characterization in breast cancer patients receiving
Cortesi L, Barchetti A, De Matteis E, Ruscelli S, Della Casa L,
Tazzioli G, Lazzaretti MG, Iannone AC, Federico MR. University of
Modena and Reggio Emilia, Modena, Italy; Carpi Hospital, Carpi,
Modena, Italy.
5076
Pathological and clinical outcomes in response to
neoadjuvant chemotherapy: a comparison of basal-like,
hormone receptor-positive and HER2-positive breast
cancers.
Allada N, Osborne CR, Xie X-J, Ashfaq R, Bian A, Tripathy D.
UT Southwestern Medical Center, Dallas, TX; Baylor Sammons
Cancer Center, Dallas, TX.
5067
Epirubicin and docetaxel as neoadjuvant treatment of
locally advanced breast cancer: a phase II study.
Lombardi D, Scalone S, Crivellari D, La Mura N, Miolo G,
Murrone A, Perin T, Coran F, Candiani E, Massarut S, Veronesi A.
Centro di Riferimento Oncologico, Aviano, PN, Italy.
5068
Neoadjuvant biweekly chemotherapy with liposomal
doxorubicin and docetaxel in patients with stage II-III breast
cancer.
Alvarez I, Modolell A, Mayordomo JI, Heras L, Villadiego K,
Rolfo CD, Garcia-Bueno JM, Pica P, Murillo L, Morales S, Valero
P, Florian J. H San Jorge, Huesca; Inst Oncologia Corachan,
Barcelona; H Clinico, Zaragoza; Cruz Roja, Hospitalet; H Sagrat
Cor, Barcelona; Clin Roger, Palma de Mallorca; Clin Serosa,
Palma de Mallorca; Hosp Infanta Cristina, Badajoz; H Reina Sofia,
Tudela; Clin Perpetuo Socorro, Lerida; Clin Infanta Luisa, Sevilla; H
Barbastro, Barbastro, Spain.
5069
Phase II study of a 3-weekly liposome-encapsulated
doxorubicin/docetaxel/pegfilgrastrim in combination
with weekly trastuzumab as primary treatment in HER2
positive (HER2+) early stage breast cancer patients (II-IIIa).
Intermediate analysis of 26 patients. GEICAM 2003-03 study.
Antón A, Ruiz-Simon A, Plazaola A, Segui MA, Muñoz M,
Calvo L, Puértolas T, Guerrero A, Alfaro J. Spanish Breast Cancer
Research Group (GEICAM), Spain.
5070
A phase IV study of neo-adjuvant combination
chemotherapy with pegylated liposomal doxorubicin
(CAELYX®) and vinorelbine for locally advanced breast
cancer.
Shen ZZ, Shao MZ, Xu HB, Wang L, Wang SY, Liu J, He QP, Su
XF, Jiang FZ, Zhang B. Fudan Univ. Affiliated Tumor Hospital,
Shanghai, China; Cancer Institute & Hospital Chinese Academy
of Medical Sciences, Beijing, China; The Fourth Military Medical
Univ. Affiliated No1. Hospital, Xi’an, Shanxi, China; Shandong
Tumor Hospital, Jinan, Shandong, China; Fujian Provincial Tumor
Hospital, Fuzhou, Fujian, China; Shanghai 6th People Hospital,
Shanghai, China; Sun Yat-Sen Memorial Hospital, Guangzhou,
Guangdong, China; 307 Hospital of PLA, Beijing, China; Liaoning
Cancer Hospital & Institute, Shenyang, Liaoning, China.
Treatment: Surgery 5077-5101
5077
Optimal loco-regional treatment of the primary tumor
in metastatic breast cancer patients is associated with a
significant survival advantage.
Vlastos G, Rapiti E, Bouchardy C, Fioretta G, Verkooijen HM,
Storme G, Vinh Hung V. Geneva University Hospitals, Geneva,
Switzerland; Institute for Social and Preventive Medicine,
University of Geneva, Geneva, Switzerland; National University of
Singapore, Singapore, Singapore; Oncology Center UZ, Brussels,
Belgium.
5078
NEW START: the United Kingdom sentinel lymph biopsy
training programme. A model of how multi-professional
training can achieve competent national performance whilst
maintaining patient safety.
MacNeill F, Mansel R, Horgan K, Keshtgar M, Kissin M, Wishart
G, Brown D, NEW START Steering Group and Trainers. Royal
College of Surgeons (England), London, United Kingdom.
5079
The effect of dedicated breast surgeons on the short term
outcomes in breast cancer.
Zork NM, Komenaka IK, Bowling MW, Norton LE, Pennington
RE, Clare SE, Goulet RJ. Indiana University School of Medicine,
Indianapolis, IN.
5080
Shared decision-making in routine clinical practice: the
example of breast cancer in a regional cancer centre in
France.
Hervé M, Nora M-F, Christelle F, Anne M, Marie Odile C. Centre
Léon Bérard, Lyon, France.
5091
Staged sentinel node biopsy to guide timing of breast
reconstruction.
Ahrendt G, Johnson R, Horton F, Bonaventura M, Falk J, Keenan
D, Soran A. Magee-Womens Hospital of University of Pittsburgh
Medical Center, Pittsburgh, PA.
5081
Paget’s disease of the nipple in a population based cohort.
Dalberg K. Danderyds University Hospital, Stockholm, Sweden.
5092
5082
Infiltration of ropivacaine efficacy on acute breast pain
after surgery for breast cancer. Preliminary results of a
multicentric study.
Emmanuelle F, Aline A-F, Catherine B, Alain B, Smail H, Max
B, Cyrus M, Jean-Remi G, Sameh Y, Serge L, Jean-Louis B, Louis
B, Catherine N, Christian J. Rene Huguenin Cancer Centre,
Saint-Cloud, France; Institut Paoli Calmettes, Marseille, France;
Institut Gustave Roussy, Villejuif, France; Ambroise Pare Hospital,
Boulogne, France.
Rib fractures: a complication of radiation therapy and tissue
expansion for breast reconstruction.
Huang AH, Wong MS, Whetzel TP, Stevenson TR. University of
California-Davis Medical Center, Sacramento, CA.
5093
Does quality of life after breast reconstruction change with
time?
Thomson HJ, Fallowfield LJ, Winters ZE. University of Bristol,
Bristol, United Kingdom; Psychosocial Oncology Group, Brighton,
United Kingdom.
5094
Three-dimensional imaging provides valuable clinical
data to aid in unilateral tissue expander-implant breast
reconstruction.
Tepper OM, Karp NS, Small K, Unger J, Pritchard A, Roses D,
Shapiro R, Guth A, Axelrod D, Choi M. New York University
School of Medicine, New York, NY.
5095
Postoperative analgesia and flap perfusion after pedicled
TRAM flap reconstruction - continuous wound instillation
with ropivacaine 0.2% - a pilot study.
Dagtekin O, Thomas A, Hotz A, Kampe S, Auweiler M, Warm
M. University of Cologne, Cologne, Germany; University of
Medicine, Charité, Berlin, Germany.
5096
Optimizing surgical technique for total skin-sparing
mastectomy.
Chattopadhyay R, Radzio A, Kumar A, Foster R, Ewing C, Shelley
H, Michael A, Esserman LJ. University of California, San Francisco,
San Francisco, CA.
5097
Quality of life and morbidity at medium term follow up
after sentinel lymph node, and immediate or delayed axillary
disssection.
Maryam ANM, Max BM, Laeticia HL, Carole TC, Jean Marc EJM,
Agnes TA, Gilles HG. Institut Paoli Calmettes, Marseille, Bouches
du Rhone, France.
5098
Radiation after axillary lymph node dissection: impact of
Kirstein LJ, MacDonald S, Abi Raad R, Taghian AG, Smith BL,
Specht MC. Massachusetts General Hospital, Boston, MA.
5099
Intraoperative ultrasound localization of nonpalpable breast
cancers.
Salmon RJ, Petitperrin F, Ngo C, Fourchotte V, Pollet AG. Institut
Curie, Paris, French Polynesia.
5100
Tumor stage of the primary breast cancer is a predictor of
the size of local recurrence.
Kahlert SD, Roth J, Mayr D, Bauerfeind I, Friese K. Klinikum
Grosshadern, LMU, Munich, Germany.
5101
Minimally invasive excision of gynaecomastia - a novel and
effective surgical technique.
Qutob O, Garimella V, Ihsan N, Drew PJ. University of Hull, Hull,
United Kingdom; Hull and East Yorkshire Hospitals NHS Trust,
Hull, United Kingdom.
5083
Surgical follow up and clinical presentation of 142 of breast
papillary lesions diagnosed by ultrasound guided breast
biopsy.
Rizzo M, Lund MJ, Oprea G, Schniederjan M, Mosunjac M. Emory
University, School of Medicine, Atlanta, GA; Emory University,
Rollins School of Public Health, Atlanta, GA.
5084
Oncologic safety of nipple areola complex preservation for
breast cancer; 5 year follow-up result.
Lee SJ, Kang SH, Baek NW, Kim EM. Yeungnam University of
Medical Center, Daegu, Republic of Korea.
5085
Breast surgery for women presenting with stage IV breast
cancer.
Barkley CR, Bafford AC, Burstein HJ, Winer EP, Lipsitz SR, Smith
BL, Iglehart JD, Golshan M. Brigham and Women’s Hospital,
Boston, MA; Dana Farber Cancer Institute, Boston, MA;
Massachusetts General Hospital, Boston, MA.
5086
Can the resection of primary breast cancer improve survival
of patients with stage IV breast cancer?
Shien T, Kinoshita T, Shimizu C, Yonemori K, Kohno T, Hojo T,
Ando M, Akashi-Tanaka S, Katsumata N, Fujiwara Y. National
Cancer Center Hospital, Tokyo, Japan.
5087
Cosmetic outcome after latissimus dorsi based breast
reconstruction: comparing the effects of radiotherapy and
time.
Thomson HJ, Greenwood RJ, Bahl A, Cawthorn S, Winters ZE.
University of Bristol, Bristol, United Kingdom; United Bristol
Healthcare Trust, Bristol, United Kingdom; Bristol Haematology
and Oncology Centre, Bristol, United Kingdom; Frenchay
Hospital, Bristol, United Kingdom.
5088
Interval inset of TRAM flaps in immediate breast
reconstruction: a technical refinement.
Comizio R, Yurkewich K, Collins D. Darmouth Hitchcock Medical
Center, Lebanon, NH; Dartmouth Medical School, Hanover, NH;
Norris Cotton Cancer Center, Lebanon, NH.
5089
Immediate two-stage breast reconstruction and irradiation
with a tissue expander and an implant: results, risk factors
for failure and self-evaluation.
Gurriet B, Padovani L, Tallet A, Letrosne E, VAINI V, Boyer A,
Houvenaeghel G, Cowen D. Hop Timone, Marseille, France; IPC
Cancer Center, Marseille, France; Axium Clinic, Aix en Provence,
France; Etoile Clinic, Puyricard, France.
5090
Skin-sparing mastectomy and immediate ‘mini-flap’
reconstruction - a novel technique.
Vestey SB, Court FG, Bristol JB, Ghilchick M, Chan CY.
Cheltenham General Hospital, Cheltenham, Gloucestershire,
United Kingdom.
Tumor Cell Biology: Estrogen and Progestin Receptors 5102-5109
5102
Evidences that progesterone receptor b decreases estrogen
receptor gene expression through its interaction to a halfPRE site at estrogen receptor gene promoter.
De Amicis F, Zupo S, Malivindi R, Andò S. University of Calabria,
Arcavacata di Rende, Italy.
5103
Influence of estrogen receptor expression on HER2 mRNA
levels in HER2-gene amplified breast cancer tumors as
measured using FISH and the novel DASL assay.
Abramovitz M, Audet R, Catzavelos C, Li Z, Provencher C,
Ponton A, Leyland-Jones B. VM Institute of Research, Montreal,
QC, Canada; McGIll University, Montreal, QC, Canada; Emory
University, Atlanta, GA.
5104
Detection of elevated HER2/neu levels in breast cancer cell
lines overexpressing estrogen receptor ĝ.
Lattrich C, Juhasz-Böss I, Ortmann O, Treeck O. University of
Regensburg, Regensburg, Germany.
5105
5106
5107
5108
5109
5114
Biomarker analyses in Japanese refractory advanced breast
cancer patients treated with lapatinib monotherapy.
Toi M, Iwata H, Fujiwara Y, Wakamatsu T, Kanezaki M, Katsura
K, Koehler M, Ellis C, Gagnon R, Allen K, Martin AM, Sasaki Y,
Takashima S. Tokyo Metropolitan Komagome Hosp, Japan; Aichi
Cancer Ctr Hosp, Japan; Nat. Cancer Ctr, Tokyo, Japan; GSK,
Japan; GSK, PA; Saitama Med Univ, Japan; Shikoku Cancer Ctr,
Ehime, Japan.
5115
EGFR, pAkt and pPI-3 kinase are co-expressed in circulating
tumor cells of breast cancer patients.
Kallergi G, Kalykaki A, Agelaki S, Mavroudis D, Georgoulias V.
School of Medicine, University of Crete, Heraklion, Crete, Greece;
University General Hospital of Heraklion, Heraklion, Crete,
Greece.
5116
Expression of estrogen receptors ĝ in triple negative breast
cancer.
Litwiniuk M, Filas V, Breborowicz J. Poznan University of Medical
Sciences, Poznan, Poland.
CD146-downstream signaling mediating breast tumour
invasion/metastasis.
Yousief ZA, Abdraboh ME, Masood HM, Ouhtit A. Louisiana
State University Health Sciences Center; Stanley S Scott Cancer
Center, New Orleans, LA.
5117
Immunohistochemical expression of CK5/6, CK17, ERß in
triple negative breast cancer patients.
Liu Z, Wu J, Ping B, Shao Z, Shen Z. Cancer Hospital, Shanghai,
China.
Xenograft model for the evaluation of breast cancer
metastatic progression.
Zang XP, Lerner MR, Brackett DJ, Pento JT. University of
Oklahoma, HSC, Oklahoma City, OK.
5118
High phosphorylation of estrogen receptor Ĝ serine 167 and
low p53 protein accumulation improve survival in estrogen
receptor-positive breast cancer patients treated with
tamoxifen.
Sugiura H, Toyama T, Kondo N, Kobayashi S, Fujii Y, Yamashita
H. Nagoya City University Graduate School of Medical Science,
Nagoya, Aichi, Japan.
Rhodiola crenulata decreases invasion and regulates
cyclooxygenase-2 expression in a highly metastatic
ER-negative breast cancer cell line.
Doerner JL, Smith-Schneider S, Arenas RB. University of
Massachusetts, Amherst, MA; Pioneer Valley Life Sciences
Institute, Springfield, MA; Baystate Medical Center, Springfield,
MA.
5119
Lymphangiogenesis in breast cancer: correlation with
lymphatic microvessel density and clinicopathologic
parameters.
Lee I-k, Park Y, Kim D, Jo B-h, Lee W, Yoon S, Kim H, Park S-y.
MizMedi Hospital, Seoul, Korea.
Mammary fibroblasts express ERĝ1 and ERĝ2 and can
modulate breast cancer behaviour in a co-culture model.
Green CA, Scott DJ, Hughes TA, Cummings M, Hanby AM,
Shaaban AA, Speirs V. University of Leeds, Leeds, W Yorks,
United Kingdom.
Characterization of estrogen receptor positive breast
cancers: gene expression analysis of archived tumours.
Thorat M, Morimiya A, Sledge G, Badve S. Indiana University,
Indianapolis, IN.
Tumor Cell Biology: Metastasis / Invasion 5110-5119
5110
5111
5112
5113
7:00-9:30
Controversies in Adjuvant Endocrine Therapy for Breast Cancer
Identification of gene expression differences in primary
breast tumors from node-negative and node-positive
women.
Field LA, Seebach JF, Love BJ, Deyarmin B, Kane J, Hooke JA,
Ellsworth RE, Shriver CD. Windber Research Institute, Windber,
PA; Walter Reed Army Medical Center, Washington, DC;
Invitrogen Informatics, Carlsbad, CA.
Sponsored by Physicians Education Resource
Register on line at: www.adjuvantai.cancerconferences.com
For information, contact:
Kathryn Wallace
214-367-3329
Fax: 214-367-3303
[email protected]
Identification of a gene expression breast cancer metastasis
profile.
Seebach J, Field LA, Love B, Hollern K, Hooke JA, Ellsworth RE,
Shriver CD. Walter Reed Army Medical Center, Washington, DC;
Windber Research Institute, Windber, PA; Invitrogen Informatics,
Carlsbad, CA.
Genomic discrimination of metastatic from non-metastatic
primary breast tumors.
Ellsworth RE, Patney HL, Ellsworth DL, Love B, Hooke JA, Shriver
CD. Windber Research Institute, Windber, PA; Invitrogen
Informatics, Carlsbad, CA; Walter Reed Army Medical Center,
Washington, DC.
Tumor microenvironment in breast cancer metastasis: direct
tissue protein profiling of tumor-associated stroma from
invasive breast cancer patients with versus without axillary
lymph node metastasis.
Ellsworth DL, Seeley EH, Ellsworth RE, Deyarmin B, Sanders ME,
Hooke JA, Caprioli RM, Shriver CD. Windber Research Institute,
Windber, PA; Vanderbilt University, Nashville, TN; Walter Reed
Army Medical Center, Washington, DC.
SATELLITE SYMPOSIUM - Ballroom A
Supported by an educational grant from Novartis
Pharmaceuticals Corporation
Sunday, December 
7:00-9:00
BREAKFAST – Exhibit Hall B
(#6001-6119, 5015)
Prognosis and Response Predictions: Prognostic Factors II
6001-6034
6001
Loss of nuclear p27 is independently associated with young
age at breast cancer diagnosis.
DeMichele A, Mick R, Beaver J, Ruddy K, Sherman L, McNally
S, Acs G, Wang Y, Feldman M, Norman S, Rebbeck T, Lee W,
Weber B. University of Pennsylvania, Philadelphia, PA.
6002
Stratifying primary operable breast cancers by steroid and
HER-2 expression status predicts short term disease free
survival.
Brouckaert O, Pintens S, Van Belle V, Van Huffel S, Amant F,
Leunen K, Smeets A, Berteloot P, Van Limbergen E, Decock J,
Hendrickx W, Weltens C, Van den Bogaert W, Vanden Bempt I,
Drijkoningen M, Paridaens R, Wildiers H, Vergote I, Christiaens
M-R, Neven P. UZ Leuven, Leuven, Belgium; ESAT; UZ Leuven.
6003
Comparison of prognostic value of hormonal receptors (HR)
and HER-2 overexpression on overall survival (OS) in breast
cancer.
Tacca O, Abrial C, Penault-Llorca F, Mouret-Reynier M-A,
Raoelfils I, Ferrière J-P, Gimbergues P, Curé H, Chollet P, Durando
X. Centre Jean Perrin, Clermont Ferrand, France; INSERM U484,
Clermont Ferrand, France; Université d’Auvergne, Clermont
Ferrand, France; Institut Jean Godinot, Reims, France.
6004
6005
6006
6007
6008
Correlation of ER/PR status and HER-2 status in invasive
breast carcinoma.
Bloom KJ, Kyshtoobayeva A, Chen S, Hii A. CLARiENT, Aliso
Viejo, CA.
Prognostic significance of HER2 status in women with
inflammatory breast cancer.
Dawood S, Broglio K, Yang W-T, Cristofanilli M, Kau S-W,
Hortobagyi GN, Gonzalez-Angulo AM. MD Anderson Cancer
Center, Houston, TX.
Validation of an immunohistochemical biomarker for
identifying Her2+ patients at high risk of recurrence.
Seitz RS, Ross DT, Ring BZ, Beck RA, Khoury T, Vardarajan R, Iqbal
J, Kulkarni S, Janarthanan BR, Hicks DG. Applied Genomics, Inc,
Huntsville, AL; Applied Genomics, Inc, Burlingame, CA; Roswell
Park Cancer Institute, Buffalo, NY.
Prognostic value of both HER-2 and VEGF-A mRNA overexpression in primary tumors of high-risk breast cancer
patients.
Fountzilas G, Skarlos D, Wirtz RM, Dafni U, Stropp U, Pectasides
D, Papakostas P, Markopoulos C, Karapanagiotis K, Polichronis
A, Timotheadou E, Grimani I, Samantas E, Kosmidis P, Kalogeras
KT. Hellenic Cooperative Oncology Group (HeCOG), Athens,
Greece; Siemens Medical Solutions Diagnostics GmbH,
Leverkusen, Germany.
The pathological characteristics of gestational breast cancer.
What is different?
Ives A, Harvey J, Sterrett G, Saunders C, Semmens J. The
University of Western Australia, Perth, WA, Australia; PathWest,
Perth, WA, Australia; Curtin University of Technology, Perth, WA,
Australia.
6009
The mitotic activity index is able to separate two prognostic
subgroups in grade II estrogen receptor (ER)-positive nodenegative breast carcinomas.
Geha S, Mazouni C, Spielmann M, Garbay J-R, Bourgier C,
Delaloge S, Andre F, Mathieu M-C. Institut Gustave-Roussy,
Villejuif, France; Hopital La Timone, Marseille, France.
6010
Assessing final pathological response to neoadjuvant
chemotherapy using diffuse optical spectroscopy.
Tanamai VW, Cerussi AE, Hsiang D, Mehta R, Tromberg BJ.
University of California, Irvine, CA.
6011
The ProEx Br immunohistochemical assay has prognostic
utility in early stage breast cancer using a manual scoring
method.
Chatterjee A, He Q, Nelson R, Gore M, Hudson R, Murphy PG,
Malinoski D, Fisher TJ, Bigras G, Hugh J, Whitehead CM. BD
Diagnostics Tripath, Durham, NC; Dynacare Kasper Medical
Laboratories, Edmonton, AB, Canada.
6012
CXCR4 coexpression with EGFR/HER2 positivity in breast
cancer is a poor prognostic factor in patients with isolated
tumor cells in bone marrow.
Cabioglu N, Igci A, Ozmen V, Muslumanoglu M, Dagoglu
T, Sahin AA, Yildirim EO, Aktas E, Bilgic S, Price JE, Deniz G,
Kecer M. University of Istanbul, Istanbul Medical Faculty,
Istanbul, Turkey; UT MD Anderson Cancer Institute, Houston,
TX; University of Istanbul, Institute of Experimental Medical
Research, Istanbul, Turkey; UT MD Anderson Cancer Center,
Houston, TX.
6013
Characterization of a good prognosis set of genes in breast
cancer patients with at least 5 involved lymph nodes.
Sevenet N, Badel A, Marquand E, Cuvier C, de Roquancourt A,
Geneix C, Janin A, Launay J-M, Cottu PH, Camproux A-C, Marc E.
Hospital Lariboisiere, Paris, France; Universite Denis Diderot, Paris,
France; Hospital Saint Louis, Paris, France; Institut Curie, Paris,
France.
6014
Cytogenetic heterogeneity within breast tumor specimens is
revealed by the eXagenBC test.
Davis LM, Tang L, Carpio C, Garcia N, Bauer R, Perrine M,
Sanchez L, Chakraborty S, Zhou F, Flejter W, Tepperberg J,
Alsobrook J. Exagen Diagnostics, Albuquerque, NM; LabCorp
America, Brentwood, TN; LabCorp America, Research Triangle
Park, NC.
6015
An alternatively spliced variant of cyclin D1 is present in
human breast carcinoma.
Gupta-Abramson V, Feldman M, Troxel A, Wang Y, Sherman
L, McNally S, Lee W, Diehl A, DeMichele A. University of
Pennsylvania, Philadelphia, PA.
6016
Evaluation of prognostic factors influencing the therapeutic
management of post-treatment metastatic breast cancer. A
retrospective study on 1096 patients who have been treated
between 1980 to 2005 at the Centre Antoine Lacassagne.
Largillier R, Chamorey E, Doyen J, Courdi A, Ettore F, Maestro C,
Raoust I, Lallement M, Namer M, Ferrero JM. Centre Antoine
Lacassagne, Nice, France.
6017
Brain metastases in HER2+ metastatic breast cancer
patients: analysis of prognostic factors.
Henry S, Pierga J-Y, Asselah J, Cottu P, Mignot L, Sigal-Zafrani B,
Bollet M, Diéras V. Institut Curie, Paris, France.
6018
Clinical outcome of patients with triple negative breast
cancer who develop brain metastasis.
Hines SL, Vallow L, Tan W, Jain A, Perez E. Mayo Clinic,
Jacksonville, FL.
6019
Characteristics of breast cancer patients with central
nervous system metastases and factors associated with
survival after development of central nervous system
metastasis.
Harputluoglu H, Dizdar O, Aksoy S, Kilickap S, Dede DS, Ozisik Y,
Guler N, Barista I, Gullu I, Selek U, Cengiz M, Zorlu F, Tekuzman
G, Altundag K. Hacettepe University Institute of Oncology,
Ankara, Turkey.
6020
Brain metastases in breast cancer: a retrospective
cohort study of 187 patients and prognostic markers
determination.
Svoboda M, Fabian P, Ondrova B, Palacova M, Grell P,
Gombosova J, Princ D, Slaby O, Slampa P, Vyzula R. Masaryk
Memorial Cancer Institute, Brno, Czech Republic.
6022
Topoisomerase 2 Ĝ gene amplification and protein
expression in fresh and recurrent breast cancers.
Tseng LM, Liu JM, Lan C, Lin LC, Hsu DH, Chang CP, Kao HL.
Taipei-Veterans General Hospital and National Yang Ming
University Medical School, Taipei, Taiwan; National Health
Research Institutes, Taipei, Taiwan; Roch Products Ltd., Taipei,
Taiwan.
6023
6024
6025
6026
6027
Cyclin-dependent kinase 1 and 2 activity as prognostic
markers in early breast cancer.
van Nes JGH, Smit VTHBM, Putter H, Kuppen PJ, Kim SJ, Masuda
N, Inaji H, Yoshidome K, Tsujimoto M, Akiyama F, Tsukamoto
F, Ishihara H, Noguchi S, van de Velde CJH. Leiden University
Medical Centre (LUMC), Leiden, Netherlands; LUMC, Leiden,
Netherlands; Graduate School of Medicine, Osaka Univ., Suita,
Japan; Sysmex Corporation, Kobe, Japan; Osaka National Hospital,
Osaka, Japan; Osaka Medical Center for Cancer & Cardiovascular
Diseases, Osaka, Japan; Osaka Police Hospital, Osaka, Japan;
Cancer Institute Hospital, Koto-ku, Japan; Osaka Kosei-Nenkin
Hospital, Osaka, Japan.
Prognosis and clinical outcome of patients with node
negative ≤ 1cm breast cancer.
Amar S, Ann ME, Geiger XJ, Rebecca MB, Winston T, Kyle
CE, Beiyun C, Boughey JC, Edith PA. Mayo Clinic Jacksonville,
Jacksonville, FL; Mayo Clinic Scottsdale, Scottsdale, AZ; Mayo
Clinic Rochester, Rochester, MN.
MAPK expression is associated with poor outcome in
patients with hormone receptor negative breast cancer.
Eralp Y, Derin D, Ozluk Y, Yavuz E, Guney N, Saip P,
Muslumanoglu M, Igci A, Kucucuk S, Dincer M, Aydiner A,
Topuz E. Istanbul University Institute of Oncology, Istanbul,
Turkey; Istanbul University, Istanbul Medical Faculty, Istanbul,
Turkey.
The role of the stromal immune response in breast cancer
recurrence.
Hall JA, Bertos N, Finak G, Pepin F, Zhao H, Sadekova S,
Meterissian S, Hallett M, Park M. McGill University, Montreal,
QC, Canada.
Comparison of patients with “triple negative” breast cancer
(ER-, PR-, HER2-) in a cohort of 1052 patients treated in a
single institution between 1999 and 2007.
Kantelhardt EJ, Pauli N, Grosse R, Vetter M, Holzhausen HJ,
Strauss HG, Thomssen C. Martin Luther University, Halle,
Germany.
6028
Obesity at diagnosis increases relapse rate and shortens
disease free interval in breast cancer patients.
Quispe D, Hussain S, Leveau MQ, Mansour R, Burton GV, Shi
R, Sun A. Louisiana State University Health Sciences Center,
Shreveport, LA.
6029
Elevated MIB-1(%) and c-myc amplification are relevant
prognosticators of ER positive/HER2 negative (“luminal A”)
primary breast cancers.
Schlotter CM, Wassmann K, Vogt U. Klinikum Ibbenbueren,
Ibbenbueren, NRW, Germany; European Laboratory Association,
Ibbenbueren, NRW, Germany.
6030
Allelic imbalance and predictors of outcome in ipsilateral
breast tumor recurrences after systemic therapy for early
Zekman R, Jaiyesimi I, Nadeau L, Mitchell C, Wallace M, McGrath
S, Wills S, Goldstein N, Vicini F. Division of Hematology/
Oncology; William Beaumont Hospital, Royal Oak, MI.
6031
Impact of progesterone receptor (PR) status on survival of
estrogen receptor (ER) positive women with invasive breast
cancer (IBC).
Ingle AM, Kumar P, Dagen T, Day K, Baney B, Galley AS.
Children’s Oncology Group, Arcadia, CA; Mount Nittany Medical
Center, State College, PA.
6032
Tumor biology of breast carcinoma in elderly women:
comparison between elderly and young postmenopausal
women.
Okanami Y, Iwase T, Kimura K, Morizono H, IIjima K, Miyagi
Y, Nishimura S, Tada K, Makita M, Horii R, Akiyama F. Cancer
Institute, Koto-ku, Ariake 3-10-6, Tokyo, Japan.
6033
A community-based single institution registry study of
treatment outcomes in breast cancer patients with 4 or
more positive lymph nodes.
Rivkin SE, Moon J, Atwood M, Tennent N. Swedish Medical
Center, Seattle, WA.
6034
HMGA2 with uPAI/PAI-1 as prognostic factors in node
negative breast cancer patients.
Wischnewsky M, Boecker W, Meyer A, Milde-Langosch K,
Bullerdiek J. University of Bremen, Bremen, Germany; University
of Muenster, Muenster, Germany; University Hospital HamburgEppendorf, Hamburg, Germany.
Epidemiology and Outreach: Advocacy/Education 6035-6046
6035
Defining endpoints for recurrence in randomized controlled
trials of systemic therapy for early breast cancer: a call for
standardization.
Kilburn LS, Peckitt C, Ireland E, Bliss JM. The Institute of Cancer
Research, Sutton, Surrey, United Kingdom.
6036
Has the quality of early breast cancer randomized controlled
trials publications improved since CONSORT? A systematic
review.
Peckitt C, Ireland E, Kilburn LS, Bliss JM. The Institute of Cancer
Research, Sutton, Surrey, United Kingdom.
6037
Moving from informed consent to informed choice: an
ethical imperative.
Devine P, Perlmutter J, Carbine N, Chingos D, Brady C. Cancer
Information & Support Network (CISN), Auburn, CA.
6038
BreastCancerTrials.org: from regional pilot to nation-wide
clinical trial matching service.
Cohen EJ, Bechtold T, Laird J, Anand A, Ernest ML, Pederson,
Melisko M, Park J, Hogarth M, Esserman LJ. UCSF, San Francisco,
CA; UC Davis, Davis, CA.
6039
Inflammatory breast cancer biorepository: research
collaboration.
Mason G, Johnson O. Inflammatory Breast Cancer Research
Foundation, Bainbridge Island, WA.
6040
Community-based outreach is an effective strategy for
linking underserved women to breast cancer screening: data
from the Avon Foundation Breast Care Fund.
Opdyke KM, Gujrati ML, McCulloch A, Gates-Ferris K, Hurlbert
M. Cicatelli Associates Inc., New York, NY; Avon Foundation
Breast Cancer Crusade, New York, NY.
6041
Improving access to care in an AVON Foundation
Comprehensive Breast Center (AFCBC) serving a
predominantly urban African American (AA) patient
population.
Gabram S, Lund MJ, Lamson P, Harrison C, Koenig E, Bates S,
Bumpers H, Green V, Gundry K, Okoli J, Rizzo M, Roberson S,
Brawley O. Winship Cancer Institute, Emory University; Georgia
Cancer Center for Excellence at Grady; Rollins School of Public
Health, Emory University; Morehouse School of Medicine,
Atlanta, GA.
6042
A comprehensive diagnostic program for medically
underserved women with abnormal breast screening
evaluations in an urban population.
Palmieri FM, DePeri ER, Mincey BA, Smith JA, Wen LK,
Chewar DM, Perez EA. Mayo Clinic, Jacksonville, FL; First Coast
Dermatology and Internal Medicine, Jacksonville Beach, FL; Pfizer
Oncology, New York, NY.
6043
Enhancing communication between oncologists and breast
cancer patients.
Kirk MC, Parker B. Y-ME National Breast Cancer Organization,
Chicago, IL.
6044
Upfront: new perspectives on breast cancer – report by
the Canadian Breast Cancer Foundation-Ontario Chapter
(CBCF-OC).
Easton B, Trussler T, Wood S, Verma S. Canadian Breast Cancer
Foundation, Ontario Chapter, Toronto, ON, Canada; Ottawa
Regional Cancer Center, Ottawa, ON, Canada.
6055
Incidence and tumor characteristics of breast cancer
diagnosed before and after implementation of a
population-based screening-program.
Hofvind S, Sørum R, Thoresen S. The Cancer Registry of
Norway, Oslo, Norway; University of Vermont, Burlington,
VT; GlaxoSmithKline Norway, Oslo, Norway.
6045
Counselling women with breast cancer - whose line is it
anyway?
Court FG, Scarrott S, Cassidy-Gray M, Thomas A, Vestey S,
Bristol J, Ghilchik M, Chan HY. Cheltenham General Hospital,
Cheltenham, United Kingdom.
6056
6046
Identification and prioritization of unmet medical,
educational and psychosocial needs in patients with
metastatic breast cancer: results of a patient survey.
Kirk M. Y-ME National Breast Cancer Organization, Chicago, IL.
The wish for pregnancy after breast cancer, results of a
French survey on 269 youngs breast cancer survivors.
Dupré P-FPF, Menez-Orieux CC, Dravet FF, Barrière PP,
Classe J-MJM. University Hospital of Brest, Brest, Finistère,
France; University Hospital of Nantes, Nantes, Loire
Atlantique, France; Anti Cancer Center, Saint Herblain,
Loire-Atlantique, France.
6057
Survival of breast cancer over the last 30 years in a
cohort of 7651 women and up-to-date estimates for
patients recently diagnosed.
Huiart L, Bardou V-J, Jacquemier J, Puig B, Tallet A, Reyrat E,
Tarpin C, Buttarelli M, Extra J-M, Houvenaeghel G. Institut
Paoli-Calmettes; FNCLCC, Paris; Institut Paoli-Calmettes,
Marseille, France.
6058
Ethnicity, multiparity and the risk of premenopausal
breast cancer. A population-based, multi-ethnic study
from Singapore.
Verkooijen HM, Yap K, Bhalla V, Chow KY, Chia KS.
National University of Singapore, Singapore, Singapore;
Geneva University, Geneva, Switzerland; Health Promotion
Board, Singapore, Singapore.
6059
Time distribution of the recurrence risk for Chinese
breast cancer patients undergoing surgery.
Yin W, Lu J, Liu G, Di G, Wu J, Shen K, Shen Z, Shao Z.
Cancer Hospital/Cancer Institute, Fudan University,
Shanghai, China.
6060
The rates of chemotherapy-induced amenorrhea in
patients treated with different regimen at different
ages in Chinese breast cancer paients.
Zhou L, Yin W, Lu J, Di G, Wu J, Shen K, Han Q, Shen Z,
Shao Z. Cancer Hospital, Shanghai, China.
Epidemiology and Outreach: Epidemiology 6047-6060
6047
6048
6049
A family history of breast or ovarian cancer further increases
the risk of secondary leukemia, especially chronic leukemia,
in breast cancer patients.
Verkooijen HM, Fioretta G, Rapiti E, Vlastos G, Neyroud-Caspar
I, Chappuis PO, Bouchardy C. Geneva Unversity, Geneva,
Switzerland; National University of Singapore, Singapore,
Singapore; Geneva University Hospitals, Geneva, Switzerland.
HER2 status in a US population-based cohort: results from
a tissue microarray-based analysis of 2,898 breast cancers
from women enrolled in the nurses’ health study.
Tamimi RM, Deitz AC, Schnitt SJ, Colditz GA, Collins LC. Brigham
and Women’s Hospital and Harvard School of Public Health,
Boston, MA; GlaxoSmithKline, Philadelphia, PA; Beth Israel
Deaconess Medical Center and Harvard Medical School, Boston,
MA; Washington University School of Medicine, St. Louis, MO.
registHER: patient characteristics and time course of CNS
metastases in patients with HER2-positive metastatic breast
cancer.
Yardley DA, Kaufman PA, Mayer M, Ulcickas Yood M, Tan-Chiu
E, Brufsky AM, Rugo HS, Tripathy D, Brammer MG, Paik S. Sarah
Cannon Research Institute, Nashville, TN; Dartmouth-Hitchcock
Medical Center, Lebanon, NH; Patient Advocate, New York, NY;
EpiSource LLC, Yale University School of Medicine, New Haven,
CT; Florida Cancer Care, Tamarac, FL; University of Pittsburgh
Cancer Center, Pittsburgh, PA; UCSF Comprehensive Cancer
Center, San Francisco, CA; University of Texas Southwestern
Medical Center, Dallas, TX; Genentech, Inc., South San Francisco,
CA; National Surgical Breast and Bowel Project, Pittsburgh, PA.
6050
Short-term cancer risk in a cohort of 2,353 women with
high-risk breast lesions.
Shim V, Puliganda B, Collins L, Jiang SF, Callahan ME, Kutner S,
Habel LA. Kaiser Permanente, Oakland, CA; Beth Israel Deaconess
Medical Center, Boston, CA; Kaiser Permanente, Santa Teresa,
CA.
6051
Carcinoma and atypical hyperplasia are frequent findings
in women with macromastia undergoing reduction
mammoplasty: a prospective study.
Ambaye AB, Goodwin A, MacLennan SE, Suppan T, Naud S,
Weaver DL. Pathology; University of Vermont, Burlington, VT.
6052
Osteoporosis and breast cancer treatment.
Quispe D, Shi R, Leveau MQ, Burton G, Sun A. Louisiana State
University Health Sciences Center, Shreveport, LA.
6053
Prevalence of anemia in hospitalized French cancer patients:
results of a one-day cross-sectional survey.
Delaloge S, Hennequin C, Lemarie E, Zureik M, Castaigne S,
Tourani J-M. Institut Gustave Roussy, Villejuif Cedex, France;
Hopital Saint Louis, Paris, France; CHU - Hopital Bretonneau,
Tours Cedex, France; Faculte de Medecine Bichat, Paris, France;
Hopital Andre Mignot, Le Chesnay, France; CHU - Hopital La
Miletrie, Poitier Cedex, France.
Treatment: Chemotherapy - New Drugs and Formulations
6061-6074
6061
HKI-272, an irreversible pan erbB receptor tyrosine
kinase inhibitor: preliminary phase 2 results in patients
with advanced breast cancer.
Burstein H, Awada A, Badwe R, Dirix L, Tan A, Jacod S,
Lustgarten S, Vermette J, Zacharchuk C. Dana Farber
Cancer Institute, Boston, MA; Medical Oncology Clinic,
Brussels, Belgium; Tata Memorial Hospital, Mumbai, India;
Medische Oncologie, Wilrijk, Belgium; Cancer Institute
of New Jersey, New Brunswick, NJ; Wyeth Research, Paris,
France; Wyeth Research, Cambridge, MA.
6062
Preliminary results of a phase 2 study of bosutinib (SKI606), a dual Src/Abl kinase inhibitor, in patients with
advanced breast cancer.
Campone M, Bondarenko I, Brincat S, Epstein RJ, Munster
PN, Dubois E, Martin EC, Turnbull K, Zacharchuk C. Centre
René Gauducheau, St. Herblain, France; Dnepropetrovsk
State Medical Academy, Dnepropetrovsk, Ukraine; Sir
Paul Boffa Hospital, Floriana, Malta; Queen Mary Hospital,
Pokfulam, Hong Kong; H. Lee Moffitt Cancer Center,
Tampa, FL; Wyeth Research, Paris, France; Wyeth Research,
Cambridge, MA.
6063
mTOR inhibitor nanoparticle albumin-bound (nab)
rapamycin is effective in a breast cancer xenograft
model.
Trieu V, De T, Yim Z, Cordia J, Yang A, Beals B, Ci S, Nguyen
P, Louie L, Desai N. Abraxis BioScience, Inc., Los Angeles, CA.
6064
6065
6066
A multicenter phase Ib study of the safety,
pharmacokinetics, biological activity and clinical efficacy of
INCB7839, a potent and selective inhibitor of ADAM10 and
ADAM17.
Infante J, Burris HA, Lewis N, Donehower R, Redman J, Friedman
S, Scherle P, Fridman J, Li J, Emm T, Troy S, Eckhardt SG. Sarah
Cannon Research Institute, Nashville, TN; Fox Chase Cancer
Center, Philadelphia, PA; Johns Hopkins Cancer Center, Baltimore,
MD; Incyte Corporation, Wilmington, DE; University of Colorado
Health Sciences Center, Denver, CO.
Preclinical characterization of INCB7839, a potent and
selective inhibitor of ErbB ligand and HER2 receptor
shedding: inhibition of ADAM10 and ADAM17 for the
treatment of breast cancer.
Fridman JS, Scherle PA, Liu X, Caulder E, Hansbury M, Yang
G, Wang Q, Lo Y, Zhou J, Yao W, Newton RC, Yeleswaram S,
Friedman SM, Vaddi K. Incyte Corporation, Wilmington, DE.
Tanespimycin (an Hsp90 inhibitor) and trastuzumab is an
active combination in patients (pts) with Her2-positive
trastuzumab-refractory metastatic breast cancer (MBC):
phase 2 trial.
Modi S, Stopeck A, Kinden H, Sugarman S, Ma W, Solit D, Kersey
K, Johnson R, Hannah AL, Hudis C. Memorial Sloan-Kettering
Cancer Center, New York, NY; Arizona Cancer Center, Tucson,
AZ; Seattle Cancer Care Alliance, Seattle, WA; Kosan Biosciences,
Hayward, CA.
6067
Withdrawn.
6068
CTEP-sponsored phase I/II trial of paclitaxel and low dose
suramin in metastatic breast cancer.
Shapiro CL, Sheils D, Barton L, Young D, Shen T, Chen L, Wei
Y, Au J. The Ohio State University Medical Center and James
Cancer Hospital, Columbus, OH; The Ohio State University
Medical Center and Comprehensive Cancer Center, Columbus,
OH; The Ohio State University, Columbus, OH.
6069
Combination therapy with the novel epothilone B analog,
ixabepilone, plus capecitabine has efficacy in ER/PR/HER2negative breast cancer resistant to anthracyclines and
taxanes.
Rugo HS, Thomas ES, Lee RK, Fein LE, Peck R, Verrill M. UCSF
Comprehensive Cancer Center, San Francisco, CA; Kaiser
Permanente, Oakland, CA; The St. Luke’s Medical Center,
Quezon City, Philippines; The Centro de Oncologia Rosario,
Sante Fe, Argentina; Bristol-Myers Squibb, Wallingford, CT;
Northern Institute for Cancer Research, Newcastle upon Tyne,
United Kingdom.
6070
A phase II trial of trastuzumab, weekly ixabepilone (BMS247550) and carboplatin (TIC) in patients with HER2/neupositive (HER2+) metastatic breast cancer (MBC): a trial
coordinated by the Eastern Cooperative Oncology Group
(E2103).
Moulder S, Wang M, Gradishar W, Perez EA, Sparano J, Pins M,
Sledge G. University of Texas, M.D. Anderson Cancer Center,
Houston, TX.
6071
A phase 1 study of ARRY-543, a potent, selective, reversible
inhibitor of ErbB receptors.
Gelmon K, Kane K, Kollmannsberger C, Maloney L, Gordon G,
D’Aloisio S, W C, Litwiler K, Berlin J, Rothenberg M. BC Cancer
Agency, Vancouver, BC, Canada; Vanderbilt-Ingram Cancer
Center, Nashville, TN; Array Biopharma, Boulder, CO.
6072
Identification of a small molecule estrogen related receptor
Ĝ specific antagonist that inhibits cell growth in MCF-7 and
T47D breast cancer cells.
Chisamore MJ, Cai S-J, Birzin ET, O’Donnell GT, Mosley RT,
Zuck PD, Flores OA, Schaeffer JM, Rohrer SP, Wilkinson HA.
Merck Research Laboratories, West Point, PA; Merck Research
Laboratories, Rahway, NJ; Merck Research Laboratories, North
Wales, PA.
6073
Exogenous histone H2A induces senescence and
differentiation in breast cancer cells.
Hadnagy A, Kaouass M, Mansour S, Beaulieu R, Balicki D. HôtelDieu du CHUM, Montréal, QC, Canada; Université de Montréal,
Montréal, QC, Canada.
6074
Safety and pharmacokinetics of motesanib diphosphate
(AMG 706) with paclitaxel or docetaxel for the treatment of
locally recurrent, unresectable or metastatic breast cancer.
de Boer R, White S, Mainwaring P, Koczwara B, Ye Y, Sun Y-N,
Parson M, Braun A, Kotasek D. Western Hospital, Footscray,
VIC, Australia; Austin Health, Heidelberg, VIC, Australia; Mater
Hospital, South Brisbane, QLD, Australia; Flinders Medical Centre,
Bedford Park, SA, Australia; Amgen Inc., Thousand Oaks, CA;
Ashford Cancer Centre, Ashford, SA, Australia.
Treatment: Other Therapies 6075-6086
6075
A prospective study to determine the prevalence of
hypovitaminosis D in women with early stage breast cancer
treated with an aromatase inhibitor and the benefit of
vitamin D supplementation on musculoskeletal symptoms
and overall QOL.
Khan QJ, Reddy PS, Kimler BF, Baxa SE, Sharma P, Fabian CJ.
University of Kansas Medical Center, Kansas City, KS; Cancer
Center of Kansas, Wichita, KS.
6076
Lapatinib and capecitabine for the treatment of brain
metastases in patients with HER2+ breast cancer - an
updated analysis from EGF105084.
Lin NU, Paul D, Dieras V, Liu M, Greil R, Roche H, Rubin SD,
Zembryki D, Oliva C, Jayawardene D, Winer EP. Dana-Farber
Cancer Institute, Boston, MA; Institut Jules Bordet, Brussels,
Belgium; Institut Curie, Paris, France; Lombardi Comprehensive
Cancer Center, Georgetown University Hospital; LKH,
Salzburg, Austria; Centre Claudius Regaud, Toulouse, France;
GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Greenford,
United Kingdom.
6077
Lapatinib Expanded Access Program (LEAP): design,
operation and initial safety data.
De Placido S, Link J, Conte PF, Tosi D, Kaufmann B, Byrne J,
Rosenlund J, Gress M, Zembryki D, Oliva C. Universita degli Studi
di Napoli Federico II, Italy; Breast Link Med Group, CA; Universita
degli Studi di Modena e Regio Emilia, Italy; Instituto Nazionale
per lo Studio e la Cura dei Tumori, Italy; Sheba Medical Centre,
Israel; GSK, PA; GSK, United Kingdom.
6078
A phase I study of sunitinib plus paclitaxel for first-line
treatment of advanced breast cancer: preliminary results.
Kozloff MF, Chuang E, Roy J, Starr A, Gowland PA, Tarpey MJ,
Collier M, Verk L, Kern K, Miller K. Ingalls Memorial Hospital,
Harvey, IL; Cornell University, New York, NY; Indiana University
Cancer Center, Indianapolis, IN; Pfizer Global Research and
Development, San Diego, CA.
6079
Exploratory evaluation of a sequential administration of
docetaxel and sunitinib in women with advanced breast
cancer.
Gianni L, Cardoso F, Mariani G, Isaksson-Friman E, BesseHammer T, Vigano L, Verk L, Rossi C, Giorgetti C, Bergh J. Istituto
Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy;
Institut Jules Bordet, Brussels, Belgium; Karolinska Institute and
University Hospital, Stockholm, Sweden; Pfizer Global Research
and Development, San Diego, CA; Pfizer Italia S.r.l., Milano, Italy.
6080
AZD2171 for refractory breast cancer: a phase 2 trial.
Mayer EL, Hamel S, Savoie J, Parker LM, Lin NU, Anderson K,
Heymach JV, Gelman R, Ivy SP, Winer EP, Burstein HJ. DanaFarber Cancer Institute, Boston, MA; The University of Texas
M. D. Anderson Cancer Center, Houston, TX; National Cancer
Institute, Rockville, MD.
6081
Vandetanib with docetaxel as second-line treatment for
advanced breast cancer: a double-blind, placebo controlled,
randomized phase II study.
Boer K, Lang I, Llombart-Cussac A, Andreasson I, Vivanco
GL, Sanders N, Pover GM, Murray E. St Margit Hospital,
Budapest, Hungary; National Institute of Oncology, Budapest,
Hungary; Hospital Universitario Arnau de Vilanova, Lleida,
Spain; Centrallasarettet, Vasteras, Sweden; Plaza de Cruces,
Bizkaia, Spain; AstraZeneca, Loughborough, United Kingdom;
AstraZeneca, Macclesfield, United Kingdom; New Groote Schuur
Hospital, Cape Town, South Africa.
6082
Preclinical efficacy in breast cancer xenografts and phase 1
results of PTC299, a novel VEGF expression inhibitor.
Hirawat S, Davis T, Weetall M, Elfring GL, Miller LL. PTC
Therapeutics Inc, South Plainfield, NJ.
6083
Radiofrequency ablation versus cryoablation of small breast
cancer with dedicated probes. Initial clinical experience.
Manenti G, Perretta T, Cossu E, Contino G, Gioia A, Bonanno
E, Masala S, Buonomo OC, Simonetti G. University Tor Vergata,
Roma, RM, Italy.
6084
Role of differing estrogen receptor status on the proliferative
effects of genistein.
Rajah TT, Du N, Drews N, Cohn R. DePaul University, Chicago, IL.
6094
Triple negative, “basal-like” breast cancer: an institutional
review.
Herms BT, Jain D, Chagpar AB. University of Louisville Health
Sciences Center, Louisville, KY.
6095
Assessment of efficacy and health related quality of life
of proprioceptive neuromuscular facilitation (PNF) arm
rehabilitation after surgical treatment of breast carcinoma.
Bonanni V, Contino G, Lezzerini S, Buonomo OC. University Tor
Vergata, Roma, RM, Italy.
6096
The physical therapist’s role in minimising impaired
shoulder movement after axillary dissection.
Tass DM. Capio Rivers Hospital, Sawbridgeworth, Hertfordshire,
United Kingdom.
6097
Management and outcome of elderly patients (70 and over)
with early stage breast cancer in rural community setting.
McCoy JA, McCoy MM, Tezcan AZ, Tezcan H. North Idaho
Cancer Center, Coeur d Alene, ID.
6098
High prevalence of vitamin D deficiency or insufficiency in
Presant CA, Bosserman L, Ampudia M. Wilshire Oncology
Medical Group, West Covina, CA.
Tumor Cell Biology: Molecular Biology 6099-6111
6085
Maintenance hormonal and immunotherapy in metastatic
breast cancer with a clinical benefit from anthracyclinepaclitaxel based induction chemotherapy.
Recchia F, Candeloro G, Necozione S, Rea S. Civilian Hospital,
Avezzano, AQ, Italy; Università degli Studi, L’Aquila, AQ, Italy.
6099
Changes in cyclins’ and CDKs’ mRNA expression during
neoadjuvant treatment with letrozole.
Larionov A, Murray E, Evans DB, Miller WR, Dixon JM. Western
General Hospital, Edinburgh, United Kingdom; Novartis Institutes
for BioMedical Research, Basel, Switzerland.
6086
Efficacy and safety of vaginal testosterone for atrophic
vaginitis in breast cancer patients on aromatase inhibitors: a
pilot study.
Witherby SM, Johnson JV, O’Brien P, Demers LM, Mount SL,
Muss HB. Fletcher Allen Health Care (FAHC)/University of
Vermont College of Medicine (UVM), Burlington, VT; FAHC/
UVM, Burlington, VT; The Pennsylvania State University, Hershey,
PA.
6100
Differences in recurrent genomic alterations between the
molecular subtypes of breast cancer.
Han W, Hwang K-T, Cho J, Jung E-M, Bae J-Y, Kang JJ, Yang S-J, Ko
E, Lee JW, Kim S-W, Park I-A, Noh D-Y. Seoul National University
College of Medicine, Seoul, Korea; Macrogen, Inc., Seoul, Korea.
6101
The corepressor SAFB in breast cancer - identification of
target genes.
Kaipparettu BA, Hille S, Tsimelzon A, Lee AV, Meyer R, Polo JM,
Melnick A, Steffi O. Baylor College of Medicine, Houston, TX;
Albert Einstein College of Medicine, Bronx, NY.
6102
The efficacy of sertraline for controlling menopausal
symptoms in women with breast cancer.
Wu M-F, Hilsenbeck SG, Tham Y-L, Kramer RM, Elledge RM,
Chang JC, Friedman LC. Baylor College of Medicine, Houston, TX;
University Hospitals Case Medical Center, Cleveland, OH.
Potential role of dopamine and cAMP-regulated
phosphoprotein, Mr 32000 (DARPP-32) in trastuzumab
response in breast cancer.
Narayan M, Kumar A, Lezon-Geyda K, Nairn AC, Harris LN. Yale
University, New Haven, CT.
6103
Persistent peripheral neuropathy in breast cancer survivors
treated with taxane chemotherapy.
Crew KD, Adelson K, Weimer LH, Raptis G, Brafman L, Fuentes D,
Ortiz Y, Hershman DL. Columbia University Medical Center, New
York, NY; Mailman School of Public Health, New York, NY.
Dysregulation of cofactor of BRCA1 expression in breast
cancers.
Sun J, Watkins G, Amleh A, Jiang WG, Li R. University of Texas
Health Science Center at San Antonio, San Antonio, TX; School
of Medicine Cardiff University, Cardiff, United Kingdom.
6104
Regulation of BRCA1 protein stability and its impact on
estrogen biosynthesis in ovarian granulosa cells.
Lu Y, Amleh A, Sun J, Li R, Hu Y. Institute of Biotechnology,
6105
A novel anti-Patched1 antibody can suppress hedgehog
signaling pathway in human breast carcinoma cells.
Kubo M, Nakamura M, Kameda C, Tanaka H, Koga K, Mikami
Y, Ikebe M, Tanaka M, Katano M. Graduate School of Medical
Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka,
Japan.
6106
MicroRNA expression in primary breast tumors.
Lowery AJ, Miller N, McNeill RE, Kerin MJ. National University of
Ireland Galway, Galway, Ireland.
6107
MicroRNAs in triple negative breast cancer.
Weidhaas J, Slack F. Yale University.
Treatment: Patient Management 6087-6098
6087
6088
6089
6090
6091
6092
Influence of chemotherapy on bone in premenopausal
Hadji P, Maskow C, Kalder M, Ziller V, Wagner U. PhilippsUniversity of Marburg, Marburg, Germany.
Standardized evaluation of regional and institutional breast
cancer outcomes.
Beatty JD, Rees J, Atwood M, Pugliese M, Bolejack V. Swedish
Cancer Institute, Seattle, WA.
Challenges in metastatic breast cancer: optimistic vs realistic
goals for treatment.
Sepucha K, Ozanne E, Partridge A, Moy B. Massachusetts General
Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA.
Differences in care of breast cancer patients in an
underinsured population.
Norton LE, Komenaka IK, Zork NM, Pennington, Jr RE, Clare SE,
Bowling MW, Goulet, Jr RJ. Indiana University, Indianapolis, IN.
6108
6109
The expression of gene transcripts of telomere-associated
genes in human breast cancer: correlation with clinicopathological parameters and clinical outcome.
Salhab M, Jiang WG, Newbold RF, Mokbel K. St George’s
University of London, London, United Kingdom; Cardiff
University School of Medicine, Cardiff, United Kingdom; Brunel
University, Uxbridge, Middlesex, United Kingdom.
Expression of the putative breast cancer gene “breast cancer
and salivary gland expression”; relationship with microRNA
154* and estrogen receptor status.
Lowery AJ, Miller N, Kerin MJ. National University of Ireland
Galway, Galway, Ireland.
6110
In vivo imaging of breast cancer using genetically engineered
light-emitting bacteria.
Park M, Yoon J, Jegal Y. Chonnam National University Hwasun
Hospital, Hwasun-eup, Jeollanam-do, Republic of Korea.
6111
The four and a half LIM-only protein 2 mediates repression
of Plk1 in breast cancer cells.
Martin BT, Kleiber K, Kaufmann M, Strebhardt K. Medical School,
University Frankfurt, Frankfurt/Main, Hessen, Germany.
6119
Rescheduled Poster
Detection and Diagnosis: Circulating Markers
5015
9:00-12:00
HER-2 gene amplification is a marker for global genomic
instability.
Ellsworth RE, Deyarmin B, Patney HL, Hooke JA, Shriver CD.
Windber Research Institute, Windber, PA; Walter Reed Army
Medical Center, Washington, DC.
6113
Array-CGH identifies CCNE1 amplification in ER/HER2
negative breast cancers.
Natrajan R, Rodriguez-Pinilla SM, Marchio C, Moreno-Bueno G,
Vatcheva R, Mahler-Araujo B, Lambros MBK, Mackay A, Palacios
J, Ashworth A, Reis-Filho JS. ICR, London, United Kingdom; CNIO,
Madrid, Spain; Instituto de Investigaciones Biomedicas Alberto
Sols, Madrid, Spain; HHUU Virgen del Rocio, Seville, Spain.
6114
Novel Mdm2 intron 1 single nucleotide polymorphisms and
their role in breast cancer.
Paulin FE, O’Neill M, McGregor G, Cassidy A, Ashfield A, Ali CW,
Baker L, Munro AJ, Lane DP, Thompson AM. Ninewells Hospital,
University of Dundee, Dundee, United Kingdom.
6115
HER2/TOP2A amplicon in breast cancer: a microarray-based
and chromogenic in situ hybridisation analysis.
Arriola E, Lambros MBK, Marchio C, Tan D, Natrajan R,
Rodriguez-Pinilla SM, Tamber N, Fenwick K, Mackay A, Jones C,
Dowsett, Ashworth A, Reis-Filho JS. Institute of Cancer Research,
London, United Kingdom; ICR, Sutton, United Kingdom.
6116
Genetic polymorphisms in the vascular endothelial growth
factor (VEGF) gene and breast cancer risk.
Langsenlehner T, Gerger A, Hofmann G, Kapp KS, Langsenlehner
U. Medical University of Graz, Graz, Austria.
6117
Molecular genetics and immunophenotypical
characterisation of micropapillary carcinomas of the breast.
Marchio C, Iravani M, Natrajan R, Lambros MBK, James M, Savage
K, Mackay A, Fenwick K, Tamber N, Schmitt FC, Ellis I, Bussolati
G, Sapino A, Ashworth A, Reis-Filho JS. Institute of Cancer
Research, London, United Kingdom; IPATIMUP, Porto, Portugal;
University of Nottingham, Nottingham, United Kingdom;
University of Torino, Torino, Italy.
6118
Impact of deleterious BRCA mutations and unclassified
BRCA variants upon breast cancer characteristics at
presentation.
Miolo G, La Mura N, Lombardi D, Scalone S, Della Puppa L, Magri
MD, De Giacomi C, Dolcetti R, Veronesi A, Viel A. Centro di
Riferimento Oncologico, Aviano, PN, Italy.
Heparanase expression in circulating lymphocytes of breast
cancer patients is induced by the primary tumor and/or by
distant metastasis.
Theodoro TR, de Matos LL, Lambiasi AVL, Pinhal MAS, del Giglio
A. Faculdade de Medicina da Fundação ABC, Santo André, Sãoi
Paulo, Brazil.
9:00
71. Disease-free survival according to local
immunohistochemistry for HER2 and central fluorescence
in situ hydridization for patients treated with adjuvant
chemotherapy with and without trastuzumab in the HERA
(BIG 01-01) trial.
McCaskill-Stevens W, Procter M, Goodbrand J, Azambuja E,
Leyland-Jones B, Ruschoff J, Dowsett M, Wermuth P, Dolci
S, Gelber RD, Piccart-Gebhart M. National Cancer Institute,
Bethesda, MD; Frontier Science, Kingussie, United Kingdom; Jules
Bordet Institute, Brussels, Belgium; Emory University, Atlanta, GA;
Klinikum Kasseland TARGOS Molecular Pathology Gmbh, Kassel,
Germany; Hoffmann-La Roche, Basel, Switzerland; Royal Marsden
National Health Service Trust, London, United Kingdom; DanaFarber Cancer Institute, Boston, MA.
9:15
72. 3-year follow-up of trastuzumab following adjuvant
chemotherapy in node positive HER2-positive breast cancer
patients: results of the PACS-04 trial.
Spielmann M, Roché H, Humblet Y, Delozier T, Bourgeois H,
Serin D, Romieu G, Canon JL, Monnier A, Piot G, Maerevoet M,
Orfeuvre H, Extra JM, Hardy AC, Martin AL, Kramar A, Genève J.
Inst Gustave Roussy, France; Inst Claudius Régaud, France; UCL
St-Luc, Belgium; Centre François Baclesse, France; CHU Poitiers,
France; Inst Ste Catherine, Avignon, France; Centre Val d’Aurelle,
France; CH ND Reine Fabiola, Belgium; CHG Montbelliard,
France; CMC les Ormeaux, Le Havre, France; Clinique St Pierre,
Ottignies, Belgium; CH Bourg en Bresse, France; Inst Curie, France;
Cl Armoricaine St Brieuc, France; FNCLCC, France
9:30
73. Safety of pertuzumab plus trastuzumab in a Phase II
trial of patients with HER2-overexpressing metastatic breast
cancer which had progressed during trastuzumab therapy.
Fumoleau P, Wardley A, Miles D, Verma S, Gelmon K, Cameron
D, Gianni L, Conte PF, Ross G, McNally V, Baselga J. Centre
Georges-François-Leclerc, Dijon, France; Christie Hospital,
Manchester, UK; Mount Vernon Cancer Centre, Middlesex, UK;
Ottawa Regional Cancer Center, Ottawa, ON, Canada; British
Columbia Cancer Agency, Vancouver, BC, Canada; Western
General Hospital, Edinburgh, UK; Oncologia Medica, Milano,
Italy; Divisione di Oncologia Medica, Modena, Italy; *Roche
products limited, Welwyn, UK; Vall d’Hebron University Hospital,
Barcelona, Spain.
9:45
74. Combination of nab-paclitaxel and bevacizumab
eradicates well-established tumors as well as lymphatic and
pulmonary metastases in a MDA-MB-231 model of a highly
metastatic human breast cancer.
Ran S, Volk L, Bivens C, Trieu V, Desai N. Southern Illinois
University, Springfield, IL; Abraxis BioScience, Inc., Los Angeles,
CA.
Tumor Cell Biology: Genetics 6112-6119
6112
Premature thelarche variant and estrogen receptor-Ĝ
coregulator single nucleotide polymorphisms.
Hartmaier RJ, Richter AS, Wit JM, Walenkamp MJE, Oesterreich
S. Baylor College of Medicine, Houston, TX; Leiden University
Medical Center, Leiden, Netherlands.
10:00
75. ErbB-2 inhibition activates notch-1 and sensitizes breast
cancer cells to a gamma-secretase inhibitor: opportunity for
a novel therapeutic combination.
Osipo I, Patel P, Hao L, Whitehouse L, Strack P, Golde T, Albain K,
Miele L. Loyola University Medical Center, Maywood, IL; Merck
Research Laboratories, Boston, MA; The Mayo Clinic College of
Medicine, Jacksonville, FL.
10:15
76. Parity regulates activation of p53 in human breast tissue.
Crisi GM, Mathews L, Bentley B, Stueber K, Jerry DJ, SmithSchneider S. Baystate Medical Center/Tufts University School of
Medicine, Springfield, MA; Pioneer Valley Life Sciences Institute,
Springfield, MA; Baystate Medical Center/Baystate Plastic Surgery
Associates, Springfield, MA.
10:30
77. Cytrochrome P450 2D6 activity predicts adherence to
Tamoxifen therapy.
Rae JM, Sikora MJ, Henry NL, Li L, Kim S, Oesterreich S, Skaar
T, Nguyen A, Desta Z, Storniolo AM, Flockhart DA, Hayes DF,
Stearns V for the COBRA investigators. University of Michigan
Comprehensive Cancer Center; University of Michigan School
of Medicine; Indiana University; Baylor College of Medicine;
Johns Hopkins University School of Medicine. COBRA is the
Consortium on Breast Cancer Pharmacogenomics, an NIH
supported Consortium of investigators at these institutions
studying pharmacogenomics in the treatment of breast cancer.
10:45
78. Preliminary results of the UK Taxotere as Adjuvant
Chemotherapy (TACT) Trial.
Ellis PA, Barrett-Lee PJ, Bloomfield D, Cameron DA, Hall E,
Johnson L, Johnston SRD, Bliss JM. Guys, Kings & St Thomas’s
Hospital, London, United Kingdom; Velindre Hospital, Cardiff,
Wales, United Kingdom; Royal Sussex County Hospital, Brighton,
Sussex, United Kingdom; University of Leeds, Leeds, United
Kingdom; Institute of Cancer Research, Sutton, Surrey, United
Kingdom; Royal Marsden NHS Foundation Trust, London,
United Kingdom.
11:00
79. Evaluating the efficacy of capecitabine given
concomitantly or in sequence to epirubicin/
cyclophosphamide « docetaxel as neoadjuvant treatment
for primary breast cancer. First efficacy analysis of the GBG/
AGO intergroup-study “GeparQuattro”.
von Minckwitz G, Rezai M, Loibl S, Fasching P, Huober J,
Tesch H, Bauerfeind I, Hilfrich J, Mehta K, Untch M. University
Hospital Frankfurt, Frankfurt, Germany; German Breast Group,
Neu-Isenburg, Germany; Senologie, Brustzentrum, Düsseldorf,
Germany; Frauenklinik mit Poliklinik, Erlangen, Germany;
Senologiezentrum Ostschweiz SENZO, St. Gallen, Switzerland;
Onkologie Bethanien, Frankfurt, Germany; Frauenklinik,
München, Germany; Frauenklinik, Hannover, Germany;
Frauenklinik, Berlin, Germany.
11:15
80. Characterizing the biology and response of locally
advanced breast cancer in women undergoing neoadjuvant
therapy: preliminary results from the I-SPY trial.
Hylton N, Carey L, DeMichele A, Blume J, Broadwater G,
Madhavan S, Rosen M, George S, Esserman L, ISPY Clinical,
Research, Pathology and Radiology Investigators. Univ of
California San Francisco, San Francisco, CA; Univ of North
Carolina, Chapel Hill, NC; Univ of Pennsylvania, Philadelphia, PA;
ACRIN, Philadelphia, PA; CALGB, Chapel Hill, NC; NCI-SPORE,
Bethesda, MD.
11:30
81. Elucidating the stem and progenitor cell hierarchy
in breast development and cancer - an essential role for
GATA-3.
Lindeman GJ, Asselin-Labat M-L, Sutherland KD, Barker H,
Thomas R, Shackleton M, Hartley L, Robb L, Grosveld FG, van
der Wees J, Visvader JE. The Walter and Eliza Hall Institute of
Medical Research, Melbourne, Australia; The Royal Melbourne
Hospital, Melbourne, Australia; Erasmus University, Rotterdam,
Netherlands.
11:45
82. Decrease in tumorigenic breast cancer stem cells in
primary breast cancers with neoadjuvant lapatinib.
Li X, Creighton C, Wong H, Hilsenbeck SG, Osborne CK, Rosen
JM, Lewis MT, Chang JC. Dan L Duncan Cancer Center at Baylor
College of Medicine, Houston, TX.
12:00
ADJOURNMENT,
30th Annual San Antonio Breast Cancer Symposium
Abstracts – Invited Speakers
ML-1
Biomarking the estrogen responsiveness of breast cancer.
Dowsett M. Royal Marsden Hospital
Bene¿t from endocrine treatment of breast cancer is con¿ned to
patients with estrogen receptor positive (ER+) disease. Development
of modern endocrine treatments has been guided by the application
of hormonal analyses, particularly of plasma estrogens, that can be
used as pharmacodynamic markers. However, while these analyses
may also be useful in de¿ning patients at risk of breast cancer they do
not differentiate breast cancer patients that bene¿t from therapy from
those that do not. Recent studies suggest that the differential bene¿t
from tamoxifen and possibly other endocrine therapies may be partly
determined by genetic host factors but molecular features of tumors are
the major determinant of clinical heterogeneity. The degree of variability
in responsiveness can be demonstrated and putative determinants
evaluated in presurgical studies of endocrine therapy. The validity of
changes in the proliferation marker Ki67 as an intermediate end-point of
treatment bene¿t was demonstrated in the IMPACT trial. Reduced Ki67
occurs in over 90% of patients treated with third-generation aromatase
inhibitors indicating that the large majority of ER+ patients bene¿t
from a slowing of tumour growth even if this does not translate to an
objective response to therapy. Similarly a global index of dependence
on estrogen (GIDE) which integrates the transcriptional changes that
occur with estrogen deprivation varies more than 30-fold among ER+
tumors. Unexpectedly, measures of apoptosis indicate that this is
reduced during endocrine therapy. These reductions in cell death are
markedly outweighed by the profound suppression of proliferation but
may contribute to the relatively slow regressions seen with endocrine
therapy. Despite compelling preclinical data, markers such as PgR
and HER2 do not appear to de¿ne patients with a particularly high
relative bene¿t of an aromatase inhibitor over tamoxifen. Further
study of the molecular changes that occur with estrogen deprivation
and association of these with clinical outcome may be expected to
identify the hallmarks of breast cancer that are supported by estrogen
stimulation and allow improved rationalisation of endocrine therapy ±
other therapeutic agents.
P-1
Management of symptoms in breast cancer survivors.
Loprinzi CL. Mayo Clinic, Rochester, MN
Given improved screening and early diagnosis of breast cancer, and also
improved treatment for localized breast cancer, there is an increase in
the number of breast cancer survivors, many destined to live for decades
after their diagnosis. Breast cancer survivors can have many untoward
symptoms related to their treatment and/or requiring different therapies
than other women. Such symptoms include cognitive dysfunction,
fatigue, chemotherapy induced neuropathy, weight gain, sexuality
issues, vaginal dryness, and hot Àashes.
For some of these symptoms, there are treatments which have been
shown to be useful. For fatigue and weight gain, exercise and calorie
restriction are helpful, while pharmacologic means of treating these
symptoms have not delineated any helpful therapies. For hot Àashes,
centrally acting agents, like newer antidepressants and gabapentin, have
been identi¿ed as being valuable for some patients.
For many of these symptoms, however, there are no good, identi¿ed
therapeutic options for management. Neither the etiologies of cognitive
dysfunction associated with cancer, or its treatment, nor helpful
pharmacologic agents for this problem have been identi¿ed. For
decreased libido, while testosterone combined with available estrogen
appears to be helpful in women in general, testosterone without
concomitant estrogen does not appear to be useful in female cancer
survivors. While vaginal estrogen effectively treats vaginal atrophy
in many women, new data demonstrating the bene¿ts of aromatase
inhibitors raise concerns about the use of any treatment that could
impact systemic estrogen in women with hormone sensitive cancers.
At this time there are no pharmacologic therapies to recommend for
preventing or treating chemotherapy-induced neuropathy.
Continued research attention to the above noted issues is necessary to
¿nd improved therapies for control of these symptoms.
S1
P-2
Multidisciplinary treatment guidelines across the continuum
of care: the NCCN experience.
Carlson RW, for the NCCN Breast Cancer Treatment Guidelines Panel.
Stanford Cancer Center, Stanford, CA
The National Comprehensive Cancer Network (NCCN) Breast Cancer
Treatment Guidelines provide multidisciplinary, comprehensive,
state-of- the-art treatment recommendations and strategies across
the continuum of cancer care. The Guidelines are developed by a
multidisciplinary expert panel using an evidence-based consensus
process and are updated at least annually. Panel members represent
the specialties of surgical oncology, medical oncology, radiation
oncology, pathology, reconstructive surgery, and patient advocacy.
Guideline modi¿cations are considered based upon recommendations
or requests from breast cancer providers within the NCCN institutions,
Panel members, patient advocacy organizations, industry, third party
payors or individuals. Panel members are required to disclose ¿nancial
conÀicts of interest verbally and in writing, must absent themselves
from discussions where meaningful conÀicts exist, and conÀicts are
published in the aggregate with the guidelines. Panel meetings over
two - three days include a series of formal, issue focused presentations
followed by an open discussion of any proposed guideline change. The
¿nal document is generated by an iterative process involving all panel
members. All recommendations made by the guideline are associated
with a corresponding category of evidence. The recommendations
are presented in graphical, algorithmic form that is designed to follow
the reasoning process of the expert clinician providing care. The
guidelines are inclusive of treatment options, and an accompanying
referenced manuscript provides the rationale and justi¿cation for
the algorithmic recommendations. The guidelines are published in
updated form annually on the NCCN web site (www.nccn.org) and in
the Journal of the NCCN on a biennial basis. The American Cancer
Society and NCCN publish a patient oriented version of the guideline
updated on an annual basis. Over 250,000 copies of the guidelines
are distributed or accessed annually. Separate, focused task forces
are used to address in depth especially controversial issues in breast
cancer treatment such as selection of adjuvant chemotherapy regimen,
PET scanning, bisphosphonate use, methods of HER2 testing, and
treatment of the older adult. The guidelines are complemented by
an NCCN Outcomes Database that monitors the actual treatment
delivered at NCCN institutions and allows for the identi¿cation of
rates of compliance with guideline recommendations. A compendium
is also published that allows third party payors to ef¿ciently identify
the pharmaceutical agents recommended for speci¿c medical situations
within the guidelines. The NCCN collaborates with breast cancer care
providers in Latin America, Japan, and China to provide economically,
socially, and culturely appropriate international, non-English versions
of the NCCN Breast Cancer Guideline.
P-3
Energy balance, insulin, and breast cancer.
Pollak M. McGill University, Montreal, QC, Canada
We will review (1) evidence for an adverse inÀuence of high body
mass index (BMI) or high caloric intake on breast cancer prognosis (2)
research regarding the underlying mechanisms and (3) implications for
breast cancer prevention and treatment.
While there is evidence that BMI inÀuences breast cancer risk, the
relationship is modest and varies with menopausal status and other
factors. BMI is more consistently identi¿ed as an important adverse
prognostic factor.
Women with higher BMI have higher circulating insulin levels
associated with “insulin resistance” of classic insulin target tissues
such as muscle and fat -- the extent to which cancer cells of a patient
with insulin resistance and hyperinsulinism are sensitive to insulin
stimulation is an important unanswered question, but insulin signaling is
a candidate mediator of the effect of BMI on breast cancer prognosis.
It has been recognized for decades that restriction of energy intake
reduces carcinogenesis and attenuates aggressive cancer behavior
in laboratory models. More recent experimental data provide early
S2
evidence that the growth of some cancers is increased when caloric
intake of the host is increased. Increasing energy intake in these models
is associated with increased insulin levels, but this does not demonstrate
causality because circulating levels of many factors that might impact
tumor growth are also changed.
Clinical research provides further circumstantial evidence for a role
of insulin or factors inÀuenced by or correlated with insulin levels in
determining breast cancer prognosis: higher fasting insulin levels or
c-peptide levels (a marker of insulin production) at time of diagnosis
are associated with worse outcome. Furthermore, it is now recognized
that breast cancers commonly express insulin receptors, IGF-I receptors,
and hybrid insulin/IGF-I receptors, and that these can activate key
downstream growth regulatory signaling pathways. All this has led to
renewed interest in the clinical relevance of work carried out decades
ago which provided evidence that insulin acts as a potent growth factor
for breast cancer in vitro.
Since obesity and hyperinsulinism are common (and increasing) in
afÀuent societies, the public health impact of the adverse impact of these
factors on breast cancer prognosis may be considerable. Furthermore,
the population also includes women who are described as “metabolically
obese, normal weight” individuals, and these may also have a relatively
poor prognosis if diagnosed with cancer.
Importantly, the metabolic abnormalities associated with obesity
represent potentially modi¿able adverse prognostic factors. Lifestyle
(diet and exercise) as well as pharmacologic (eg metformin) strategies
are known to improve hyperinsulinism and the other metabolic
abnormalities associated with obesity. Inhibitors of insulin/IGF
signaling are also under study.
There are important opportunites to use the post-operative adjuvant
treatment setting to advance knowledge in this area. We hypothesize
that any bene¿t of lifestyle or pharmacologic strategies that lower
insulin levels will not be be homogeneously distributed in the breast
cancer population, but rather will be of most bene¿t to those who are
hyperinsulinemic at baseline.
P-4
Radiation treatment planning for breast cancer: a journey
through time.
Pierce L.
Recent improvements in breast cancer-speci¿c and overall survival
shown best in the Overview are attributed, in part, to signi¿cant
improvements in loco-regional control following comprehensive
radiotherapy. The gains in survival, however, have been tempered by
costly rates of excess mortality from causes other than breast cancer,
primarily heart disease. Therefore treatment planning approaches which
minimize treatment to uninvolved tissues are critical to the ultimate
success achieved with radiation. Radiation treatment planning for breast
cancer has changed dramatically through the years with modi¿cations
in clinical target volumes, treatment delivery systems, and techniques.
Early target volumes reÀected a Halstedian philosophy in which
extensive (loco-) regional ¿elds were felt to be necessary for cure but
through successive studies, volumes have been re¿ned that maintain
high rates of loco-regional control while minimizing toxicity. Treatment
delivery systems and techniques have evolved from clinically placed
¿elds treated with the limited depth dose characteristics of orthovoltage
to two- and three-dimensional forward planned ¿elds and now, in some
cases, to complex inversely planned ¿elds delivered with intensity
modulated radiotherapy. The clinical bene¿t of these changes has
been demonstrated in recent outcome studies. Optimization of each of
these components of treatment planning has resulted in a convergence
of treatment goals with the intent to optimize survival while decreasing
toxicity. However, no one approach can be applied to all patients; thus,
treatment planning must be individualized in each case. Trade-offs of
treatment planning directives will be presented.
MS1-1
Systems approach to growth factor signaling and to
therapeutic intervention in breast cancer.
Yarden Y. Weizmann Institute of Science, Rehovot, Israel
Growth factors and their transmembrane receptors contribute to all
steps of tumor progression, from the initial phase of clonal expansion,
through angiogenesis and tmetastasis. Hence, the information relay
system involved in growth factor signaling provides potential site for
signal interception and tumor inhibition. A relevant example comprises
the epidermal growth factor (EGF) and the respective receptor tyrosine
kinase, namely ErbB-1/EGFR, which belongs to a prototype signaling
module that drives carcinoma development. The extended module
includes two autonomous receptor, EGFR and ErbB-4, and two nonautonomous receptors, namely: a ligand-less oncogenic receptor, HER2/
ErbB-2, and a kinase-dead receptor (ErbB-3). This signaling module
is richly involved in human cancer and already serves as a target for
several cancer drugs. Due to inherent complexity and a large amount
of experimental data, we propose a systems approach to understanding
ErbB signaling. EGF - to - ErbB signaling is envisioned as a bow-tie
con¿gured, evolvable network, sharing modularity, redundancy and
control circuits with robust biological and engineered systems. My
presentation will concentrate on system controls, a plethora of negative
feedback loops, which include E3 ubiquitin ligases, receptor endocytosis
and newly transcribed genes. Because network fragility is an inevitable
tradeoff of robustness, systems level understanding is expected to
identify therapeutic opportunities for targeting aberrant activation of
the network in human pathologies. Speci¿c examples will be discussed
with an emphasis on gene expression and the control of metastsis.
MS1-2
Targeting the HER network in breast cancer: therapeutic
successes and failures.
Osborne CK, Schiff R. Baylor College of Medicine, Houston, TX
The HER network is a robust, complex, and redundant network
providing important proliferation and survival signals to a subset of
human breast cancer. It is a layered system consisting of an input layer
of four receptors and their eleven ligands, a core processing unit or
signaling pathway from the membrane to the nucleus, and an output
layer consisting of transcription factors and the genes they regulate.
The network is also controlled by a system of positive and negative
regulatory circuits to ¿nely tune the system. Gene ampli¿cation of
HER2, a critical player in the input layer, in 25% of breast cancer led to
development of drugs targeting the pathway. In breast cancer, drugs that
are currently in use target the receptor input layer to block the pathway.
Trastuzumab binds to the external domain of HER2 and, thereby,
inhibits signaling through the network. In metastatic breast cancer, the
drug used alone induces responses in 30% of patients while the majority
demonstrate de novo resistance. In the adjuvant setting about 50% of
patients with HER2 expressing tumors bene¿t from trastuzumab with
a sizable improvement in time to progression and survival. Still many
patients demonstrate either de novo or acquired resistance to the drug.
Considering the complexity of the network, resistance to trastuzumab
could develop at several levels. One potential mechanism is incomplete
blockade of signals generated by the various dimer pairs formed by
this family of receptors. However, other drugs have been developed
that target the pathway in slightly different ways including the tyrosine
kinase inhibitors lapatinib, ge¿tinib, or erlotinib or the dimerization
inhibitor pertuzumab. In preclinical models these drugs used in various
combinations to more completely block signals from all heterodimers
pairs is a more effective strategy than any of the agents used alone and
is capable of completely eradicating some xenograft models of human
breast cancer. Other xenograft models are resistant to combination
therapy suggesting alternative mechanisms of resistance. The strategy
of combining more than one HER pathway inhibitor in patients is
now being studied in metastatic disease as well as the neoadjuvant
and adjuvant settings. Strategies to identify and then circumvent other
mechanism of resistance are an active area of research.
MS1-3
Identi¿cation of biomarkers of resistance to HER2 targeted
therapy using loss of function genetic screens.
Bernards R. The Netherlands Cancer Institute, Amsterdam,
Netherlands
Unresponsiveness to therapy is remains a signi¿cant problem in the
treatment of cancer, also with the new classes of targeted therapeutics.
In my laboratory, we use functional genetic approached identify
biomarkers that can be used to predict responsiveness to clinicallyrelevant cancer therapeutics. We focus on the well-established targeted
cancer drugs such as Trastuzumab. This drug targets a speci¿c molecule
(HER2) that is over-expressed or in breast cancer. Nevertheless, it
remains poorly explained why a signi¿cant number of tumors, which
express the drug target, do not respond to the therapy. We aim to
elucidate the molecular pathways that contribute to unresponsiveness
to targeted cancer therapeutics using a functional genetic approach.
This will yield biomarkers that can be used to predict how individual
patients will respond to speci¿c drugs. Furthermore, this work may
allow the development of drugs that act in synergy with the established
drug in the treatment of cancer.
To identify biomarkers that control tumor cell responsiveness to cancer
therapeutics, we use both genome-wide gain-of-function genetic screens
(with cDNA expression libraries) and genome wide loss-of-function
genetic screens (with RNA interference libraries) in cancer cells that
are sensitive to the drug-of-interest. We search for genes whose overexpression or down-regulation in cultured cancer cells confers resistance
to the drug-of-interest. Once we have identi¿ed such genes, we ask if
their expression is correlated with clinical resistance to the drug-ofinterest using tumor samples of cancer patients treated with the drug
in question, whose response to therapy is documented.
In this presentation, I will discuss how loss-of-function genetic screens
can be used to identify mechanisms of resistance to Trastuzumab in
breast cancer.
MS2-1
The Women’s Health Initiative randomized trials of
menopausal hormone therapy: results and impact on
clinical practice.
Chlebowski RT. Los Angeles Biomed Res Institute, Torrance, CA
The Women’s Health Initiative (WHI) trial of combined conjugated
equine estrogens (CEE) plus medroxyprogesterone acetate (MPA)
was stopped early and reported in 2002 when overall health risks
including coronary heart disease, stroke, pulmonary embolism and
invasive breast cancer exceeded bene¿ts. Invasive breast cancers
were diagnosed more frequently in the CEE + MPA group; hazard
ratio (HR), 1.24 p=0.003 and were diagnosed at more advanced stage
(p=0.04) compared with those in the placebo group. In the combined
hormone group mammograms with abnormalities were increased by
74% after one year (p<0.001) and, in a sub-study, mammographic
breast density was also signi¿cantly increased. The WHI trial of CEE
alone for women with prior hysterectomy continued until 2006 and the
global index of chronic disease events was equivalent in the hormone
and placebo groups with no overall bene¿t seen for CEE alone use.
Fewer invasive breast cancers were diagnosed in the CEE alone group
(HR 0.80, p=0.09) and the frequency of mammograms requiring short
interval follow-up was signi¿cantly increased, but not those with
more serious abnormalities, in the CEE compared to placebo group
(p<0.001). The risk bene¿t ratio for both the global index of chronic
diseases and invasive breast cancer differed for CEE + MPA use in
women with an intact uterus compared to results with CEE alone use
in women with prior hysterectomy. As the clinical characteristic of the
two study populations differ in several aspects, cautious interpretation
is required. Subsequent to the WHI report of the CEE+MPA trial, a
nearly 50% reduction in menopausal hormone therapy use occurred
in the US, followed by a sharp decrease in breast cancer incidence
S3
especially in postmenopausal women for receptor positive breast cancer
beginning in 2003 and sustained through 2004. Potential associated
factors inÀuencing this decrease will be discussed.
WHI Investigators. JAMA 288:321, 2002; Chlebowski RT, Hendrix
S, Langer R et al. JAMA 289:3243, 2003; Anderson GL, Limacher M,
Assaf AR, et al. JAMA 292:1701, 2004; Stefanick M, Chlebowski RT.
JAMA 242:1048, 2006; Anderson GL, Chlebowski RT, Rossouw J, et
al. Maturitas 54:478, 2006.
MS2-2
Hormone replacement therapy and breast cancer – a
summary of results from other studies.
Cuzick J. Wolfson Institute of Preventive Medicine
The Women’s Health InitiativeWHI) has produced a wealth of
interesting and provocative ¿ndings on the the risk of breast cancer
and heart disease in relation to the use of hormone replacement
therapy. For breast cancer, WHI found an increased risk associated with
combined estrogen and progesterone therapy, but no increase and even
a suggestion of a decreased risk with estrogen only therapy. While the
¿rst of these ¿ndings has generally been supported by most of the other
studies, the second has not, where increased risks, which are generally
smaller than those with combined therapy are the consensus ¿nding.
While WHI has the undeniable strength of being a randomised study
and so is not subject to the potential biases of obsevational studies, it
does have limitations, primarily related to the late age at which women
were randomised ( mean age 63y). The results of this study are compared
and constrasted to those of the Oxford case-control overview, Harvard
Nurse’s study, Million women study and other recent relevant ¿ndings
with regard to these issues. Other points including the risks associated
with use of progestin only preparations and tibolone, the potential
interaction with other risk factors for breast cancer, duration of use and
duration of risk after stopping treatment and the type/prognosis of the
excess cancers are also examined.
MS3-1
Learning from the brain: cancer stem cells in therapeutic
resistance and as molecular targets.
Rich JN. Duke University Medical Center
Cancer biologists increasingly recognize that tumors are complex organs
formed not only by neoplastic cells but also by supporting vasculature,
immune cells, and ¿broblasts. This complexity of cellular heterogeneity
of cancers has also extended to the neoplastic cells themselves. In an
increasing number of cancers (most clearly in hematopoietic, central
nervous system, and breast cancers), a restricted subset of tumor cells
share have been de¿ned functionally as cancer stem cells through
maintained self-renewal and in vivo tumorigenesis. Cancer stem cells
may contribute to tumor growth, progression, and spread.
In a recently published study (Bao, Nature, 2006), we demonstrated
that radiation enriches for brain cancer stem cells and that cancer stem
cells survive radiation treatment at a greater rate than the majority of
tumor cells. Cancer stem cells form tumors after standard radiation
doses with essentially no loss of potency. As radiation induces cell
death primarily through DNA damage, we examined the role of the
DNA damage checkpoint in cancer stem cell radioresistance. Cancer
stem cells preferentially activate ATM and the checkpoint kinases, and
a checkpoint kinase inhibitor sensitizes cancer stem cells to radiation.
Studies from other groups investigating breast cancer cell line models
con¿rmed that cells expressing cancer stem cell markers are resistant
to radiation but also demonstrated that ectopic expression of Wnt
or beta-catenin augmented the radioresistance of cancer stem cells
(Phillips et al., 2006; Chen et al., 2007; Woodward et al., 2007). In
additional unpublished studies, we have found that the development of
chemotherapy resistance selects for speci¿c subpopulations of cancer
stem cells. In summary, we have demonstrated that cancer stem cells
are highly resistant to cytotoxic therapies through speci¿c molecular
mechanisms that may be targeted with novel therapies.
In another recent study (Bao, Cancer Research, 2006), we demonstrated
that brain cancer stem cells promote tumor angiogenesis through
S4
expression of VEGF. Further, a novel anti-angiogenic therapy in
clinical use for glioblastomas (bevacizumab, Avastin) speci¿cally
blocks the impact of cancer stem cells on endothelial cells and potently
attenuates tumor growth of cancer stem cells but not other tumor cells.
In unpublished studies, we have found that cancer stem cells exhibit
differential responses to a key regulator of tumor angiogenesis, hypoxia,
than the majority of cancer stem cells. We have also determined that
cancer stem cells display a highly invasive phenotype.
Therapy directed against cancer stem cells may be more effective
in controlling tumor growth but these therapies may have increased
toxicities against somatic stem cells. We have initiated research
efforts to identify molecular targeted therapies that may be effective
against cancer stem cells and have identi¿ed gene products speci¿cally
expressed by cancer stem cells that contribute to tumor malignancy
suggesting that anti-cancer stem cell therapies can be developed to
improve tumor control.
Abstracts – General Sessions
11
High-dose chemotherapy with autologous stem-cell support
versus standard-dose chemotherapy: meta-analysis of
individual patient data from 15 randomized adjuvant breast
cancer trials.
Berry DA, Ueno NT, Johnson MM, Lei X, Lopez V, Caputo J, Bregni M,
Demirer T. MDACC-EBMT Meta-Analysis Group, Houston, TX
Background: The role of adjuvant high-dose chemotherapy (HDC)
with autologous hematopoietic stem-cell transplantation for primary
breast cancer at high risk of recurrence (at least 4 involved axillary
lymph nodes) has not been well de¿ned. Individually, the available
trials have limited power to determine whether HDC has any bene¿t
for this indication, or for any subgroup of patients.
Methods: Individual patient data from 15 known randomized trials were
merged into a single database. Disease-free survival (DFS) was de¿ned
as time from surgery to recurrence or death. Breast cancer speci¿c
survival (BCSS) was de¿ned as time from surgery to death resulting
from breast cancer or treatment-related toxicity. Overall survival
(OS) was de¿ned as time from surgery to death. Cox proportional
hazards regression compared the effect of HDC vs standard-dose
chemotherapy (SDC) on DFS, BCSS and OS adjusted for age, trial
and hormone receptor (HmR) status (positive if either estrogen (ER)
and/or progesterone (PgR) receptor positive). Subgroup analyses were
by age and HmR status.
Results: A total of 6210 patients (3118 HDC, 3092 SDC) had median
follow-up of 6 years (range 0 to 15.3). Median age was 46 years
(range 20 to 67). HmR was positive in 46.8%, negative in 23.7% and
missing in 29.5%. After adjusting for age and trial, HDC signi¿cantly
prolonged DFS (hazard ratio (HR) 0.87; 95%CI 0.81-0.94; p=0.0001)
but not BCSS (HR 0.93; CI 0.85-1.02; p=0.10) or OS (HR 0.95; CI
0.87-1.02; p=0.16). After adjusting as well for HmR in the subset for
which it was available, HDC signi¿cantly prolonged DFS (HR 0.83;
CI 0.77-0.90; p<0.0001) and had a modest and marginally signi¿cant
bene¿t on BCSS (HR 0.88; CI 0.79-0.97; p=0.013) and OS (HR 0.89;
CI 0.82-0.98; p=0.016). For BCSS and OS, neither age nor HmR had
a statistically signi¿cant interaction with treatment yet there was a
signi¿cant interaction between age and treatment for DFS.
Conclusions: HDC as used in our 15 randomized trials prolongs DFS
in adjuvant breast cancer. HDC has at most a modest bene¿t on BCSS
and OS. Any bene¿ts of HDC in the context of contemporary regimens
such as taxanes and targeted therapies are unknown.
S5
12
Extended follow-up and analysis by age of the US Oncology
Adjuvant trial 9735: docetaxel/cyclophosphamide is
associated with an overall survival bene¿t compared to
doxorubicin/cyclophosphamide and is well-tolerated in
women 65 or older.
Jones S, Holmes F, O’Shaughnessy J, Blum J, Vukelaj S, McIntyre K,
Pippen J, Bordelon J, Kirby R, Sandbach J, Hyman W, Khandelwal P,
Negron A, Richards D, Mennel R, Boehm K, Meyer W, Asmar L, Muss
H, Savin M. US Oncology Research, Inc., Houston, TX; Vermont Cancer
Center, Burlington, VT
Background: At SABCS 2005 we reported 5-year results of a
randomized trial of 4 cycles of docetaxel/cyclophosphamide (TC)
compared to 4 cycles of standard (doxorubicin/cyclophosphamide
(AC) in women with node(-) (∼50%) and node(+) early breast cancer
(BC). A signi¿cant improvement in disease-free survival (DFS), but not
overall survival (OS), was observed. (Jones, et al. JCO. 2006;24:5381)
Older women are not commonly enrolled on adjuvant chemotherapy
(CT) trials. Muss, et al reported that only 8% of women on CALBG
trials were >65. (Muss, et al. JAMA. 2005;293:1073) In the AC/TC
trial 16% (160 pts) were >65 years (yrs) of age. With 2 more yrs of
follow-up, we now report on OS as well as the effect of treatment by
age (using 65 as the cutoff) on outcome and toxicity.
Patients and Methods: Pts were eligible if they had Stage I-III operable
invasive BC with complete surgical excision of the primary tumor.
Between June 1997 and December 1999, 1016 pts were assigned to
4 cycles of either standard-dose AC (60/600/mg/m2) [n=510], or TC
(75/600mg/m2) [n=506], by intravenous infusion every 3 weeks as
adjuvant CT. Radiation therapy (as indicated) and tamoxifen, for pts
with hormone receptor positive disease, were given after completion
of CT.
Results: Baseline characteristics of all pts and those in the 2 age
subgroups were well-matched. The median age in women <65 was
50 (range, 27-64) and for women >65 was 72 (range, 65-77). Median
follow-up is now 6.9 yrs and the difference in OS between TC and AC
is signi¿cant. Results are summarized in the table below:
In the TC group, there were 75 DFS events (15%) and 57 deaths (11%);
the AC group had 108 DFS events (21%) and 83 deaths (16%). Younger
women in both the TC and AC groups had less febrile neutropenia (4.4%
and 2.3%, respectively) compared with older women (7.7% and 3.7%,
respectively [not signi¿cant]). Toxicity, by treatment, was similar in
both age groups to the groups as a whole, and will be presented.
Conclusions: With longer follow-up, TC was associated with improved
DFS as well as OS compared to standard AC. TC should now be a
standard non-anthracycline combination for early BC. In addition, TC
was well-tolerated in older women without excessive toxicity compared
to their younger counterparts, and may be preferable due to its lack of
cardiotoxicity.
Supported by a research grant from sano¿-aventis, Bridgewater, NJ.
6-year Results (%) by Regimen
TC
(# of pts)
Overall DFS
85% 506
OS
88% 506
DFS <65
88% 428
DFS 65
82% 78
AC
79%
84%
82%
75%
(# of pts)
510
510
428
82
P value
0.018
0.045
(HR)
(0.69)
(0.73)
(0.64)
(0.69)
13
Role of anthracycline-based therapy in the adjuvant
treatment of breast cancer: ef¿cacy analyses determined
by molecular subtypes of the disease.
Slamon DJ, Mackey J, Robert N, Crown J, Martin M, Eiremann W,
Pienkowski T, Bee V, Taupin H, Villalobos I, Lindsay M-A, Riva A,
Hurvitz S, Glaspy J, Pauletti G, Sauter G, Press M. Cancer International
Research Group (CIRG), Edmonton, AB, Canada
Background: The use of anthracycline-based therapies for the adjuvant
treatment of high-risk breast cancer has now become a common standard
part of clinical practice. The evidence supporting this approach was
initially controversial but ¿nally thought to be resolved when the
Oxford overview demonstrated a 4-5 % survival advantage in favor
of anthracycline-based therapies over those that did not contain an
anthracycline.
S6
Materials and Methods: We performed a systematic review of
published data from randomized, controlled adjuvant chemotherapy
trials reporting HER2 subtype, i.e. HER2 positive vs. HER2 normal
breast cancers. In addition, the analysis of two recent and separately
conducted adjuvant trials of HER2 positive and HER2 normal breast
cancers respectively, that were further sub-classi¿ed by whether or not
they contained co-ampli¿cation of the topoisomerase II alpha (topo
IIa) gene were included.
Results: The published data demonstrate a remarkably consistent ¿nding.
Speci¿cally, the incremental ef¿cacy bene¿t attributed to anthracyclinebased therapies is restricted to the HER2 positive subgroup. A recent
analysis of the BCIRG 006 (HER2+) and 005 (HER2-) studies reveals
that topo IIa ampli¿cation is con¿ned to cancers that contain the HER2
amplicon. In >1,600 HER2 FISH negative samples there is not a single
topo IIa ampli¿ed case. Conversely, deletion of topo IIa was found in
5% of HER2+ and 3% of HER2– tumors respectively. An analysis of
the impact of topo IIa co-ampli¿cation demonstrates that the improved
ef¿cacy imparted by an anthracycline vs. a non anthracycline-based
regimen is restricted to the HER2/topo IIa co-ampli¿ed cancers. These
constitute 35% of the HER2+ cancers. In these cancers the ef¿cacy
resulting from an anthracycline-based regimen alone was similar in
magnitude to the addition of trastuzumab to adjuvant therapy.
Conclusion: The use of anthracyclines in the adjuvant treatment of all
breast cancer is not supported by the existing data. Given the known
long-term cardiac and leukemogenic/MDS toxicities of anthracyclines
and the lack of an incremental bene¿t in non HER2/topoIIa co-ampli¿ed
cancers (which is ∼92% of the overall breast cancer population), other
approaches to the adjuvant treatment of breast cancer should now be
adopted.
14
Outcome of breast cancer therapies for adjuvant versus
advanced disease: how much do they differ? Critical
comments towards the present process of randomized trials
as a pre-requisite for adjuvant therapy guidelines.
Ragaz J, Spinelli JJ. McGill University Health Centre, Montreal, QC,
Canada; British Columbia Cancer Agency, Vancouver, BC, Canada
INTRODUCTION
Thanks to technological advances, an accelerated rate of development
of “targeted therapy” is seen – with advent of new drugs with curative
potential for human cancer. Their development from early clinical
trials into guidelines requires more swiftness, speed and ef¿ciency than
seen presently. This study will review if results generated in stage IV
(advanced, metastatic) breast cancer con¿rming with evidence level I
and / or with statistical signi¿cance a) safety b) ef¿cacy c) superiority
over placebo & standard therapy could be applicable to adjuvant setting,
with a possibility of avoiding sizable number of breast cancer deaths
much earlier than presently seen.
OBJECTIVES AND METHODOLOGY
Relative Risk rates (RR) or Hazard rates (HR) obtained from recent
pivotal randomized studies, conducted ¿UVW in stage IV advanced
disease, and WKHQ in the adjuvant setting, were compared, focusing
on Aromatase Inhibitors (e.g. letrozole) versus Tamoxifen trials (AIs
vs. TAM); and trastuzumab versus placebo (trastuz vs Plac) trials.
Relative Risk rates (or HR) of classical stage IV outcomes (response
rates, duration of response / median survival) were compared with the
HR of disease free survival (DFS) in adjuvant setting.
CONCLUSION
This study con¿rms the constancy of RR rates between stage IV and
adjuvant trials of Breast Cancer. Additional analogous observations will
be discussed from the 1980’s trials involving Tamoxifen and or adjuvant
CMF-based chemotherapy regimens, where documented responses /
clinical bene¿t in stage IV disease led consistently to improve DFS and
reduced mortality in adjuvant setting.
These data con¿rm that if agents & regimens are documented to be
safe and more effective than standard therapy LQVWDJH,9GLVHDVH, they
will be effective LQDGMXYDQWVHWWLQJ with a great potential for affecting
mortality. In those instances, placebo-control randomized adjuvant trials
may not be indicated in majority of these instances. Instead, biomarker
studies selecting optimum cohorts for new therapies, duration studies
or other comparators not including placebo, ought to be considered.
These recommendations, if adopted, will lead to a substantially more
rapid materialization of signi¿cant survival gains, with great dollar cost
and number of lives saved.
RESULTS
RR rates (HR - Hazard Rates)
Stage IV (Reference)
Adjuvant (Reference)
Als (Letrozole) vs TAM: 0.70 Mouridsen JCO May 01 0.57 MA-17 NEJM Nov 03
0.82 BIG 1-98 JCO Feb 07
Trast. vs Plac:
0.58 Slamon NEJM 01
0.48 N9831 Ҝ B31 NEJM Oct 05
0.54 HERA NEJM Oct 05
0.42 FinHER NEJM Feb 06
0.48 BCIRG ASCO 06
21
Long-term results of a randomized trial of accelerated
hypofractionated whole breast irradiation following breast
conserving surgery in women with node negative breast
cancer.
Whelan T, Pignol JP, Julian J, Grimard L, Bowen J, Perera F, Schneider
K, Fyles A, Gulavita S, Shelley W, Freeman C, Szechtman B, Levine
M. Juravinski Cancer Centre, Hamilton, ON, Canada; McMaster
University, Hamilton, ON, Canada; Toronto Sunnybrook Regional
Cancer Centre, Toronto, ON, Canada; Ottawa Regional Cancer Centre,
Ottawa, ON, Canada; Northeastern Ontario Regional Cancer Centre,
Sudbury, ON, Canada; London Regional Cancer Centre, London, ON,
Canada; Windsor Regional Cancer Centre, Windsor, ON, Canada;
Princess Margaret Hospital, Toronto, ON, Canada; Northwestern
Regional Cancer Centre, Thunder Bay, ON, Canada; Kingston Regional
Cancer Centre, Kingston, ON, Canada; McGill University Health
Centre, Montreal, QC, Canada
BACKGROUND: Breast irradiation after lumpectomy is an integral
component of breast conserving therapy. The optimal fractionation for
whole breast irradiation is unknown. 50 Gy in 25 fractions in 5 weeks
has been widely used but recently there has been renewed interest
in hypofractionation due to potential radiobiological advantages,
convenience and lower cost. However, long-term effects are a
concern. The purpose of this study was to determine if an accelerated
hypofractionated 3-week fractionation schedule was equally effective
to a more traditional 5-week schedule of whole breast irradiation.
METHODS: Women with invasive breast cancer treated by lumpectomy
with pathologically clear resection margins and negative axillary nodes
were randomly assigned to receive whole breast irradiation of 42.5 Gy
in 16 fractions over 22 days (arm A) or 50 Gy in 25 fractions over 35
days (arm B). The primary outcome was local recurrence of invasive
cancer in the treated breast. The secondary outcomes included disease
free survival, overall survival, and radiation morbidity.
RESULTS: From April 1993 through September 1996 1,234 women
were randomly assigned to treatment (622 in arm A and 612 in arm
B). Results previously reported (JNCI 2002; 94:1143-50) at a median
follow-up of 69 months showed similar rates of local recurrence, disease
free survival, overall survival and radiation morbidity. Long-term results
of this trial with a median follow-up now of over 140 months will be
updated for presentation. This will include both ef¿cacy and long-term
radiation morbidity data.
CONCLUSIONS: Initial results of trials of hypofractionation in early
breast cancer have been quite promising, but there continues to be
reluctance to adopt this approach until long-term results are available.
Results of this study should have important implications for the use of
hypofractionation in early breast cancer.
22
dHER2 cancer immunotherapeutic: clinical response in
breast cancer patients is associated with an induction
of functional antibodies and the generation of speci¿c T
cells.
Limentani SA, Curigliano G, Campone M, Dorval T, Romieu G, Vogel
C, White S, de Boer R, Lehmann F, Cormont F, Louahed J. Blumenthal
Cancer Center, Charlotte; Ist. Eur. Oncol., Milan, Italy; Cent. R.
Ganducheau, Nantes, France; Inst. Curie, Paris, France; CRLCC,
Montpellier, France; Cancer Res. Network, Boca Raton; Austin
Hosp., Heidelberg, Australia; Royal Melbourne Hosp., Parkville Vic.,
Australia; GSK Bio, Rixensart, Belgium
Background We designed an Antigen-Speci¿c Cancer Immunotherapeutic
ASCI to induce T cells able to recognize HER2 protein epitopes and a
polyclonal antibody reponse
Methods The dHER2 ASCI is a recombinant HER2 protein, including
a truncated intra-cellular sequence ICD and the complete extracellular
sequence ECD, combined with immunological adjuvant AS15 (GSK
proprietary). Dose escalation from 20 to 500 µg of HER2 protein was
evaluated in a Ph I study in adjuvant breast cancer setting. In another
ongoing Ph II study in metastatic breast cancer patients, 500 µg dHER2
ASCI is given in the 1st or 2nd line metastatic setting, before or after
Herceptin™ therapy. The immunization schedule comprised 2 cycles of
q2w x 6, followed by 1 cycle of q3w x 6. Clinical and immunological
evaluation was assessed after each immunization cycle.
Results In both studies, dHER2 ASCI treatment was well tolerated, no
symptomatic cardiotoxicity was recorded. In the Ph I study (61 patients)
a dose response for antibody titer was observed, but poor maintenance of
anti-ECD Ab titer associated with a lower IgG switch has been observed
in about ½ of the patients. The dHER2 ASCI treatment induces speci¿c
CD4+ and CD8+ T cells. Incubation of serum from 2 patients with
breast cancer cell lines showed that the impact on molecular pathways
resembled that of Herceptin™.
In the metastatic trial, in contrast to the adjuvant trial, anti-ECD Ab
responses demonstrated rapid IgG switch with sustained Ab-titer during
immunization schedule. 1 complete clinical response (1st line setting)
on skin lesions (3 cm) and 2 patients with stable diseases ≥ 6 months
were recorded. Signs of minor clinical activity have also been recorded
in other patients.
Clinical activity is associated with high anti ECD antibody titers
and T cell response magnitude. These titers are higher than these
obtained in the adjuvant setting or non-responder patients, suggesting
that overcoming immunotolerance may be key to achieve clinical
ef¿cacy.
In vitro, the anti ECD abs. of clinical responders bound HER2
overexpressing breast-cancer cell lines and were able to induce abdependent cellular cytotoxicity and growth inhibition of these cell
lines. Preliminary assays show that speci¿c T cells were obtained
in patients presenting clinical activity. Conclusions Overall, dHER2
ASCI treatment is well tolerated. In the metastatic setting, a complete
response and 2 stabilizations of disease have been obtained. Clinical
activity is associated with speci¿c T cell response and high anti ECD
ab titer against HER2. In contrast to the adjuvant setting, the antibody
response was maintained over time of immunizations with a rapid
IgG switch.
23
Fulvestrant 500 mg vs 250 mg: ¿rst results from NEWEST,
a randomized, phase II neoadjuvant trial in postmenopausal
women with locally advanced, estrogen receptor-positive
breast cancer.
Kuter I, Hegg R, Singer CF, Badwe R, Lowe E, on Behalf of the
NEWEST Investigators. Massachusetts General Hospital, Boston;
University of Sao Paulo & Perola Bygton Hospital, Sao Paulo, Brazil;
Medical University of Vienna, Vienna, Austria; Tata Memorial Hospital,
Mumbai, India; AstraZeneca, Wilmington
Background: The neoadjuvant setting represents a unique opportunity
to assess the relationship between pharmacological dose/exposure,
response, and effect on biomarkers in breast cancer therapy. Fulvestrant
(Faslodex®) is an estrogen receptor (ER) antagonist licensed for the
S7
treatment of postmenopausal women with advanced breast cancer
progressing or recurring on an antiestrogen. Two studies have assessed
the activity of fulvestrant in a presurgical setting, demonstrating a dosedependent downregulation of ER and the proliferation marker Ki67
with doses up to 250mg; however, clinical response was not assessed,
nor was it established whether fulvestrant 250 mg is the optimal dose
for use in the neoadjuvant setting.
Methods: NEWEST (Neoadjuvant Endocrine Therapy for Women with
Estrogen-Sensitive Tumors) is a randomized, open-label, multicenter,
phase II study comparing fulvestrant at the approved dose (AD; 250
mg/month) and at a high dose (HD; 500 mg/month plus 500 mg on
day 14 of month 1) as neoadjuvant therapy for postmenopausal women
with newly diagnosed, ER-positive, locally advanced (T2,3,4b, N0-3, M0)
breast cancer. No prior breast cancer treatment was permitted. Patients
received treatment for 16 weeks immediately prior to de¿nitive surgery.
Tumor biopsies were taken at baseline, week 4 and at surgery (week 16),
and assessed for changes in ER, progesterone receptor (PgR), HER1,
HER2 and Ki67 labeling index (LI), and for exploratory biomarker/gene
array analysis.
The primary objective was to compare the effect of fulvestrant AD
and HD on Ki67 LI after 4 weeks of treatment. Secondary objectives
included: assessment of tolerability; correlation between Ki67 LI
changes and changes in ER and PgR expression; tumor response
(assessed by ultrasound); correlation of response at 16 weeks to changes
in biological endpoints (ER, PgR, HER1 and HER2) at weeks 4 and
16; and extent of breast surgery performed. Other secondary objectives
included a comparison of the effects of fulvestrant AD and HD on
endometrial thickness/uterine dimensions and serum bone markers.
Results: A total of 212 women were recruited to this trial between
February 9 2005 and January 22 2007. These patients were recruited
from 36 centers across 6 different countries (Brazil, Austria, India,
Germany, USA, and UK). The last patient is expected to complete this
study on July 9 2007.
Discussion: NEWEST is the ¿rst study to compare the fulvestrant
AD and HD regimens in the neoadjuvant setting and to assess directly
the relationship between fulvestrant dose, duration of treatment,
magnitude of Ki67 LI and ER downregulation, and clinical activity
of the drug. Activity and tolerability data from the NEWEST trial will
be reported.
24
Anti-estrogens promote an invasive phenotype in intercellular
adhesion de¿cient breast cancer cells.
Borley AC, Barrett-Lee PJ, Gee JMW, Shaw VE, Nicholson RI, Hiscox
SE. Velindre Cancer Centre, Cardiff, United Kingdom; Tenovus Centre
for Cancer Research, Cardiff, United Kingdom
Background: Anti-estrogens classically exert gene inhibitory effects
during the drug responsive phase in estrogen receptor positive (ER+)
breast cancer cells. Paradoxically, however, these drugs are also able to
induce the expression of genes which, in the appropriate cell context,
may contribute to an adverse cell phenotype. Here we have investigated
the effects of anti-estrogen treatment on invasive signalling.
Methods: The effect of estrogen (E2, 10-12 M), 4-hydroxy tamoxifen
(TAM, 10-7M) or fulvestrant (FAS, 10-7M) on the invasive capacity of
endocrine-sensitive MCF cells, in the presence or absence of functional
E-cadherin, was determined by Matrigel invasion assays. Western
Blotting using phospho-speci¿c antibodies was performed to ascertain
changes in invasive signalling whilst Affymetrix microarray analysis
with PCR veri¿cation was used to explore gene changes in response to
anti-estrogen versus E2 treatment.
Results: TAM or FAS alone did not signi¿cantly alter MCF-7 cell
invasion versus E2 treatment. Disruption of intercellular adhesion
promoted a modest increase in invasive capacity, which was reduced
by inclusion of E2 (p<0.05); in contrast to this, both TAM and
FAS promoted a striking increase in cell invasion in the absence of
intercellular adhesions (p<0.02), with an accompanying increase
in Src kinase activity. Subsequently, anti-estrogen-induced cellular
invasion in these cells was reduced by inclusion of the Src kinase
inhibitor SU6656 (1µM; p<0.05). Affymetrix analysis and subsequent
PCR validation revealed that TAM and FAS induced the expression of
several genes (RhoE, δ-catenin, LYN, PAK2) which have been linked
to invasive behaviour and whose protein products may be regulated
by Src kinase.
S8
Discussion: These data demonstrate that anti-estrogens can promote
an invasive phenotype in ER+ breast cancer cells under conditions of
poor cell-cell contact and suggest a role for Src kinase and associated
pro-invasive genes in this process. This invasion-promoting ability of
anti-estrogens may have major clinical implications for those patients
whose tumours display inherently poor intercellular adhesion. In
such cases, combination treatment with anti-Src agents may prove
therapeutically valuable.
25
The VEGF-R inhibitor PTK787/ZK222584 (PTK/ZK)
also inhibits aromatase: preclinical studies of PTK/ZK in
Banerjee SN, Thornhill A, Evans DB, Littlewood-Evans AJ, Dowsett M,
Martin L-A. Institute of Cancer Research, London, United Kingdom;
Novartis Institute for BioMedical Research-Basel, Basel, Switzerland
Background: Angiogenesis and Vascular Endothelial Growth Factor
(VEGF) are key components of breast cancer growth, invasion and
metastasis. Clinical studies provide support for targeting VEGF in
breast cancer. Estrogen Receptor (ER) and VEGF signalling pathways
may be linked and increased VEGF levels have been associated with
endocrine-resistance. Targeting both signalling pathways concomitantly
may provide enhanced therapeutic bene¿t. We report the ¿rst studies
of the oral, VEGF-R tyrosine kinase inhibitor, PTK/ZK, in in-vitro and
in-vivo models of endocrine-resistant and -sensitive disease.
Methods: The effects of PTK/ZK and endocrine therapy were
investigated in human breast cancer cell lines engineered to express
aromatase: MCF7-AROM1 (ER+HER2-; endocrine-sensitive) and
BT474-AROM3 (ER+, HER2++; endocrine-resistant). The effect of
PTK/ZK ± tamoxifen or letrozole was assessed in proliferation and
ER alpha-mediated transcription assays. The effect of PTK/ZK on
aromatase activity was measured in the tritiated water assay. Xenograft
studies with MCF7-AROM1 cells were carried out to compare the effect
of escalating doses of PTK/ZK on tumor growth over 28 days. Dynamic
changes in the tumor neovasculature were monitored by confocal
microscopy using lectin perfusion and CD31 staining.
Results: Escalating doses of both E2 and androstenedione (AND) induced
a proliferative response and increased ER-mediated transcription which
were inhibited by 4OH-T or LET in both MCF7-AROM1 and BT474AROM3 cells in vitro. PTK/ZK alone and in the presence of E2 had
no effect on proliferation or ER/ERE-mediated transcription. However,
in the presence of AND, PTK/ZK suppressed both AND-stimulated
proliferation and ER-transactivation in a concentration-dependent
manner suggesting PTK/ZK has angiogenic-independent effects.
Combinations of PTK/ZK with 4OH-T or LET enhanced the antiproliferative and ER-mediated transcriptional effects of these agents.
Further analysis using tritiated water assays showed PTK/ZK possessed
unexpected anti-aromatase activity. Early data from MCF7-AROM1
xenografts showed that PTK/ZK (50mg/kg) reduced tumor volumes
together with an associated decrease in tumor vasculature assessed by
lectin perfusion and concomitant CD31 staining.
Conclusion: PTK/ZK has novel anti-aromatase activity in addition to
its anti-angiogenic effects. Since this represents a previously unknown
action and potential facet of its clinical activity, studies are ongoing to
assess the degree to which the anti-aromatase activity of PTK/ZK may
contribute to its anti-tumor activity.
26
Bone mineral density (BMD) at 5 years after diagnosis in
premenopausal patients with endocrine-responsive breast
cancer, after 3 years of adjuvant endocrine treatment with
goserelin and tamoxifen or anastrozole or both treatments
in combination with zoledronic acid – new results from
ABCSG-12.
Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F,
Kaessmann H, Piswanger-Soelkner C, Seifert M, Schippinger W, Menzel
C, Dubsky P, Fitzal F, Steger G, Greil R, Marth C, Kubista E, Samonigg
H, Jakesz R, on Behalf of the ABCSG. Austrian Breast and Colorectal
Cancer Study Group, Vienna, Austria
Background: Cancer treatment-induced bone loss (CTIBL) is now
generally accepted as a major side effect of modern endocrine therapies.
Long-term adjuvant ovarian function suppression plus tamoxifen
or aromatase inhibitors in premenopausal patients with endocrineresponsive breast cancer can lead to signi¿cant CTIBL (Gnant et al,
JCO 2007; 25: 820-8). This randomized study investigates the use of
the bisphosphonate zoledronic acid (ZA) in order to prevent CTIBL
and reports on late BMD results 2 years after completion of adjuvant
treatment.
Patients and Methods: ABCSG-12 is a randomized, open-label,
phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and
goserelin (3.6 mg every 28 days subcutaneously) ± zoledronic acid (4
mg intravenously every 6 months) versus anastrozole (1 mg/d orally)
and goserelin ± zoledronic acid for 3 years in premenopausal women
with endocrine-responsive breast cancer. In a BMD subprotocol,
patients underwent serial BMD measurements at 0, 6, 12, 24, 36, and
60 months.
Results: Of 1,801 patients in the trial, 404 were prospectively included
in a bone substudy using standardized quality-controlled DEXA at
prede¿ned time points. 201 patients received adjuvant ZA together with
their endocrine treatment whereas 203 patients did not. Median patient
age at diagnosis was 44 years. After 3 years of treatment, patients who
did not receive ZA showed a BMD loss of 11.3 per cent as compared
to baseline (p<0.0001). CTIBL was more pronounced if anastrozole
was used in combination with goserelin as compared to tamoxifen
(-13.6% vs. -9%). At 60 months of follow-up, i.e. two years after the
completion of treatment, patients without ZA still showed impaired
BMD as compared to baseline (-6.8%, p=0.0005). In contrast, patients
who received ZA showed unchanged BMD at 36 months (+.3%, p=0.85)
and increased BMD at 60 months (+3.9%, p=0.02).
Discussion: Adjuvant endocrine therapy using goserelin plus
tamoxifen or anastrozole for three years causes signi¿cant CTIBL in
premenopausal women with breast cancer. While there is some recovery
after completion of treatment, patients show still compromised BMD
after 5 years, particularly those who received goserelin plus anastrozole.
Zoledronic acid 4 mg every 6 months for three years completely inhibits
CTIBL, and leads to improved BMD at 5 years.
27
The effect of zoledronic acid on aromatase inhibitorassociated bone loss in postmenopausal women with early
breast cancer receiving adjuvant letrozole: the Z-FAST
study 36-month follow-up.
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H,
Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group; Novartis
Pharmaceuticals, East Hanover, NJ
Background: Aromatase inhibitor (AI) therapy effectively increases
disease-free survival in postmenopausal women (PMW) with ER+ and/
or PR+ BCa. However, the use of AIs in this patient population results
in nearly complete ablation of estrogen production which can lead to
accelerated bone loss and increased fracture risk. The Z-FAST study
evaluates the ef¿cacy and safety of Zoledronic acid (ZA) in preventing
AI associated bone loss in PMW with early breast cancer (EBC) who
are receiving adjuvant Letrozole (LET) therapy.
Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+
BCa starting LET (2.5 mg qd x 5 yrs) were randomized to upfront
ZA (4 mg IV q 6 mos) vs delayed ZA in 94 centers in the US and
Canada. The delayed group receives ZA when either the post-baseline
T-score decreases to <-2 or a clinical fracture occurs. All patients (pts)
are treated with calcium and vitamin D. The primary endpoint, the
percent change in lumbar spine (LS) bone mineral density (BMD) at
12 mos, was reported at ASCO 2005. The results of 36 mos follow-up
are reported here.
Results: Baseline characteristics were similar between groups. At 36
mos, the upfront ZA group (n=189) showed a mean increase of 3.72%
in LS BMD while the delayed group (n=188) showed a mean decrease
of 2.95%, resulting in an absolute difference of 6.7% (p<0.001). The
upfront group (n=189) showed a mean increase of 1.66% in total hip
(TH) BMD while the delayed group (n=187) showed a mean decrease
of 3.51%, resulting in an absolute difference of 5.2% (p<0.001). The
overall difference in LS and TH BMD between the two groups was
8.2% and 6.7%, respectively, when BMD data in the delayed group was
excluded after pts started ZA. Among pts with baseline T score between
-1 and -2, 40.4% of upfront pts (7.6% of delayed pts) returned to normal
T score (T score >-1) and 13.4% of delayed pts (2.1% of upfront pts)
became severely osteopenic (T <-2). 15% of delayed pts had a decrease
in BMD that required initiation of ZA. Fractures occurred in 5.6% of
upfront pts and 6.3% of delayed pts. 199 upfront pts and 191 delayed
pts had baseline and 36 mos spinal x-rays. 0.5% upfront pts and 0.52%
delayed pts had a radiological fracture detected at 36 mos. The study
was not designed to detect a signi¿cant difference in the fracture rate
between treatment arms. Administration of ZA q 6 mos for up to 36
mos was safe and well tolerated. No serious renal adverse events and
no con¿rmed osteonecrosis of the jaw cases were reported. Disease
recurrence was reported in 9 (3.0%) pts in the upfront group, and 14
(4.7%) pts in the delayed group (p=0.24).
Discussion: The 36 mos follow-up of the Z-FAST trial show that the
overall difference in the percentage change in BMD between the upfront
and delayed ZA treatment groups, at both LS and TH, progressively
increased from baseline through 36 mos. These data demonstrate that
ZA 4mg IV q 6 mos is effective in preventing bone loss associated with
adjuvant AI therapy in PMW with EBC.
28
Effect of anastrozole on bone mineral density after one
year of treatment: results from bone sub-study of the
International Breast Cancer Intervention Study (IBIS-II).
Singh S, Cuzick J, Edwards R, Blake G, Truscott J, Coleman R, Eastell
R, Howell A. Wolfson Institute of Preventive Medicine, London; Kings
College School of Medicine, London; University of Leeds, United
Kingdom; University of Newcastle, Australia; Christie Hospital,
Manchester, United Kingdom; Northern General Hospital, Shef¿eld,
United Kingdom
Background: The third generation aromatase inhibitors have been
shown to reduce bone mineral density when compared with tamoxifen
in the advanced, adjuvant and neoadjuvant settings in women with early
breast cancer. No trial to date has compared the effect of anastrozole
treatment versus placebo on bone mineral density in the prevention
setting.
Materials and Methods: The bone sub-protocol of IBIS-II assessed
changes in the bone mineral density in postmenopausal women aged
40-70 years with a high risk of breast cancer receiving anastrozole 1
mg/day versus placebo for 5 years. Out of 1540 women recruited to
date in the prevention study, 613 women have taken part in the bone
sub-protocol of the study. Lumbar spine and femoral neck BMD have
been assessed at baseline and 1 year by DXA scans for 250 women at
the time of analysis. Results are expressed as mean percentage change.
Out of 250 women, 162 with normal BMD joined stratum-I of the study
and received only monitoring without bisphosphonate treatment, 59
osteopenic women joined stratum-II and were further randomised to
receive either risedronate or placebo, 29 osteoporotic women joined
stratum-III of the study and all received treatment with risedronate.
Results: In stratum-I, a greater BMD loss was observed in the
anastrozole vs placebo group at both the lumbar spine (-2.5% vs. 0.97%; P= .002), and total hip (-1.34 vs. -0.37%; P= .02). In stratum-II,
women randomised to risedronate had higher BMD scores both in the
anastrozole and in the placebo arm. The BMD changes were (risedronate
vs. non-risedronate group; Spine 0.32% vs. -0.17%, P=0.75, Hip 0.67%
vs. -2.27%, P= .01) in the anastrozole arm, and (Spine 0.84% vs.
S9
-0.25%, P=.36; Hip -0.35% vs. -1.2%, P=.23) in the placebo arm. In
stratum-III, the BMD changes observed were (Spine 1.8% vs. 4.17%,
P= .03; Hip -0.13% vs. 1.5%, P=.06) in the anastrozole and placebo
group, respectively.
Discussion: Women with normal BMD at baseline had a signi¿cant
BMD loss with anastrozole treatment. However, women on anastrozole,
who joined the trial with an osteopenic or osteoporotic T-score, gained
BMD after receiving risedronate treatment for a year. This data con¿rms
the BMD losses observed with third generation AIs on breast cancer
patients, but it is also reassuring that BMD loss can be controlled if
women receive DXA scans at baseline and bisphosphonate treatment
as needed along with AIs. Longer-term follow-up and analysis on more
BMD data is required to con¿rm the above results. These data will be
further updated at the time of meeting.
29
Risk stratification based on the CYP2D6 tamoxifen
metabolizing gene within the Italian tamoxifen prevention
trial.
Bonanni B, Maisonneuve P, Johansson H, Macis D, Serrano D,
Guerrieri-Gonzaga A, Basso D, Zambon C, Plebani M, Nicoloff M,
Fontecha M, Hillman G, Wieczorek L, Rotmensz N, Decensi A. European
Institute of Oncology (EIO); EIO, Milan, Italy; University-Hospital of
Padova, Padova, Italy; Roche Molecular Diagnostics, Pleasanton, CA;
E.O. Ospedali Galliera, Genova, Italy
Background: Plasma levels of the active tamoxifen (TAM) metabolites
are associated with the cytochrome CYP2D6 genotype. We recently
published results (JCO 24:3708-9, 2006) indicating that women
with the CYP2D6*4/*4 genotype had a reduced likelihood to bene¿t
from TAM as a chemopreventive agent for breast cancer (BC) using
real-time TaqMan CYP2D6*4 Allelic Discrimination Assay (Applied
Biosystems). These ¿ndings warranted an expanded genotyping study
to gain a deeper understanding of the role of CYP2D6 variation in
predicting response to TAM.
Objectives: The aim of this research was to screen participants in the
case-control study of the Italian TAM Prevention Trial for additional
CYP2D6 polymorphisms. We used the AmpliChip® CYP450 Test
(Roche Molecular Diagnostics) to investigate whether Poor and
Intermediate Metabolizers (PM, IM) receiving TAM are less likely to
bene¿t from treatment and how Ultra-rapid Metabolizers (UM) respond
to TAM treatment.
Methods: The study included 182 subjects (135 controls and 47 BC
cases). The AmpliChip® CYP450 Test queries 32 CYP2D6 alleles and
classi¿es subjects into 4 phenotypes: PM (no activity), IM (reduced
activity), Extensive Metabolizers (EM, normal activity) and UM
(excess activity).
Results: The clinical effect of CYP2D6 phenotype (poor vs other
metabolizers) on BC risk was con¿rmed. Among women in the tamoxifen
arm, PM had higher risk of BC (p=0.035) (Table 1). We found no
correlation between IM and BC risk. In addition, 3 UMs were identi¿ed
in the placebo arm. Interestingly, having at least one CYP2D6*2A
allele was strongly associated with lower risk for BC (p=0.0008) in
the TAM arm. Of the women with a CYP2D6*2A allele (n=58), 10
developed BC (9 placebo, 1 TAM). This statistically signi¿cant effect
was not seen with other functioning alleles (CYP2D6*1, CYP2D6*35),
nor those with reduced activity (CYP2D6*9, *10, *41) or null alleles
(CYP2D6*3, *4, *5, *6, *7).
Conclusions: Our results con¿rm the utility of CYP2D6 genotyping in
predicting response to TAM as a chemopreventive agent. PMs are less
likely to bene¿t from TAM. In addition, we report a novel ¿nding that
women on TAM carrying a CYP2D6*2A allele appear more likely to
bene¿t from treatment, although these data need to be independently
con¿rmed. These ¿ndings provide new perspectives on the clinical
application of pharmacogenetics in tailoring patient care in oncology.
Table 1: CYP2D6 Predicted Phenotype in the Tamoxifen Arm
Phenotype Total
Control Breast cancer P-value
TOTAL
85
65
20 (23.5%)
UM
EM
73
59
14 (19.2%)
IM
7
5
2 (28.6%)
PM
4
1
3 (75.0%)
P=0.035 (poor vs other metabolizers)
NO CALL 1
1
S10
31
Genomic approaches to breast cancer subset identi¿cation
and treatment.
Albertson D, Chin K, Devries S, Feiler H, Pinkel D, Spellman P,
Waldman F, Wang N, Hennessy B, Mills G, Barcellos Hoff MH, Bissell
M, Guan Y, Hu Z, Kuo W-L, McCormick F, Neve R, Stampfer M, Wooster
R, Yaswen P, Das D, Fridlyand J, Correll E, Jin J, Nordmeyer B, Sudar
D, Chew K, Dairkee S, Ljung BM, Hwang S, Esserman L, Arbushites
M, Benz C, Koehler M, Marks JD, Zhou Y, Park J, Weber B, Gray
J. University of California, San Francisco, CA; Lawrence Berkeley
National Laboratory, Berkeley, CA; MD Anderson Cancer Center,
Houston, TX; GlaxoSmithKline, King of Prussia, PA; California Paci¿c
Medical Center, San Francisco, CA; Buck Institute for Age Research,
Novato, CA; Genentech, South San Francisco, CA
Genome-wide analyses of the epigenome, genome and transcriptome
in human breast cancers have revealed a wide range of molecular
defects that likely contribute to cancer pathophysiology. Moreover,
these analyses have revealed subsets of breast cancers carrying speci¿c
recurrent aberration signatures that progress and respond differently
to speci¿c therapies. Two of these subtypes – designated as basal and
luminal/ampli¿er – often do not respond well to current chemotherapy
and tend to recur or progress so that new treatment strategies are needed.
Hundreds of candidate therapeutic agents are under development in
academia and industry that can be considered for subtype speci¿c
therapy. We have developed an in vitro system comprised of 50 wellcharacterized breast cancer cell lines that we are using to identify
therapeutics that will be effective against the basal and luminal/ampli¿er
breast cancer subtypes, develop assays that will predict individual
responses within subtypes and identify mechanisms of response that
may guide selection of complementary therapeutic agents. We have
applied this approach to assess responses to 26 approved or experimental
anticancer drugs. Drug induced changes in viable cell number were
assessed for each cell line at 9 different drug concentrations and each
analysis was performed in triplicates. Three general results emerge
from these studies. (a) Many approved and experimental drugs show
strong breast cancer subtype speci¿city. (b) Correlative analyses of
associations between biological response and pretreatment molecular
features yield multivariate predictors of individual response. The
magnitude of biological response varies considerably between drugs and
predictors of individual response are most accurate for drugs showing
high variability of response between cell lines. (c) Drugs designed to
target speci¿c genomic defects are most effective in cell lines with
those defects thereby validating the overall correlative approach. For
example, Lapatinib and Herceptin are most effective against tumors over
expressing ERBB2. An assessment of the utility of markers developed
using the in vitro cell line collection that predict cell line responses to
Lapatinib to predict results in the EGF30001 trial of Paclitaxel-placebo
vs Paclitaxel-Lapatinib will be presented.
32
Genome-wide analysis of DNA copy number alterations in
conjunction with gene expression pro¿ling identi¿es DNA
ampli¿cation loci that predict distant recurrence in lymph
node-negative (LNN) primary breast cancer patients.
Zhang Y, Klijn J, Yu J, Jiang J, Jatkoe T, Sieuwerts A, Martens J, Wang
Y, Foekens J. Johnson & Johnson, San Diego, CA; Erasmus MC,
Rotterdam, Netherlands
Background: In our previous gene expression study of lymph nodenegative (LNN) breast cancer patients, we have identi¿ed a 76-gene
signature that stratifies patients to provide better means of risk
assessment on an individual basis for breast cancer patients (The
Lancet 365:671-679, 2005). The aim of this study was to identify DNA
copy number alterations from the same cohort of patients to provide
alternative/complementary means for risk assessment of recurrence.
Material and Methods: The genomic DNA of frozen tumor tissue
specimens from 314 LNN breast cancer patients samples was extracted
and hybridized using Affymetrix GeneChips@ Human Mapping 100K
Array Set. All the patient samples were collected between 1980-1995
and none of the patients received systemic adjuvant endocrine- or
chemotherapy. The mean age is 54 years old and the median follow-up
is 102 months. 199 patients are ER positive and 114 patients had distant
recurrences. The DNA copy numbers of the genes were determined
using Affymetrix CNAT software. We analyzed the DNA copy numbers
and the gene expression levels of the samples to identify genomic
loci that showed high correlation to distant recurrence in LNN breast
cancer. The patients were randomly divided into a 200-patient training
set and 114-patient testing set. The candidate loci were identi¿ed from
the training set and validated on the testing set. First, the loci where
the DNA copy number alterations correlated with patient’s prognosis
were identi¿ed by the Cox proportional hazards regression. Then these
alterations at the DNA level were con¿rmed using the concordant
changes in gene expression regulation on the mRNA level.
Results: From the training set, we identi¿ed a panel of 6 genomic
loci that showed high DNA ampli¿cation in patients who developed
distant recurrence, and these gene ampli¿cations were supported by
the concordant up-regulation of these genes at the mRNA level. When
tested on the independent 114 patients of the testing set, the genomic
ampli¿cations of these loci identi¿ed a subset of breast cancer patients
that had high probability of recurrences (hazard ratio of 3.2, C.I. 1.56.9, P=0.002).
Discussion: Our study highlights the feasibility of identifying prognostic
markers on the genomic DNA level. The clinical implication for such
prognostic assays is to signi¿cantly reduce the number of patients that
receive unnecessary treatment. Our result suggests that DNA copy
number alterations, together with gene expression pro¿les, provide a
strategy to combine several molecular markers and build mathematical
models of risk assessment.
33
Gene expression pro¿les of ER+/PR-breast cancer are
associated with genomic instability and Akt/mTOR
signaling, and predict poor patient outcome better than
clinically assigned PR status.
Creighton CJ, Osborne CK, van de Vijver M, Foekens JA, Wang Y,
Zhang Y, Klijn JGM, Horlings HM, Hilsenbeck SG, Lee AV, Schiff
R. Baylor College of Medicine, Houston, TX; Netherlands Cancer
Institute, Amsterdam, Netherlands; Erasmus MC-Daniel den Hoed,
Rotterdam, Netherlands; Veridex LLC, a Johnson & Johnson Company,
San Diego, CA
Background: Patient prognosis and response to endocrine therapy in
breast cancer correlate with protein expression of both estrogen receptor
(ER) and progesterone receptor (PR), with poorer outcome in patients
with ER+/PR- compared to ER+/PR+ tumors.
Materials and Methods: To better understand the underlying biology of
ER+/PR- tumors, we examined RNA expression (n>1000 tumors) and
DNA copy number pro¿les (n= total 89 tumors) from ¿ve previously
published studies of human breast cancers with clinically assigned
hormone receptor status (ER+/PR+, ER+/PR-, and ER-/PR-).
Results: We identi¿ed an expression “signature” of genes with either
elevated or diminished RNA levels speci¿cally in ER+/PR+ compared
to ER-/PR- and most ER+/PR- tumors. We similarly identi¿ed a gene
signature speci¿c to ER-/PR- tumors. ER+/PR- tumors, on the other
hand, were a mixture of three different subtypes: tumors manifesting
the ER+/PR+ signature, tumors manifesting the ER-/PR- signature,
and tumors not associating entirely with ER+/PR+ nor with ER-/PRtumors but sharing patterns with both. Tumors in this third group were
considered to be distinctive ER+/PR- tumors at the transcriptome level
and showed gene expression patterns that were intermediate between
ER+/PR+ and ER-/PR-; these ER+/PR- tumors shared similarities with
ER+/PR+ tumors, in that they did not manifest the signature speci¿c to
ER-/PR- tumors, and with ER-/PR- tumors, in that they did not manifest
the ER+/PR+ signature. In analyses of patients treated with tamoxifen
(263 patients in the dataset from Loi et al.) and of those who received
no adjuvant therapy (155 patients in the dataset from van de Vijver et
al.), ER+/PR- breast cancers de¿ned by gene expression pro¿ling (i.e.
tumors neither truly ER+/PR+ nor ER-/PR- but sharing expression
patterns with both) tended to have poor outcome as compared to those
with pure ER+/PR+ or ER-/PR- patterns (Loi P=0.02, van de Vijver
P=0.0006, log-rank statistic); these differences were not observed when
using the LBA and IHC clinical assays to assign ER and PR status
(P>0.1). ER+/PR- tumors showed approximately twice as much DNA
copy gain or loss compared to ER+/PR+ and ER-/PR- tumors (78 with
fold change >1.5 compared to 32 for ER+/PR+, and 38 for ER-/PR-,
based on analysis of 89 CGH pro¿les consisting of 2149 DNA probes).
Targets of transcriptional up-regulation by speci¿c oncogenic pathways,
including PI3K/Akt/mTOR, were enriched in both ER+/PR- and ER/PR- compared to ER+/PR+ tumors.
Discussion: Gene expression pro¿les may provide a better assay over
current clinical methods for inferring PR status for diagnostic and
therapeutic purposes.
34
Expression of alphavbeta6 supersedes Her2 and triplenegative/basal classi¿cation of breast cancer and de¿nes
novel subgroups with poor survival: implications for breast
cancer classi¿cation and treatment.
Jones JL, Thomas GJ, Duffy SW, Chou P, Gabe R, Ellis I, Green A,
Saha A, Mulligan KT, Ryder K, Gillet C, Violette S, Weinreb P, Hart
IR, Marshall JF. Bart’s and the London, Queen Mary’s School of
Medicine and Dentistry, London, United Kingdom; Nottingham City
Hospital, Nottingham, United Kingdom; Guy’s Hospital, London,
United Kingdom; Biogen Idec, Cambridge, MA
Background:
Molecular characterization permits a more functional classi¿cation
of breast cancer. The epithelial-speci¿c integrin alphavbeta6 shows
negligible expression on normal tissues but may be upregulated by many
types of carcinoma. This study examined the functional and prognostic
importance of expression of this integrin in breast cancer.
Method:
Involvement of alphavbeta6 expression in breast cancer cell invasion
in vitro was assessed and alphavbeta6 levels were analyzed in 1800
breast cancers relative to conventional prognostic indices, molecular
subtypes and survival.
Results:
alphavbeta6 contributed signi¿cantly to the invasive behavior of
breast cancer cell lines and, in patient samples, was associated with
high tumor grade, negative ER and PR status, and distant metastasis
(p<0.001). Strong alphavbeta6 expression superseded ER negative
tumor categorization into triple-negative/basal or Her2 -positive
subgroups as a predictor of reduced survival, even when adjusted for
tumor grade, size and lymph node status [HR 1.70; CI 1.19-2.44]. Thus
alphavbeta6 expression correlated with both the triple-negative/basal
subtype (p=<0.007) and Her2-positive status (p<0.001) but was of
greater prognostic importance than either, de¿ning poor prognosis
subsets within these groups. In Cox proportional hazards regression
analysis alphavbeta6 was associated with a signi¿cant reduction in
survival (10 year survival for Her2+ve/alphavbeta6+ve cases 34%
vs Her2+ve/alphavbeta6-ve (52%) or Her2-ve/alphavbeta6-ve (79%)
subgroups; p=0.006).
Conclusions:
alphavbeta6, possibly through promotion of cancer cell invasion,
identi¿es a novel sub-group of poor prognosis breast cancers. We
suggest that determining alphavbeta6 expression should precede
classi¿cation into Her2-positive and triple-negative/basal subtypes.
Such an algorithm identi¿es alphavbeta6 as a promising new target in
aggressive breast disease.
S11
35
A stroma-related gene signature predicts resistance to
epirubicin-containing neoadjuvant chemotherapy in breast
cancer.
Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette
V, André S, Piccart M, Campone M, Tubiana-Hulin M, MacGrogan
G, Petit T, Jassem J, Rouanet P, Blot E, Bogaerts J, Bergh J, Iggo R,
Delorenzi M. National Centre of Competence in Research (NCCR)
Molecular Oncology, Swiss Institute for Experimental Cancer Research
(ISREC), Epalinges, Switzerland; Swiss Institute of Bioinformatics
(SIB), Lausanne, Switzerland; European Organisation for Research
and Treatment of Cancer (EORTC), Breast Cancer Group, Brussels,
Belgium; The Swiss Group for Clinical Cancer Research (SAKK), Bern,
Switzerland; The Anglo-Celtic Cooperative Oncology Group (ACCOG),
Edinburgh University, Edinburgh, United Kingdom; The Swedish Breast
Cancer Group (SweBCG), Karolinska Institute, Stockholm, Sweden
Background: Biological markers predicting sensitivity of breast tumours
to speci¿c chemotherapies would allow selection of the optimal therapy
for individual patients. The goal of this study was to identify a gene
expression signature predicting for a pathological complete response
to neo-adjuvant Àuorouracil, epirubicin and cyclophosphamide (FEC)
therapy in patients with large operable breast cancer.
Material and Methods: A total of 63 samples from ER negative tumors
enrolled in EORTC 10994/BIG 00-01 study (28 pCR) were hybridized
to Affymetrix X3P arrays.
Results: Using linear models to ¿nd groups of genes highly correlated
to a speci¿c biological process, we found that activated stroma was
significantly associated with resistance to FEC treatment (AUC
0.70; p < 0.01). In a multivariate analysis that included pre-treatment
classic- clinico-pathological variables (clinical size & node status,
grade and ERBB2), the stroma signature was the only covariate that
remained signi¿cant. Using data from an independent experiment for
which epithelial and stromal tumor tissues were separated with laser
dissection microscopy prior hybridization on microarrays, we could
show that genes included in this signature are speci¿cally expressed
in the reactive-stroma. The association of stroma with resistance to
chemotherapy was validated in an external cohort of 53 ER negative
patients treated with T-FAC (Hess et al. J. Clin. Oncol. 2006): AUC 0.70
[0.52-0.85] (CI 95%), odds ratio 3.41, p < 0.05. A Gene Set Enrichment
Analysis showed a signi¿cant association for both Wnt and TGFβ
targets genes and the stroma expression module.
Discussion: These ¿ndings identify a novel resistance mechanism
of ER negative breast carcinoma to FEC treatment which is stroma
activation.
36
The clinical signi¿cance of polysomy 17 in the HER2+ N9831
intergroup adjuvant trastuzumab trial.
Reinholz MM, Jenkins RB, Hillman D, Lingle WL, Davidson N, Martino
S, Kaufman P, Kutteh L, Perez EA. Mayo Clinic College of Medicine,
Rochester, MN; John Hopkins, Baltimore, MD; The Angeles Clinic and
Research Institute, Santa Monica, CA; Dartmouth Hitchcock Medical
Center, Lebanon, NH; Oncology Associates of Cedar Rapids, Cedar
Rapids, IA; Mayo Clinic College of Medicine, Jacksonville, FL
Background: Recent preliminary ¿ndings suggest an association
between chromosome 17 number anomalies and trastuzumab bene¿t
in metastatic breast cancer patients. Purpose: The objective of this
study is to determine the correlation between HER2 gene copy
and chromosome 17 number anomalies with outcome (disease free
survival-DFS) of patients treated with or without trastuzumab.
Patients/Methods: This analysis included 1888 patients from the
HER2+ N9831 intergroup adjuvant trastuzumab phase III clinical
trial who were not or concurrently treated with trastuzumab. Disease
free survival was the primary endpoint of the study. Fluorescent in
situ hybridization (FISH) was centrally performed in the Mayo Clinic
Clinical Cytogenesis Laboratory using a dual probe mixture for HER2
(17q11.2-12/ centromere 17) from Vysis (Downers Grove, IL). Sixty
non-overlapping interphase nuclei were counted using an Axioplan-2
microscope (Zeiss) with a triple-pass ¿lter. Results: Interestingly,
patients who did not receive trastuzumab and had p17 had a 34%
lower DFS rate (p = 0.04) than the non-trastuzumab-treated patients
S12
who had n17. Patients whose tumors were ampli¿ed with polysomy 17
(p17) and with normal 17 number (n17) and treated with trastuzumab
had improved DFS with hazard ratios of 0.52 (p = 0.006) and 0.37
(p = 0.0004), respectively. We had an insuf¿cient number of events
to address the ef¿cacy of trastuzumab in patients with monosomy
17 (m17), small clone ampli¿cation or duplication FISH results (see
Table and Figure). Conclusions: Patients treated only with standard
chemotherapy and who had p17 bene¿ted more than those who had
n17, whereas both groups of p17 and n17 patients bene¿ted from
trastuzumab as compared to standard therapy with similar 3 and 5 year
DFS rates. These results suggest that chromosome 17 number status is
not predictive of trastuzumab response.
with progression or survival: only 7 of 16 studies showed signi¿cant
associations, but follow-up was short.
Of 11 sestamibi imaging studies, 10 showed a signi¿cant association
between shorter retention and higher levels of MDR1/gp170, suggesting
active protein pumping of contrast agent.
For the ¿rst time, a large number of studies (11) of multidrug reversing
agents could be reviewed. None of these agents produced even a partial
clinical response in >25% of previously refractory patients. However,
studies included patients who did not express MDR1/gp170, who would
not be expected to respond to reversing agents.
Conclusion. This meta-analysis includes nearly 3 times as many studies
as our 1997 analysis. MDR1 is expressed in approximately half of breast
cancer patients, and is induced by chemotherapy. 56% of patients who
express MDR1 after chemotherapy fail to achieve a clinical response.
Sestamibi gives the strongest support that MDR1/gp170 is associated
with active efÀux of agent from cells. Further follow-up is needed to
determine the impact on survival, and multidrug reversing agents must
be tested in more rigorously designed studies. Given the major role of
anthracyclines and taxanes in breast cancer therapy, the MDR1 pathway
may be an important contributor to modern chemotherapy resistance.
41
ATAC: 100 month median follow-up (FU) shows continued
superior ef¿cacy and no excess fracture risk for anastrozole
(A) compared with tamoxifen (T) after treatment
completion.
37
Multidrug resistance and breast cancer: a meta-analysis of
MDR1 and its clinical signi¿cance.
Trock B, Leonessa F, Clarke R. Johns Hopkins, Baltimore, MD;
Uniformed Services University of Health Sciences, Bethesda, MD;
Georgetown University, Washington, DC
Background. The clinical signi¿cance of MDR1/gp170 as a mechanism
of multidrug resistance in breast cancer has not been established,
despite the 2 leading classes of breast cancer drugs, anthracyclines and
taxanes, both being substrates for this gene. Ten years ago we published
a meta-analysis examining MDR1/gp170 in breast cancer, based on a
relatively small number of studies with clinical endpoints, and prior to
widespread use of taxanes. We now report an updated meta-analysis
with signi¿cantly more clinical data.
Methods. Published papers on MDR1/gp170 and breast cancer were
identi¿ed by searching literature databases and bibliographies of
published papers. Standard methods for pooling data in meta-analysis
were applied.
Results. 84 studies with >2000 patients were included in analysis:
63 measured MDR1/gp170 expression, 21 measured response to
chemotherapy, 11 measured sestamibi efflux, and 11 evaluated
multidrug resistance reversing agents.
MDR1/gp170 expression was induced by chemotherapy: it was
detected in 46% of breast tumors prior to treatment vs. 67% after
treatment (p<0.0001). gp170 expression did not differ by antibody
type (p=0.57).
Failure to respond to chemotherapy with MDR1 substrates, such as
anthracyclines or taxanes, was nearly three times as frequent when
tumors measured after chemotherapy were positive for MDR1: 56%
(128/228) vs patients with negative tumors: 18% (32/176), p<0.0001.
When weighted by study variance, the pooled relative risk of nonresponse was 1.9 (95% CI 1.5-2.5). However, if MDR1 was measured
prior to induction by chemotherapy it was no longer signi¿cantly
associated with response, p=0.27. There was no clear association
Forbes JF, Cuzick J, Buzdar A, Howell A, Baum M, on Behalf of
the ATAC Trialists’ Group. University of Newcastle, Calgary Mater
Hospital, NSW, Australia; Cancer Research UK, United Kingdom;
M.D. Anderson Cancer Center; Christie Hospital, United Kingdom;
Portland Hospital, United Kingdom
Background: ATAC has shown that A (N = 3125) is signi¿cantly more
effective than T (N = 3116) in preventing recurrences and is better
tolerated, but associated with a higher risk of fractures on treatment.1,2
Little data exist on whether ef¿cacy bene¿ts or side effects persist after
AI treatment is completed. New data comparing A with T at a median
FU of 100 months are presented.
Methods: The primary endpoint, disease-free survival (DFS), and
secondary endpoints of time to recurrence (TTR), incidence of new
contralateral breast cancer (CLBC), time to distant recurrence (TTDR),
overall survival (OS) and death after recurrence, were assessed in both
the total (ITT) and hormone receptor-positive (HR+ve) populations
(84% of ITT). After treatment completion, fractures and serious adverse
events continued to be collected in a blinded fashion.
Results: Signi¿cant improvements were seen for A compared with
T for DFS, TTR, TTDR and CLBC. In the HR+ve population: DFS
(hazard ratio (HR) 0.85; 95% CI 0.76, 0.94; p=0.003), TTR (HR 0.77;
95% CI 0.67, 0.88; p=0.0001) TTDR (HR 0.84; 95% CI 0.72 – 0.98;
p=0.027), and CLBC (OR 0.6; 95% CI 0.42, 0.85; p=0.004). Absolute
differences for A and T increased over time (TTR 2.7% at 5 yrs and 4%
at 9 yrs) and hazard rates remained lower on A compared with T after
treatment completion. Breast cancer deaths were non-signi¿cantly(ns)
fewer with A than T (351 vs 380 ITT; 246 vs 268 HR+ve), but there was
no difference in OS (HR= 0.97 HR +ve). After treatment completion
fracture rates for A and T were similar and safety bene¿ts were
maintained. No new safety concerns were seen. Myocardial infarction
rates on A were identical to T, on or off-treatment, and endometrial
cancer rates remained lower for A than T off-treatment (Table 1).
Conclusion: After a median FU of 100 months, the significant
advantage for A over T for TTR, CLBC and DFS has been maintained.
TTDR was also signi¿cantly superior with A compared to T. Deaths
after recurrence remain ns lower on A than T. After treatment completion
fracture rates on A were not different to T and no new side-effects were
seen. These data con¿rm the long-term superior ef¿cacy and safety of
A over T as initial adjuvant therapy for post-menopausal women with
hormone sensitive early breast cancer.
References
1. ATAC Trialists Group Lancet 2005; 365: 60-62
2. The ATAC Trialists GroupLancet Oncol 2006; 7: 633-43
42
Mid-term ef¿cacy of a breast cancer screening program for
women with a familial or genetic susceptibility: update of
the Dutch MRI screening study (MRISC).
Rijnsburger AJ, Obdeijn I-M, Kriege M, Boetes C, Oosterwijk JC,
Tollenaar RAEM, Peterse H, Bergers E, Tilanus-Linthorst MMA, de
Koning HJ, Rutgers EJT, Klijn JGM, on Behalf of the MRISC Study
Group. Erasmus MC, University Medical Center Rotterdam, Rotterdam,
Netherlands; University Medical Center Nijmegen, Nijmegen,
Netherlands; Groningen University Medical Center, Groningen,
Netherlands; Leiden University Medical Center, Leiden, Netherlands;
Netherlands Cancer Institute, Amsterdam, Netherlands; Free University
Medical Center, Amsterdam, Netherlands
Introduction
First results of prospective studies have shown that magnetic resonance
imaging (MRI) appears to be more sensitive than mammography in
detecting tumors in women with a familial or genetic susceptibility
to breast cancer. We evaluated the mid-term ef¿cacy of MRI and
mammography for screening in this group of women with increased
breast cancer risk.
Methods
In the Dutch MRISC study, a non-randomized prospective multicenter
study, women with >15% cumulative lifetime risk (CLTR) of
developing breast cancer were screened every six months with a
clinical breast examination (CBE) and once a year by mammography
and MRI. Participants were divided into three subgroups according to
their estimated CLTR of developing breast cancer: BRCA1/2 mutation
carriers (50-85% CLTR), a high-risk group (30-50% CLTR) and a
moderate risk-group (15-30% CLTR). The imaging modalities were
assessed according to the BI-RADS classi¿cation, with independent
readings.
Results
From November 1999 to March 2006, 2283 women were included in
the study, including 600 proven carriers of a BRCA1 (n=427) or BRCA2
mutation (n=173) and 1080 women in the high-risk group. The mean
age at entry was 40 years (range 19-75); the median follow-up time 5.3
years. Ninety-four malignant breast tumors were detected, including
19 DCIS (20%); 78 breast cancers were detected by screening. The
overall rate of detection was 43.2 per 1000 women, with the highest
rate in BRCA2 mutation carriers (92.5 per 1000 women). Ten of the 13
interval cancers were found in BRCA1 mutation carriers. The relative
sensitivity of CBE was 21%, of mammography 44% and of MRI 69%.
For DCIS these numbers were 13%, 67% and 33% respectively. The
speci¿city of CBE was 98%, of mammography 95% and of MRI 90%.
In BRCA1 and BRCA2 mutation carriers, 7% resp. 37% of the tumors
was DCIS. In BRCA1 mutation carriers, 31% of the tumors was > 2
cm, compared to 10% in BRCA2 mutation carriers and 20% in the total
group of women. The distribution of nodal status did not show much
difference between BRCA1 and BRCA2 mutation carriers.
Conclusions
Mid-term results still show a higher sensitivity and lower speci¿city of
MRI compared to mammography. Based on the results of this update,
¿rstly the high incidence of DCIS is striking, especially in BRCA2
mutation carriers. Secondly, in BRCA1 mutation carriers, the high
number of interval cancers, a low incidence of DCIS and an unfavorable
tumor size at diagnosis is clinically very relevant; adaptation of the
screening schedule may be necessary for this speci¿c subgroup.
S13
43
Detection of enhancing lesions on contrast-enhanced MRI
of the breast using real-time virtual sonography: fusion of
MRI and sonography data.
Nakano S, Yorozuya K, Takasugi M, Mouri Y, Fukutomi T, Arai O,
Mitake T. Aichi Medical University, Aichi-gun, Aichi, Japan; Hitachi
Medical Corporation, Kashiwa-city, Chiba, Japan
Purpose
Contrast-enhanced MR imaging (MRI) is the most sensitive imaging
method for detecting invasive breast cancer. Due to the limited
speci¿city of MRI, attempts have been made to re-identify enhancing
incidental lesions on sonography in order to more rapidly assess lesions.
We recently developed a real-time virtual sonography (RVS) system,
enabling both breast sonography and contrast-enhanced MRI cutaway
images of the same site to be displayed in real time. The objective of
this study was to assess the accuracy, reproducibility and clinical value
of the RVS system for breast imaging.
Materials and Methods
Between May 2006 and May 2007, a total of 85 women with newly
diagnosed breast cancer underwent breast surgery in our hospital. Of
these, 35 women with histologically proven invasive ductal carcinoma
underwent RVS. All patients were examined using mammography,
sonography, and dynamic breast MRI before core needle biopsy or
surgical resection. Results were correlated with histopathological
¿ndings. MR images were obtained on a Magnetom 1.5-T imager
using a Àexible body surface coil. All patients were examined in the
supine position as near as possible to the sonography/surgical position.
Both non-enhanced and contrast-enhanced images were acquired using
coronal T1-weighted 3-D FLASH sequences.
Results
Of 35 women with invasive ductal carcinoma, 3 patients displayed
1 additional malignant lesion. A total of 17 foci of 38 lesions were
palpable (median size, 14 mm; range, 7-54 mm). Lumpectomy was
performed for 18 women, and 17 women underwent mastectomy.
Sensitivity was 89% (34/38) for sonography, 94% (36/38) for MRI,
and 94% (36/38) for the RVS system. As 2 lesions were not visualized
on MRI, RVS was performed in 36 enhancing lesions. A virtual
MPR image of the target tumor was displayed under good condition
correspondence with the sonography image in all patients(Fig.1).
Furthermore, RVS was largely unaffected by respiratory movements.
Enhancing incidental lesions present in 5 lesions were not seen using
conventional techniques. Of these, 3 lesions (60%) could be identi¿ed
only on repeated sonography, but all 5 incidental lesions could be
identi¿ed easily using the RVS system. Of the 2 lesions (40%) not
initially seen on sonography, one was a benign hemangioma, and the
other was a small breast cancer.
Conclusions
The RVS system could project enhanced MRI information onto a body
surface correctly while checking sonography form images without
large-scale equipment or radiation exposure. The present results suggest
that the RVS system offers excellent accuracy for identi¿cation of
enhancing incidental lesions.
S14
44
MRI for diagnosing pure ductal carcinoma in-situ.
Kuhl CK, Schrading S, Wardelmann E, Braun M, Kuhn W, Schild HH.
University of Bonn, Bonn, Germany
Background: Diagnosing breast cancer in its intraductal stage may be
helpful to prevent the development of invasive cancer. We investigated
the detection rates of ductal carcinoma in situ (DCIS) by mammography
and breast MRI, and compared the biologic pro¿le of mammographydetected versus MRI-detected DCIS.
Methods: During a 5-year study period, women who were referred
to an academic national breast center were offered MRI in addition to
mammography for diagnostic assessment and screening. Mammograms
and breast MRI studies were interpreted independently by two
radiologists. A total 193 women received the ¿nal surgical pathology
diagnosis of pure DCIS, without associated invasive breast cancer or
micro-invasion. Of those, 167 had undergone both imaging tests preoperatively. We investigated the mode of detection (diagnosed with
both modalities, diagnosed with neither modality, diagnosed only by
mammography or diagnosed only by MRI) and compared the biologic
pro¿le (nuclear grading, receptor status, size) of mammographydiagnosed DCIS with MRI-only detected DCIS. In addition, we
investigated the risk profile of women with DCIS diagnosed by
mammography versus those who were diagnosed by MRI.
Results: Overall, 93 of the 167 DCIS (56%) were diagnosed by
mammography, and 153 (92%) by MRI (p < 0.001). With increasing
nuclear grade, sensitivity of mammography decreased; it was highest
in low grade DCIS and lowest in high grade DCIS. It even dropped
further (to 35%) in high grade DCIS without necroses. The sensitivity
of MRI was superior to that of mammography across all DCIS subtypes.
In addition, sensitivity increased with nuclear grade of DCIS; it was
lowest in low grade DCIS (80%) and highest in high grade DCIS (98%),
independent of presence of absence of necroses. The risk pro¿le of
women with MRI-only diagnosed DCIS did not differ signi¿cantly
from women with mammography diagnosed DCIS. In particular,
women with mammography-negative (only MRI-detected) DCIS had
the same personal or familial risk pro¿le, the same age and age range,
and the same mammographic breast density as those whose DCIS was
diagnosed by mammography.
Discussion: Mammographic sensitivity for DCIS is indeed limited.
This holds especially true for high grade DCIS: Half of all high grade
DCIS that came to diagnosis during the study period was only MRI
detected. Thus, MRI improves our ability to diagnose DCIS overall,
but in particular regarding high grade DCIS. Thus, MRI may help avoid
potentially aggressive invasive breast cancer.
45
Noninvasive monitoring of neoadjuvant chemotherapy
using optical tomography with ultrasound localization:
initial experience.
Tannenbaum S, Hegde P, Kane M, Xu C, Kurtzman S, Baccaro N, Iyer
M, Wilson L, Deckers P, Zhu Q. University of Connecticut, Farmington,
CT; University of Connecticut, Storrs, CT
PURPOSE: To investigate the feasibility of using optical tomography
using near infrared light (NIR) combined with ultrasound (US)
localization (NIR/US) to monitor tumor vascular changes during
chemotherapy and assessing tumor pathological response. We were
also interested in a comparison of NIR/US with contrast-enhanced
Magnetic Resonance Imaging (MRI) in predicting residual cancer
following neo-adjuvant chemotherapy.
PATIENTS AND METHODS: 11 female patients who underwent
neoadjuvant chemotherapy were studied at intervals during their
treatments with a combined imager consisting of a commercially
available US system coupled to a near infrared imager constructed
by our group. A centrally located US transducer and NIR sensors
surrounding it (NIR/US) was used to simultaneously acquire coregistered US images and optical data. Tumor vascular content was
assessed based on calculated total hemoglobin (tHb) concentration and
volume. Percentage blood volume index (PBVI) was calculated as the
product of tHb concentration and volume using the pretreatment image
as baseline. Based on the pathological assessment of the specimen,
patients were classi¿ed into three response groups: complete or near
complete responders A, partial responders B, and non-responders C.
Student’s t distribution was used to calculate statistical signi¿cance on
the PBVI between three groups.
RESULTS: The mean PBVI of groups of A, B and C were 23.6%4.2%,
42.6%5.5%, 86.8% 30.1%, respectively. The PBVI in A is signi¿cantly
lower than B (p<0.01) and C (p<0.02); while the PBVI in B is
signi¿cantly lower than non-responder group C (p<0.05). The PBVI
results from responders (A+B) obtained at the end of cycles two, four
and prior to surgery were also evaluated. Reduction in PBVI was
noted in most responders at the ¿rst response assessment compared
to pre-treatment levels. At the end of cycle four, the PBVI of the
responder group is signi¿cantly lower than non-responders (p<0.01);
the signi¿cance increases prior to surgery (p<0.001). NIR/US images
revealed different patterns of response in all patient groups emphasizing
the heterogeneity of these large tumors. NIR/US was comparable to
MRI in distinguishing non-responders (C) from the responding groups
(Aand B).
Conclusion: Our ¿ndings indicate that NIR/US using volumetric tHb
concentration as de¿ned by PBVI has great potential to repeatedly
monitor tumor vascular changes during chemotherapy. The PBVI
correlates well with the pathologic response in this pilot study. In this
study, NIR/US appears comparable to MRI in distinguishing responding
from non-responding tumors. Additionally, it distinguished the degree
of response between complete (A) and partial (B) responders.
46
Tomosynthesis for the detection of breast cancer in a clinical
setting.
Ikeda DM, Ruschin M, Timberg P, Svahn T, Zackrisson S, Andersson
I. Lund University, Malmoe University Hospital, Malmoe, Sweden;
Stanford University School of Medicine, Stanford, CA
Purpose: To compare the performance of tomosynthesis to digital
mammography for cancer detection in a clinical setting
Material and Methods: Patients were selected from a digital
mamographic screening (14) or clinical (15) series for subtle signs of
breast carcinoma. Tomosynthesis (TS) was performed in the projection
in which the ¿nding was least visible or not visible. The digital
mammograms (DM) were obtained on Siemens Mammomat Novation,
the TS on a prototype adapted from the Mammomat Novation. For
the TS 25 projection images were aquired over an angular range of
50 degrees at a dose that was approximately double that of one DM
image and using the same beam quality as determined by the automatic
exposure control of the DM unit (W/Rh). All patients had a complete
work-up including in addition to DM, US, and needle biopsy followed
by surgery. DM and TS images were reviewed for signs of breast cancer
by 2 expert breast imagers who classi¿ed ¿ndings for lelsion visibility
and probability of breast carcinoma using BIRADS categories.
Findings: Twenty-nine women (average age 59 years, range 34 – 84)
with 33 breast cancers in 30 breasts were eligible for the study. Average
tumor size was 1.4 cm. The histologic types included 17 invasive ductal
cancers (IDC), 9 invasive lobular cancers, 3 IDC with ductal carcinoma
in situ (DCIS), 1 DCIS alone and 1 intracystic papillary carcinoma.
On TS 15 spiculated masses were found (including 2 found by TS
alone), 6 masses combined with calci¿cations, 5 cases of architectural
distortion and 2 cases with clustered calci¿cations. In 5 cases no lesion
was visible, Findings were more conspicuous on TS compared to DM in
22 cases, equally visible in 10 and not visible in one. Two cancers were
seen on tomosynthesis alone, both were unexpected second spiculated
masses in dense breast tissue in breasts with one known spiculated
cancer. The BIRADS classi¿cation was upgraded from BIRADS 1-3
on DM to 4 - 5 on TS in 17 patients.
Conclusion: These results suggest that the sensitivity of TS is superior
to DM for the detection of breast cancer in this clinical setting.
51
Is completion axillary dissection always required after a
positive sentinel node biopsy? NSABP B-32.
Julian TB, Anderson SJ, Fourchotte V, Brown AM, Boudros E,
Mamounas EP, Bear H, Costantino JP, Wolmark N. NSABP Medical
Affairs, NSABP Investigators & NSABP Operation & Biostatistical
Centers, Pittsburgh, PA
Background: A positive sentinel node biopsy (SNB) is usually followed
by an axillary dissection (AD). In the majority of clinically node
negative patients the risk for positive non-sentinel axillary nodes (NSN)
is low. Factors affecting the positive NSN rate and the necessity of AD
following a positive SNB are evaluated in NSABP B-32.
Materials and Methods: After strati¿cation, women with operable
invasive breast cancer and clinically negative nodes were randomized to
Sentinel Node Resection (SNR) with immediate conventional Axillary
Disection (AD) [Group 1] or to SNR without AD [Group 2]. Group
2 patients with positive SNs underwent AD. A multivariate analysis
of SN positive patients for whom both a SNR and an AD had been
performed was used to assess the need for AD following SNB. Their
nodes were classi¿ed as either SNs or NSNs, de¿ned as all axillary
dissection nodes plus any intramammary or other nodes that were not
resected as SNs
Results: Between May 1999 and February 2004, 5,611 patients were
entered into NSABP Protocol B-32. 2,807 were assigned to Group
1 and 2,804 were assigned to Group 2. There was a total of 1,361
SN positive patients with AD from Groups 1 and 2. Data from 1,166
patients were available for multivariate analysis (595 from Group 1;
571 from Group 2).
Results from the multivariate analysis indicated that a signi¿cantly
higher percentage of Group 2 patients had positive NSN compared
to Group 1 (41.5% vs. 35.5%, p=0.032). Clinical tumor size was a
signi¿cant predictor for positive NSN (p=0.0010). Percentages of
patients having positive NSN were signi¿cantly increased by the
number of positive SNs (p<0.0001). Lymphovascular invasion was a
signi¿cant predictor for positive NSN (p<0.0001). The percentages of
patients with positive NSN signi¿cantly decreased as the number of
hot spots identi¿ed increased (p=0.0047), and as the number of SNs
removed increased (p<0.0001). Age at study entry, type of biopsy
performed, histologic grade, HER-2 status, location of tumor and
ER/PR status were not signi¿cant multivariate predictors of having
positive NSN. Predictive modeling for positive NSN probability will
be presented.
Conclusion: Completion AD following a positive SNB, although
helpful in prognosis and treatment planning, may not be required
in patients with small tumors and in the absence of lymphovascular
invasion.
52
The impact of micrometastases in the sentinel nodes of
patients with invasive breast cancer.
Hansen NM, Grube BL, Ye C, Turner R, Brennan M, Brenner J, Giuliano
AE. John Wayne Cancer Institute, Santa Monica, CA; Saint John’s
Hospital and Health Center, Santa Monica, CA
Background: Lymph node metastases ar the most signi¿cant prognostic
indicator for patients with breast cancer. With the emergence of sentinel
node biopsy (SNB) and the ability to evaluate multiple levels of a sentinel
node (SN), there has been an increase in the detection of metastases
in the SN (s) both with routine hemoxylin and eosin stains (H&E) as
well as with the addition of immunohistochemical stains (IHC). Most
of the increase is due to the identi¿cation of micrometastases. This
prospective study was designed to determine the survival impact of
micrometastases in SN(s) of patients with invasive breast cancer. The
study is based on the new 6th ed AJCC staging criteria which de¿nes
a negative lymph node N0 if it is negative on H&E, pN0(i+) if there
is a tumor deposit<0.2mm detected by IHC alone, a micrometastases
as pN1mic as a tumor deposit measuring between 0.2mm and 2mm
and a macrometastases as pN1 with a tumor deposit >2mm. Any case
done prior to the new 6th ed AJCC staging criteria was re-evaluated
and classi¿ed according the most current staging critieria.
Results: Between 1/92 and 4/30/99, 790 paitents underwent SNB at our
institution. The SN was examined by H&E and if the SN was negative
S15
on H&E, then IHC stains were added. The patients were divided into
4 groups based on the size of the SN metastases as follows: Group I:
pN0 (n=486), Group II: pN0(i+) (n=84), Group III: pN1mic (n=54)
and Group IV: pN1 (n=166). The majority of patients in all 4 groups
chose a breast conserving procedure. 76.5% of patients received some
form of adjuvant therapy. Of the patients treated with adjuvant therapy,
43.9% received hormonal therapy alone, 21.2% received chemotherapy
alone and 34.9% received a combination of chemotherapy and hormonal
therapy. At a median follow up of 72.5 months, the size of SN metastases
was a signi¿cant predictor of disease free survival (DFS) and overall
survival (OS) only for patients in Group IV. There was no signi¿cant
difference in 8-yr DFS or OS among patients in Groups I, II and III.
Conclusions: Patients with micrometastastic tumor deposits in the
SN de¿ned as pN0(i+) or pN1mic do not appear to have a worse 8-yr
DFS or OS compared to SN negative patients. There was a signi¿cant
decrease in 8-yr DFS and OS in patients with pN1 disease in the SN.
The true signi¿cance of these micrometastatic depositis is still unclear
but may help to eventually better de¿ne which patients should receive
maximum adjuvant therapy, medical or surgical and in which patients
additional therapy could be avoided.
DFS and OS by Group
Group
I
II
III
IV
8-yr DFS (%)
92.9
92.8
89.6
77.5
8-yr OS (%)
94.6
100
94.1
79.6
53
High sensitivity of a molecular assay for breast metastases
in sentinel lymph nodes that are dif¿cult to detect by frozen
section.
Blumencranz P, Deck KB, Whitworth PW, McCue P, Reintgen DS,
Chagpar AS, Beitsch P, Julian TB, Mamounas M, Saha S, Giuliano
A, Simmons R. Morton Plant Mease Healthcare, Clearwater, FL;
Saddleback Memorial Hospital, Laguna Hills, CA; Nashville Breast
Center, Nashville, TN; Jefferson Medical College, Philadelphia, PA;
Lakeland Regional Medical Center, Lakeland, FL; James Brown Cancer
Center, Louisville, KY; Dallas Surgical Group, Dallas, TX; Allegheny
General Hospital, Pittsburgh, PA; Aultman Hospital, Canton, OH;
McLaren Regional Medical Center, Flint, MI; John Wayne Cancer
Institute, Santa Monica, CA; Weill-Cornell Brest Center, New York,
NY
Background: Metastases in the lymph nodes of patients with grade
I tumors, stage I tumors, invasive lobular carcinomas, or post neoadjuvant treatment are dif¿cult to identify due to being smaller or
dif¿cult to assess. An accurate diagnosis requires a highly skilled
pathologist with extensive experience. RT-PCR may offer a more
accurate intra-operative method for diagnosing nodal metastases.
Methods: A prospective study was conducted at 12 clinical sites with
a rapid RT-PCR assay (GeneSearchTM Breast Lymph Node (BLN)
Assay; Veridex, LLC) for the detection of nodal metastases in invasive
breast cancer patients. The RT-PCR assay includes genetic markers
cytokeratin 19 and mammaglobin to detect metastases > 0.2 mm and
evaluates half of the node. Performance calculations used permanent
section H&E as the comparator.
Results: 319 patients had intra-operative frozen section H&E (FS)
results and RT-PCR assay results. 45 patients (14.1%) were diagnosed
with invasive lobular carcinoma only. 187 patients (58.6%) were stage
I; 176 patients (55.2%) were grade I; 9 patients (2.8%) had neoadjuvant
therapy. Results for BLN Assay and FS performance against permanent
section histology are shown in the table below.
Conclusions: The data indicate the rapid RT-PCR assay has high
sensitivity to detect nodal metastases as compared to frozen section in
patients with invasive lobular breast cancer, tumor grade I, tumor stage I
and neo-adjuvant therapy. Comparable speci¿city is seen with both tests.
These data indicate that the RT-PCR assay that allows intra-operative
evaluation of 50% of the node, rather than the <5% by frozen section
S16
histology, may offer a better opportunity for avoiding second surgeries
for complete axillary dissection in these dif¿cult-to-detect cases.
BLN Assay and FS Performance Characteristics
Patient Category N
Performance Measure BLN Assay (95% CI)
Lobular
45 Sensitivity
100% (76.8 – 100)
Speci¿city
93.5% (78.6 – 99.2)
Stage I
187 Sensitivity
96.2% (80.4 – 99.9)
Speci¿city
96.3% (92.1 – 98.6)
Grade I
176 Sensitivity
97.3% (85.8 – 99.9)
Speci¿city
92.8% (87.2 – 96.5)
Neo-adjuvant
9
Sensitivity
66.6% (9.4 – 99.2)
Speci¿city
100% (54.1 – 100)
FS (95% CI)
64.3% (35.1 – 87.2)
96.8% (83.3 – 99.9)
84.6% (65.1 – 95.6)
98.1% (94.7 – 99.6)
83.8% (68.0 – 93.8)
98.0% (93.8 – 99.6)
33.3% (0.84 – 90.6)
83.3% (35.9 – 99.6)
54
Increased sentinel lymph node lymphangiogenesis predicts
non-sentinel axillary lymph node involvement in breast
cancer patients with a positive sentinel node.
Van den Eynden GG, Vandenberghe MK, van Dam P-JH, Colpaert CG,
van Dam P, van Marck EA, Vermeulen PB, Dirix LY. (Lab Pathology
University of Antwerp/University Hospital Antwerp, Wilrijk; Oncology
Center, GH St-Augustinus, Wilrijk, Belgium), Antwerp, Belgium
Background: Lymph node (LN) lymphangiogenesis has recently been
shown to be important in the premetastatic niche of sentinel LNs. To
study its role in the further metastatic spread of human breast cancer, we
investigated the association of angiogenesis and lymphangiogenesis in
sentinel LN metastases with the presence of non-sentinel LN metastases
in breast cancer patients with a positive sentinel LN.
Methods: Angiogenesis and lymphangiogenesis -quantified as
endothelial cell proliferation fraction (ECP%) and lymphatic endothelial
cell proliferation fraction (LECP%)- were assessed in sentinel LN
metastases of 65 T1/T2 breast cancer patients using respectively
CD34/Ki67 and D2-40/Ki67 immunohistochemical doublestains.
Correlations were analysed between non-sentinel LN status, ECP%,
LECP% and previously established factors predicting non-sentinel
LN status (number of metastatically involved sentinel LNs, size of
the primary tumour and LN metastasis, presence of lymphovascular
invasion in the primary tumour and of extracapsular growth in the
sentinel LN metastasis).
Results: Metastatical involvement of 1, 2, 3 or 4 sentinel LNs was
found in respectively 45 (69.2%), 11 (16.9%), 8 (12.3%) and 1
(1.5%) patient. Thirty seven out of 65 patients (56.9%) had at least
one metastatically involved non-sentinel LN (median = 3). Size of
the sentinel LN metastasis (p = 0.001), lymphovascular invasion (p =
0.02), extracapsular growth (p = 0.02) and LECP% (p = 0.01) were
correlated with a positive non-sentinel LN status. Nor the size of the
primary tumour, nor Nottingham grade, nor ER, PR or Her2 status,
nor the metastatical involvement of more than one sentinel LN, nor
ECP% in the lymph node metastases were correlated with the presence
of non-sentinel LN metastases. The multivariate logistic regression
model retained high LECP% (OR = 4.2, p = 0.01) and the presence of
extracapsular growth (OR = 3.38, p = 0.04) as independent predictive
factors for the presence of non-sentinel LN metastases.
Conclusions: Increased sentinel LN metastasis lymphangiogenesis
predicts metastatical involvement of non-sentinel axillary LNs. These
are the ¿rst data in human samples supporting the hypothesis that
lymphangiogenesis in sentinel LN metastases is involved in further
metastatic spread of human breast cancer. Our data furthermore
suggest that including sentinel LN lymphangiogenesis might improve
instruments to predict the likelihood of additional LN metastases in
breast cancer patients with a positive sentinel LN biopsy, such as the
Memorial Sloan Kettering Cancer Center nomogram.
61
The inÀuence of a very high vegetable-fruit-¿ber, low-fat
diet on prognosis following treatment for breast cancer:
results from the Women’s Healthy Eating and Living
(WHEL) randomized trial.
Pierce JP, Natarajan L, Cann BJ, Parker BA, Greenberg ER, Flatt
SW, Rock CL, Kealey S, Al-Delaimy WK, Bardwell WA, Carlson R,
Emond JA, Faerber S, Gold EB, Hajek RA, Hollenbach K, Jones LA,
Karanja N, Madlensky L, Marshall J, Newman VA, Ritenbaugh C,
Thomson CA, Wasserman L, Stefanick ML. Moores UCSD Cancer
Center, University of California, San Diego, La Jolla, CA; Kaiser
Permanente Northern California, Oakland, CA; Fred Hutchinson
Cancer Research Center, Seattle, WA; Stanford Comprehensive Cancer
Center, Stanford University, Stanford, CA; University of California,
San Diego; University of California, Davis, Davis, CA; M.D. Anderson
Cancer Center, The University of Texas, Houston, TX; Center for Health
Research, Portland, OR; Roswell Park Cancer Institute, Buffalo, NY;
University of Arizona, Tucson, AZ; Arizona Cancer Center, Arizona
Prevention Center, University of Arizona, Tucson, AZ; Stanford
Prevention Research Center, Stanford University, Stanford, CA
Context: Evidence is lacking that a dietary pattern high in vegetables,
fruit, and ¿ber and low in total fat can inÀuence breast cancer recurrence
or survival.
Objective. To assess whether a major increase in vegetable, fruit, and
¿ber intake and a decrease in dietary fat affects risk for recurrent and
new primary breast cancer or mortality in breast cancer survivors.
Design, Setting, and Participants. A multi-institutional randomized
controlled trial of dietary change in 3088 women previously treated for
early stage breast cancer, aged 18-70 years at diagnosis. Women were
enrolled between 1995 and 2000, and followed through June 1, 2006.
Intervention. A telephone counseling program supplemented with
cooking classes and newsletters promoted daily targets of 5 vegetable
servings, 16-oz vegetable juice or vegetable equivalents, 3 fruit servings,
30 g ¿ber, and 15-20% energy intake from fat. The comparison group
was provided national dietary guidelines.
Main Outcome Measures. Invasive breast cancer event (recurrence
or new primary) or death from any cause.
Results. From comparable dietary patterns at baseline, a conservative
imputation analysis showed that the intervention group (N=1537)
achieved and maintained the following statistically significant
differences from the comparison group (N=1551) through 4 years:
servings of vegetables, +65%; fruit, +25%; ¿ber, +30% and energy
intake from fat, -13%. Large differences in plasma carotenoid
concentrations validated changes in fruit and vegetable intake.
Throughout the study, women in both groups received similar clinical
care. We will report breast cancer endpoints and overall mortality on
over 95% of both study groups through the 7.3-year average followup period. We will discuss the differences between our results and the
previously published WINS.
Trial Registration: http://www.clinicaltrials.gov/ct/show/
NCT00003787?order=1
Identi¿er: NCT 00003787.
62
Outcome prediction for clinical stage II and III ER+
breast cancer based on treatment response, pathological
stage, tumor grade, Ki67 proliferation index, and estrogen
receptor status after neoadjuvant endocrine therapy.
Ellis MJ, Tao Y, Luo J, Evans DB, Bhatnagar AS, Chaudri Ross H,
von Kameke A, Miller WR, Eiermann W. Washington University, St.
Louis, MO; Novartis Pharma AG, Basel, Switzerland; WWS Group
Ltd, Muttenz, Switzerland; Edinburgh University, Scotland; Red Cross
Women’s Hospital, Munich, Germany
Introduction: Long-term follow up of postmenopausal women with
estrogen receptor positive (ER+) Stage II and III breast cancer too
large for breast conservation enrolled into a randomized neoadjuvant
endocrine therapy study facilitated the development of a model for
risk of relapse based on the short-term anti-tumor effects of letrozole
or tamoxifen.
Methodology: Post-treatment ER status, Ki67 proliferation index,
histological grade, pathological tumor size, node stage, and treatment
response were analyzed by Cox proportional hazards modeling to
identify independent predictors for relapse free and overall survival.
Since there was no difference between neoadjuvant letrozole and
tamoxifen in terms of RFS and OS and almost all patients received
adjuvant tamoxifen, the two groups were pooled for analysis.
Results: Median follow-up was 61.2 months from the initiation of
endocrine therapy. Patients with con¿rmed baseline ER+ tumors
that were down-staged to Stage 1 at surgery had 100% relapse free
survival (RFS) (P=0.0006). Multivariate testing of post-treatment
tumor characteristics revealed that pathological tumor stage, node
status, Ki67 level, tumor grade, ER status, and clinical response were
signi¿cant independent factors. A predictive model incorporating this
information differentiated among four groups of patients with RFS
within the observation period of 100%, 82%, 52%, and 0% with a
Harrell’s optimism-corrected c discrimination index of 0.73 (95% CI:
0.70-0.84).
Conclusions: Clinical stage II or III patients down-staged to Stage
1 or 0 with endocrine therapy are at very low risk of relapse at ¿ve
years of follow up. A multivariate predictive model provides additional
information to discriminate between patients with the extremes of
breast cancer outcomes. Four months of neoadjuvant endocrine
therapy followed by a response assessment is a promising approach
for predicting the course of ER+ breast cancer in postmenopausal
women.
63
Prognostic utility of the 21-gene assay compared with
Adjuvant! in hormone receptor (HR) positive operable
breast cancer with 0-3 positive axillary nodes treated with
adjuvant chemohormonal therapy (CHT): an analysis of
intergroup trial E2197.
Goldstein L, Ravdin P, Gray R, Yoshizawa C, Childs B, Rowley S, Shak
S, Badve S, Baehner FL, Davidson N, Sledge GW, Sparano JA. Eastern
Cooperative Oncology Group, Brookline, MA; MD Anderson Cancer
Center, Houston, TX; Genomic Health, Inc., Redwood City, CA; Sano¿
Aventis, Bridgewater, NJ
Background: Although previous reports have compared multigene
markers to clinical features in multivariate models, there is little
information about the utility of such markers in the context of validated
instruments incorporating clinical features and treatment interventions
such as Adjuvant!.
Methods: A sample of 465 patients (pts) with HR-positive disease from
E2197 who did (N=99) or did not have a recurrence after CHT and had
available tissue had an Oncotype DX Recurrence Score (RS) assay, and
also had recurrence risk estimated by Adjuvant! E2197 included 2885
evaluable pts with 0-3 positive nodes treated with four 3-week cycles
of doxorubicin (60 mg/m2) plus cyclophosphamide 600 mg/m2 (AC)
or docetaxel 60 mg/m2 (AT) and tamoxifen. Median follow-up was
76 months. Tumor grade, HR expression, and Her2 expression were
determined centrally. Five-year recurrence estimates were computed
by Adjuvant! with a batch processor (using central grade), and pts were
classi¿ed as “low”, “intermediate”, or “high” Adjuvant! risk similar in
proportion to the standard RS risk groups. The prognostic utility of RS
was evaluated in each Adjuvant! risk group.
Results: Similar to node-negative disease, 46% had low (< 18), 30%
had intermediate(18–30), and 24% had a high RS (≥ 31). RS was a
highly signi¿cant predictor of recurrence (local and distant), including
node-negative (P = 0.0007) and positive (P=0.0004) disease. Low
RS predicted low recurrence (< 5%) irrespective of nodal status. RS
provided additional information to Adjuvant! (see table); more detailed
analyses comparing the prognostic utililty of Adjvuant! and RS will
be presented.
Conclusions: Oncotype DX RS provides additional prognostic
information in HR-positive operable breast cancer treated with
adjuvant CHT when outcome is modeled by Adjuvant!, particularly
in those projected by Adjuvant! to have better outcomes. Although
both Adjuvant! and Oncotype DX have been prospectively validated
for 10 year outcomes (including only node-negative tam-treated pts
S17
for the latter), this analysis demonstrates that multigene signatures
provide additional prognostic information to clinical variables in this
population treated with CHT.
Odds Ratio for Recurrence by Oncotype DX RS in Adjuvant ! Risk Groups
Adjuvant! Low (N=202) Adjuvant! Int. (N=138) Adjuvant! High (N=125)
RS Ratio:
2.55 (1.11,5.85) P=0.03 9.37 (3.01,2.92) P<0.001 0.89 (0.3,2.63) P=0.83
Inter/Low
RS Ratio:
4.00 (1.73, 9.25) P=0.001 5.78 (1.7,19.6) P=0.004 2.62 (1.05,6.51) P=0.04
High/Low
Odds ratio for recurrence (95% con¿dence intervals)
64
Value of centrally-assessed Ki-67 labeling index as a marker
of prognosis and predictor of response to adjuvant endocrine
therapy in the BIG 1-98 trial of postmenopausal women
with estrogen receptor-positive breast cancer.
Viale G, Giobbie-Hurder A. BIG 1-98 Collaborative Group
and International Breast Cancer Study Group (IBCSG), Bern,
Switzerland
Background: Ki-67 protein has been shown to have prognostic value;
however, as a marker of response to endocrine therapy, the results are
less clear. We explore Ki-67 labeling index (Ki-67 LI) as a predictive
marker using data from the BIG-1-98 trial, a randomized, double-blind,
phase III trial which showed that letrozole (L) improved disease-free
survival (DFS) as compared with tamoxifen (T) for postmenopausal
women with hormone receptor-positive disease.
Methods: Between March 1998 and May 2003, 8,010 postmenopausal
women with hormone receptor-positive breast cancer were enrolled
in the BIG 1-98 trial, of whom 4,922 were randomly assigned to the
two monotherapy arms (L or T for 5 years; 51 months median followup). 2,685 of 4,922 women had ER+ (> 1% immunoreactive cells by
central review) tumors and also had tumor material assessed by the
IBCSG Central Pathology Laboratory for Ki-67 LI using the Mib-1
monoclonal antibody (Dako). Ki-67 LI data were analyzed divided
at the median of the distribution of values. Cox modeling estimated
hazard ratios comparing L vs T on DFS and assessed treatment-bycovariate interactions.
Results: Ki-67 showed prognostic value: DFS was signi¿cantly worse
in the cohort with higher Ki-67 LI (log-rank p=0.0001). A differential
treatment effect of L vs. T was observed (p= 0.07 interaction) suggesting
greater bene¿t in the L arm for the cohort with higher Ki-67 LI.
4-Yr DFS %
(S.E.)
Overall 2,685 89.1 (0.68)
Ki-67
N
0%-11% 1,433 92.2 (0.80)
> 11%
1,252 85.6 (1.12)
Treatment
L
T
L
T
L
T
4-Yr DFS %
(S.E.)
91.8 (0.85)
86.5 (1.06)
93.4 (1.01)
90.9 (1.27)
89.6 (1.41)
81.5 (1.73)
Hazard Ratio
95% CI
(L:T)
0.64
(0.51, 0.80)
0.82
(0.58, 1.16)
0.54
(0.40, 0.72)
Conclusion: The value of Ki-67 as a marker of prognosis in
postmenopausal women with ER+ tumors is clear. A possible predictive
role for response to adjuvant endocrine therapies is suggested and will
be further explored.
65
Erythropoietin receptor expression in breast cancer and
correlation to tamoxifen response.
Larsson A-M, Jirstrom K, Rydén L, Landberg G, Pahlman S. Lund
University, University Hospital MAS, Malmo, Sweden
Background: Erythropoietin (EPO) stimulates erythropoiesis in
response to hypoxia. The biological effects of EPO in erythropoiesis
are mediated through its receptor (EPOR), which initiates intracellular
signalling cascades that lead to increased proliferation, differentiation
and survival. In recent years EPO and EPOR have also been detected
in various cancer forms, but it is still not fully elucidated in what way
this expression affects tumours. Recombinant EPO is also used for
treating anaemia in cancer patients and there are contradicting results
regarding direct effects on tumour growth and behaviour. The aim
with this study was to evaluate the expression of EPOR in a clinical
breast tumour material and to investigate if this expression could add
predictive or prognostic information in relation to Tamoxifen treatment
in premenopausal breast cancer patients.
S18
Material and methods: A tissue microarray based on 500 tumours from
a clinical trial with premenopausal women randomized to receive two
years of either Tamoxifen or no adjuvant treatment was evaluated for
EPOR expression using immunohistochemistry (IHC) (anti-EPOR
antibody, C-20, Santa Cruz). The speci¿city of the antibody was
veri¿ed by Western blot and IHC analyses in MCF-7 breast carcinoma
cells with EPOR expression knocked down by EPOR siRNA. The
staining intensity was scored semi-quantitatively as weak, moderate
or strong.
Results: EPOR expression was significantly associated with age
(p=0.001), and inversely associated with tumour size (p=0.011). There
was also a strong positive correlation between EPOR and VEGFR2
expression (p=0.005). Tamoxifen signi¿cantly increased recurrence
free survival (RFS) in patients with ER and/or PR positive (ER/PR+)
tumours and low expression of EPOR (p=0.001). In tumours with
a high expression of EPOR, no statistically signi¿cant effect was
detected in the Tamoxifen-treated patients compared to controls
(p=0.98), indicating that EPOR might be a negative predictive marker,
associated with Tamoxifen resistance. In the untreated cohort, RFS
was signi¿cantly improved for patients with ER+ tumours with a high
EPOR expression. In ER- tumours there was no difference in RFS
in relation to EPOR expression. This indicates that EPOR might add
prognostic information in patients with ER+ breast cancer not treated
with Tamoxifen.
Discussion: EPOR is expressed in breast cancer cells but its function
there is not fully known. Here we show that high expression of
EPOR is related to Tamoxifen resistance. The biological signi¿cance
behind this observation is not known. However, EPOR and VEGFR2
expression covariate in the studied material and one hypothesis is
that the intracellular signalling pathways downstream of EPOR and
VEGFR2 might interfere with ER pathways independent of Tamoxifen.
Our ¿ndings suggest that EPOR expression in breast carcinoma affects
tumour behaviour, and it is of great importance to further unravel the
functions of EPOR in tumour cells and how tumours are affected by
EPO stimulation.
66
Inflammatory breast cancer pathogenesis is mediated
in signi¿cant part by translation initiation factor eIF4G
ampli¿cation and unorthodox protein synthesis.
Silvera D, Arju R, Darvishian F, Levine PH, Formenti SC, Schneider
RJ. New York University School of Medicine, New York, NY; The George
Washington University School of Public Health and Health Services,
Washington, DC
Background: The molecular mechanisms that drive development of
inÀammatory breast cancer (IBC) are unknown. IBC is unusual in
generation of tumor emboli, which are highly metastatic cell clusters
that strongly over-express VEGF-A, which in turn permeabilizes
the vasculature and sustains emboli proliferation. IBC also uniquely
over-expresses the adhesion molecule E-cadherin, which promotes
metastasis by blocking adherence of IBC emboli to stroma. Using
patient IBC specimens and development of modi¿ed IBC cell lines
and animal models, we show that many of the extreme pathological
disease characteristics of IBC, including VEGF-A and E-cadherin
overexpression, result in large part from overexpression of a single
gene encoding translation initiation factor eIF4G. eIF4G overexpression
reprograms the protein synthetic machinery of IBC cells for increased
translation of a small group of mRNAs that promote IBC tumor
cell survival, vascular permeabilization/angiogenesis, and emboli
formation.
Materials and Methods: Protein factor levels expressed in IBC tissues
were determined by immunohistochemistry (IHC), and in IBC cell lines
by immunoblot analysis. eIF4G expression was silenced by shRNA
adenoviruses. To analyze tumor growth and vasculogenesis we used the
chicken chorioallantoic membrane (CAM) model, and xenograft cell
subcutaneous implantation in nude mice. Maintenance of silencing of
eIF4G protein, expression of VEGF and E-cadherin levels, as well as
angiogenesis, were monitored by immuno-staining techniques.
Results & Discussion: Gene expression and IHC studies revealed
that the SUM149 IBC cell line, as well as 70% of IBC specimens
(n= 42; p<0.01) strongly over-expressed eIF4G compared to normal
tissue, with no alteration in other translation factors. In animal models,
shRNA silencing of eIF4G by ∼90% only slightly reduced global protein
synthesis, but selectively inhibited IBC tumor growth, VEGF, and
p120 catenin mRNA translation, as well as cell surface retention of Ecadherin, vasculature permeabilization and angiogenesis– key hallmarks
of IBC. E-cadherin is retained on the cell surface by interaction with
p120 catenin. Engineered overexpression of p120 restored E-cadherin
to the cell surface and IBC tumor formation. Surprisingly, analysis
of VEGF-A and p120 catenin mRNAs showed they contain capindependent translation elements known as an Internal Ribosome Entry
Sites (IRES), which required high levels of eIF4G for translation. These
and other data demonstrate that high levels of eIF4G are singularly
responsible for many of the unique properties of IBC. Inhibition of
eIF4G might constitute an attractive target for development of new
therapeutics for IBC.
71
Disease-free survival according to local
immunohistochemistry for HER2 and central Àuorescence
in situ hydridization for patients treated with adjuvant
chemotherapy with and without trastuzumab in the HERA
(BIG 01-01) trial.
McCaskill-Stevens W, Procter M, Goodbrand J, Azambuja E, LeylandJones B, Ruschoff J, Dowsett M, Wermuth P, Dolci S, Gelber RD,
Piccart-Gebhart M. National Cancer Institute, Bethesda, MD; Frontier
Science, Kingussie, United Kingdom; Jules Bordet Institute, Brussels,
Belgium; Emory University, Atlanta, GA; Klinikum Kasseland TARGOS
Molecular Pathology Gmbh, Kassel, Germany; Hoffmann-La Roche,
Basel, Switzerland; Royal Marsden National Health Service Trust,
London, United Kingdom; Dana-Farber Cancer Institute, Boston,
MA
Background: Recent American Society of Clincal Oncology guidelines
for the use of immunohistochemistry (IHC) and Àuorescence in situ
hydridization (FISH) to determine which patients have HER-2 gene
ampli¿cation or protein overexpression for treatment of breast cancer
with trastuzumab have been published (Wolff, et al., JCO 2007).
Evidence-based data are required to determine the best assay to use
and to ¿ne tune criteria for positivity.
Methods: In the HERA trial, tissue for patients with local IHC 3+ and 2+
were submitted for central assessment prior to randomization. Patients
with central IHC 3+ or centeral FISH + were eligible for enrollment.
We analyzed data from women in the HERA trial randomized to 1 year
of trastuzumab or observation. Disease-free survival (DFS) was the
primary endpoint and treatment differences were assessed using KaplanMeier estimates and hazard ratios. At 23.5 months median follow-up,
the 3-year DFS percent was 80.4% for the trastuzumab group (n=1703)
compared with 74.4% for the observation group (n=1698) (HR 0.64,
95% CI [0.54, 0.76]) (Smith, et al., Lancet 2007).
Conclusion: Local IHC assessment and central FISH assessment
of HER2-positivity in the HERA trial did not indicate substantial
heterogeneity in the relative treatment effect of 1-year trastuzumab
compared with observation following completion of all adjuvant
chemotherapy; this appears to be in contrast with a subset analysis of
the NCCTG 9831 trial suggesting a lack of bene¿t in the IHC 2+/FISH
+ subpopulation.
No. of
No. (%) of
3-year DFS % Hazard ratio
patients* DFS events
(95% CI)
(95% CI)
Local IHC 3+/no central
FISH assessment
1 year Trastuzumab
1075
144 (13.3%) 78.7 (74.4, 82.8) 0.64 (0.52, 0.79)
Observation
1112
221 (19.9%) 74.6 (71.4, 77.8)
Local IHC 3+/central
FISH +
1 year Trastuzumab
376
48 (12.8%)
82.2 (77.3, 87.1) 0.78 (0.53, 1.14)
Observation
358
56 (15.6%)
74.5 (67.5, 81.5)
Local IHC 2+/central
FISH +
1 year Trastuzumab
179
19 (10.6%)
83.0 (73.4, 92.7) 0.51 (0.29, 0.92)
Observation
145
29 (89.4%)
74.0 (65.1, 82.9)
* Not including 156 patients (73 trastuzumab, 83 observation) who do not meet the criteria
for any of the above categories.
Population/Treatment
72
3-year follow-up of trastuzumab following adjuvant
chemotherapy in node positive HER2-positive breast cancer
patients: results of the PACS-04 trial.
Spielmann M, Roché H, Humblet Y, Delozier T, Bourgeois H, Serin D,
Romieu G, Canon JL, Monnier A, Piot G, Maerevoet M, Orfeuvre H,
Extra JM, Hardy AC, Martin AL, Kramar A, Genève J. Inst Gustave
Roussy, France; Inst Claudius Régaud, France; UCL St-Luc, Belgium;
Centre François Baclesse, France; CHU Poitiers, France; Inst Ste
Catherine, Avignon, France; Centre Val d’Aurelle, France; CH
ND Reine Fabiola, Belgium; CHG Montbelliard, France; CMC les
Ormeaux, Le Havre, France; Clinique St Pierre, Ottignies, Belgium;
CH Bourg en Bresse, France; Inst Curie, France; Cl Armoricaine St
Brieuc, France; FNCLCC, France
Background: Following the PACS 01 trial, this randomised,
multicentre, phase III trial was designed to evaluate the bene¿t of
concomitant docetaxel (D) and epirubicin (E) versus anthracyclines,
and the sequential use of Trastuzumab (T) in the adjuvant treatment of
node-positive (N+) early breast cancer (EBC).
Method: Women aged ≤65 years (yr) with N+ EBC were randomised
initially to receive Arm A: 6 cycles (cy) of adjuvant 5-Àuorouracilepirubicin-cyclophosphamide (FEC100: F and C 500 mg/m2, E 100
mg/m2), or Arm B: 6 cy of concomitant ED (E and D 75 mg/m2) every
3 weeks. Radiotherapy (RT) was performed after chemotherapy and
Hormonal therapy was prescribed to patients (pts) with hormonereceptor-positive tumours. As soon as HER2 status was available, pts
with HER2+ (IHC3+ or IHC2+/FISH+) tumours were randomised to
Arm C: observation only, or Arm D: 1 yr of T (8 mg/kg loading dose, 6
mg/kg 3qw). T was started after completion of RT for pts with normal
cardiac function. The primary endpoint was 3-yr DFS for C and D
arms. All survival times were calculated from ¿rst randomisation. To
ensure a minimal power of 80% with a one sided α=5% (HR=0.625),
520 pts were to be randomized to Arm C or D and 118 events were
to be observed. Assuming a 20% HER2+ sub-population and a 10%
drop-out rate before ¿rst T administration, it was estimated that a whole
population of 3000 pts were to be recruited.
Results: 3010 pts (Arm A: n=1515, Arm B: n=1495), were randomized
between 02/2001 and 08/2004. 528 HER2+ pts (18%) were randomised
to Arm C (n=268) or Arm D (n=260). Baseline demographic and disease
characteristics were well balanced between arms A and B as well as
between C and D. 96% pts received 6 chemotherapy cy in arms A and
B. 10% of pts in arm D did not receive T and 82% of the 233 pts in this
Arm received T for more than 9 m, with a median cumulative dose of
109 mg/kg. Overall, 400 ¿rst events have been observed after a median
follow-up of 36 months(m), but data are not mature for a comparative
analysis between arms A and B. As of 30 April 2007, after a median
follow-up of 40.5 m, 115 ¿rst events have been observed in HER2+ pts
(18 locoregional relapses, 88 metastasis, 7 controlateral breast cancers,
and 2 deaths) and the overall 3-yr DFS rate was 78%. Final ef¿cacy
and safety analysis will be presented for HER2+ pts.
Conclusion: This study will determine the potential benefit of
combining ED in pts with N+ EBC and adding sequential T to FEC100
or ED75 in pts with HER2+ disease.
73
Safety of pertuzumab plus trastuzumab in a phase II trial of
patients with HER2-overexpressing metastatic breast cancer
which had progressed during trastuzumab therapy.
Fumoleau P, Wardley A, Miles D, Verma S, Gelmon K, Cameron D,
Gianni L, Conte PF, Ross G, McNally V, Baselga J. Centre GeorgesFrancois-Leclerc, Dijon, France; Christie Hospital, Manchester,
United Kingdom; Mount Vernon Cancer Centre, Middlesex, United
Kingdom; Ottawa Regional Cancer Center, Ottawa, ON, Canada;
British Columbia Cancer Agency, Vancouver, BC, Canada; Western
General Hospital, Edinburgh, United Kingdom; Oncologia Medica,
Milano, Italy; Divisione di Oncologia Medica, Modena, Italy; Roche
Products Limited, Welwyn, United Kingdom; Vall d’Hebron University
Hospital, Barcelona, Spain
Background: Pertuzumab (P) is a humanized MAb, the ¿rst of a
new class of HER dimerization inhibitors (HDI), that binds to HER2
S19
blocking HER2 homodimerization as well as heterodimerization
between HER2 and other HER receptors, targeting multiple HER
pathways. In contrast, trastuzumab (Herceptin®, H) binds to the
juxta-membrane epitope preventing both HER2 signal transduction
and shedding of the extracellular domain of the receptor. Xenograft
studies suggest that the complementary mechanisms of action of P&T
could lead to increased ef¿cacy when combined. An understanding of
the adverse event (AE) pro¿le of this combination, particularly cardiac,
is of importance.
Methods: Pts with measurable, centrally tested HER2-overexpressing
metastatic breast cancer (MBC) who had received 3 prior lines of
therapy (including adjuvant therapy), who had progressed during H as
most recent treatment, with a baseline left ventricular ejection fraction
(LVEF) 55% without decline to <50% during prior H treatment, were
eligible for this single-arm, two-stage trial. Consenting patients receive
H at 2 mg/kg qw (4 mg/kg loading dose [LD]) or 6 mg/kg q3w (8 mg/kg
LD) plus P at 420 mg q3w (840 mg LD) starting within 9 weeks of the
last dose of H. LVEF is assessed regularly in all pts.
Results: By end-April 2007, 42 pts had received 1 dose of therapy and
33 had 1 tumor evaluation while on treatment. Activity in these 33 pts
was: CR 1 (3%); PR 5 (15%); SD 6 months 7 (21%); SD <6 months
10 (30%); PD 10 (30%). Of 42 pts evaluable for safety, 34 had 1
AE. Frequent AEs (>10%) included: diarrhea (57%), nausea/vomiting
(33%), fatigue (31%), rash (28%), muscle spasms (17%), cough (14%),
headache (12%), dyspnea (12%), nasopharyngitis (12%). Over 80% of
these AEs were grade 1 or 2. Five pts had an AE grade 3, including
diarrhea (n=1), rash (n=1), and deep vein thrombosis (n=1); only
diarrhea was considered treatment related (the rash was attributed to
CT contrast medium). 64.3% of pts had received prior anthracycline.
One pt experienced the protocol-de¿ned AE of fall in LVEF of 10%
to <50%; this pt remained asymptomatic and was withdrawn from the
study for PD.
Discussion: The combination of P&H is active and well tolerated
in HER2-positive MBC patients who had progressed during prior H
therapy. AEs have been generally grade 1 or 2 and no patient has been
withdrawn because of treatment-related AEs. Updated safety data will
be presented at the meeting. Further studies on pts with either MBC or
early breast cancer are planned.
74
Combination of QDE-paclitaxel and bevacizumab eradicates
well-established tumors as well as lymphatic and pulmonary
metastases in a MDA-MB-231 model of a highly metastatic
human breast cancer.
Ran S, Volk L, Bivens C, Trieu V, Desai N. Southern Illinois University,
Spring¿eld, IL; Abraxis BioScience, Inc., Los Angeles, CA
Background: Nab-paclitaxel (Abraxane®, ABX) is a 130-nm,
albumin-bound paclitaxel that has shown greater anti-tumor ef¿cacy
and a better safety pro¿le than solvent-based paclitaxel (Taxol®) and
docetaxel (Taxotere®) in xenograft models and clinical trials. The goal
of the present study was to determine the effects of nab-paclitaxel and
bevacizumab (Avastin®, AVA), as a single or combined therapy, on the
rate and metastasis of the large orthotopic tumors of MDA-MB-231
modeling a highly metastatic human breast cancer.
Material and Methods: Luciferase-tagged MDA-MB-231 cells were
implanted orthotopically into the mammary fatpad of female SCID
mice and allowed to reach 460 mm3 in size before treatment. A group
of 6-8 mice were treated with two cycles of ABX (30 mg/kg, qdx5,
MTD) followed by injection of AVA(4 mg/kg) twice a week for 10
weeks. Additional groups received ABX or AVA alone or saline. Mice
were monitored for tumor growth and signs of toxicity, and sacri¿ced
when the tumor volume reached 2000 mm3. Luciferase activity was
measured in extracts from proximal and contralateral lymph nodes
and both lobes of lungs.
Results: ABX-treated mice did not gain weight for the duration of the
treatment (3 weeks) but no additional signs of toxicity were observed in
that or other experimental groups. AVA-treated mice had nearly identical
tumor growth rate as the controls indicating lack of the effect of this
drug given alone. On day 37 after last treatment the tumor volume in
the ABX-treated group showed a TGI of 84% (P<0.0001 vs. saline).
However, all tumors regrew and reached the same volume as controls
S20
45 days after reaching their minimal size. In contrast, 100% mice treated
with ABX plus AVA therapy had signi¿cant tumor inhibition (TGI 94%
on day 37, P<0.0001 vs. saline and ABX alone) and complete regression
of tumors (TGI 100%, P<0.0001 vs. saline and ABX alone) by day 48
after last injection. Tumors did not regrow for the combination treatment
and the study was terminated on day 75. Neither ABX nor AVA alone
inhibited metastasis as compared with control mice with 100% mice
(7/7 for ABX and 6/6 for AVA alone) being positive for lymph node
and pulmonary metastasis. In contrast, 100% mice (6/6) treated with
the combination were metastasis-free in either proximal or contralateral
lymph nodes as well as in lungs.
Discussion: Bevacizumab alone did not suppress well-established
tumors or metastasis. Nab-paclitaxel alone showed a TGI of 84%;
however, tumors re-grew in 100% of the mice. Neither drug alone was
able to reduce the incidence or total metastatic burden in lymph nodes
or lungs. In contrast, nab-paclitaxel plus bevacizumab successfully
eradicated the primary tumors (TGI 100%) as well as lymph node and
pulmonary metastasis in 100% of the treated mice for the duration of
experiment. Nab-paclitaxel and bevacizumab combination is highly
effective in treatment of primary tumors as well as distant metastases
in an aggressive breast cancer model.
75
ErbB-2 inhibition activates notch-1 and sensitizes breast
cancer cells to a gamma-secretase inhibitor: opportunity
for a novel therapeutic combination.
Osipo C, Patel P, Hao L, Whitehouse L, Strack P, Golde T, Albain
K, Miele L. Loyola University Medical Center, Maywood, IL; Merck
Research Laboratories, Boston, MA; Mayo Clinic, The Mayo Clinic
College of Medicine, Jacksonville, FL
BACKGROUND: ErbB-2 is ampli¿ed or overexpressed in aggressive
breast tumors-associated with the poorest overall survival. Notch-1 is
a potent cell fate determinant and oncogene that is also overexpressed
with its ligand Jagged-1 in aggressive breast cancers. Notch signaling
is important for survival and proliferation of breast tumor initiating
cells. ErbB-2 positive tumors are treated with trastuzumab plus
chemotherapy. Unfortunately, trastuzumab resistance is common and
recurrence inevitable. Therefore, we investigated whether a novel
crosstalk between ErbB-2 and Notch-1 contributes to resistance.
MATERIALS AND METHODS: SKBr3, BT474, and stably
transfected lines, MCF-7/Neo and MCF-7/HER2-18, cells were used in
the studies. Notch transcriptional activity was measured using a pGL2CBF-1-Luc reporter construct. Expression of PY-ErbB-2, total ErbB-2,
Notch-1, Notch-1 targets: Hes5, Hey1, Hes1 was detected by Western
blotting. Cellular localization of Notch-1, Jagged-1, and Dynamin 2
was measured using confocal microscopy. Cell surface localization of
Notch-1 and Jagged-1 was measured by biotinylating surface proteins
at 4oC, immunoprecipitation and Western blotting. Activity of gammasecretase was measured using a ligand-independent cleavage assay. Cell
proliferation was measured using DNA content. Early apoptosis was
detected by Annexin V staining. RESULTS: MCF-7/HER2-18 cells
have 5-fold lower Notch transcriptional activity than MCF-7/Neo cells.
Conversely, either trastuzumab or a dual EGFR/ErbB-2 tyrosine kinase
inhibitor (TKI) increased Notch transcriptional activity by 2-6-fold in
ErbB-2 positive breast cancer cells. Trastuzumab increased amount
and nuclear accumulation of active intracellular Notch-1 (Notch1IC) and Notch target proteins, Hes5, Hey1, and Hes1. Trastuzumab
polarized the localization of both Notch-1 and ligand Jagged-1 near
the cell surface. This surface accumulation was abrogated by inhibiting
endosomal transport with a dominant negative Dynamin 2 (K44A).
In addition, trastuzumab increased the interaction between Notch-1
and presenilin-1 and increased the proteolytic activity of g-secretase,
which was inhibited by a inhibitor (GSI). Cell proliferation of SKBr3
or MCF-7/HER2-18 cells was inhibited more effectively in response
to trastuzumab plus a GSI than by either agent alone. Similar results
were observed with a dual EGFR/ErbB-2 TKI. CONCLUSIONS:
Inhibition of ErbB-2 by trastuzumab or a TKI reactivates Notch-1,
a potent breast oncogene, by at least two mechanisms: 1) Increasing
the availability of Notch-1 and Jagged-1 at the cell surface through a
Dynamin 2-dependent process and 2) Increasing g-secretase activity.
These results suggest that trastuzumab- or TKI-GSI combinations may
be effective in ErbB-2 positive tumors and may delay or prevent the
onset of resistance.
76
Parity regulates activation of p53 in human breast tissue.
Crisi GM, Mathews L, Bentley B, Stueber K, Jerry DJ, Smith-Schneider
S. Baystate Medical Center/Tufts University School of Medicine,
Spring¿eld, MA; Pioneer Valley Life Sciences Institute, Spring¿eld,
MA; Baystate Medical Center/Baystate Plastic Surgery Associates,
Spring¿eld, MA
Early parity (≤ age 24) is associated with a signi¿cant reduction in breast
cancer risk. Studies in rodents have suggested that p53 becomes more
sensitive to DNA damage after pregnancy. Furthermore, mice lacking
p53 are unable to mount a protective response to chemical carcinogens
after undergoing parity, proving that p53 actively participates in this
response. We hypothesized that women who had an early full term
pregnancy (EP) would have increased levels of p53 as compared to
nulliparous women (NU), or from women who had a later pregnancy
(LP).
Materials and Methods: Women undergoing elective breast reduction
surgery were asked to voluntarily enroll in an IRB sanctioned study.
A pre-operative questionnaire was administered to obtain pertinent
information: onset of menses, last menses, parity, age at ¿rst pregnancy,
family history of breast cancer. Two 500 mg portions of tissue were
cultured on gelatin sponges for 24 hours in a 37º incubator. Cultures
were then exposed to ionizing radiation (5 Gy), and re-incubated for
6 hours. Duplicate control cultures remained unirradiated. The tissues
were formalin ¿xed and paraf¿n-embedded. Immunohistochemical
(IHC) staining was performed using a polyclonal antibody to p53 (DO7) (1:400). Semiquantitative immunoreactivity for p53 in epithelial cells
was scored as follows: percentage of cells staining: none (N), 1 = less
than 10%, 2 = 10-50%, 3 = greater than 50%; intensity of cell staining:
0 = none, 1+ = weak, 2+ = moderate, 3+ = strong. Differences in p53
scores between each patient’s non-irradiated and irradiated tissue, were
calculated and reported.
Results: A total of 42 patients have been enrolled, 11 nulliparous (NU),
24 with a ¿rst pregnancy before age of 25 years (early parity - EP), 7
with a ¿rst pregnancy at age greater than 26 years (late parity –LP). A
signi¿cant increase in percentage of cells staining positive for p53 was
observed in EP patients (50%) when compared to NU patients (23%)
(p-value = 0.004). LP patients demonstrated 37% of cells staining
positive for p53; this was not statistically signi¿cant when compared
to either NU or EP.
Conclusion: We demonstrate for the first time that, as in rodent
models, an increase in responsiveness of p53 is seen in cultured human
mammary tissue from women who had a full term pregnancy at an early
age. Our ¿ndings demonstrate that, like in mice, parity enhances the
responsiveness of p53, implying that p53 confers protection to women
who have an early full term pregnancy, and thus puts them at a lesser
risk for the development of breast cancer.
77
Cytochrome P450 2D6 activity predicts adherence to
tamoxifen therapy.
Rae JM, Sikora MJ, Henry NL, Li L, Kim S, Oesterreich S, Skaar
T, Nguyen AT, Desta Z, for the COBRA Investigators. University of
Michigan Comprehensive Cancer Center, University of Michigan School
of Medicine, Indiana University, Baylor College of Medicine, Johns
Hopkins University School of Medicine, COBRA is the Consortium on
Breast Cancer Pharmacogenomics, an NIH supported Consortium of
investigators at these institutions studying pharmacogenomics in the
treatment of breast cancer
Background: The selective estrogen receptor modulator tamoxifen has
been shown to reduce mortality in estrogen receptor positive breast
cancer and to reduce the incidence of the disease in high-risk women.
The metabolism of tamoxifen to its active metabolite, endoxifen, by
cytochrome P450 2D6 (CYP2D6) is believed to be required for antitumor activity. Previously, we showed that patients with CYP2D6
polymorphisms had lower response rates and less hot Àashes while on
tamoxifen than patients with wild-type CYP2D6 genotype. Studies of
adherence to tamoxifen therapy suggest that nearly one third of breast
cancer patients stop taking their medication before the recommended 5
years. Side effects including hot Àashes are the main causes of treatment
discontinuation. In the current study, we tested the hypothesis that
CYP2D6 genotype is predictive of non-adherence to tamoxifen.
Methods: Women with breast cancer (n=297) enrolled in a prospective
clinical trial testing associations between genetic polymorphisms and
clinical response were genotyped for CYP2D6, CYP2C19, CYP3A5
and estrogen receptor (ESR) variants. Using genotype information,
patients were assigned a CYP2D6 “score” based on known speci¿c
allele activities from 0 (no activity) to 2 (high activity).
Results: Twenty eight patients (10.5%) stopped taking tamoxifen during
the ¿rst year of treatment due to side effects. All women with a CYP2D6
score of 0 completed tamoxifen treatment, while increasing scores
correlated with increasing rates of drop out. Linear regression and a
nonlinear Michaelis-Menten Model both describe a strong correlation
between increasing CYP2D6 score and drop out rates (R2 = 0.75, p =
0.057 and R2 = 0.935, p = 0.018, respectively). Polymorphisms in other
CYP450s or ERs did not correlate with adherence.
Conclusions: The presence of active CYP2D6 alleles predicts a higher
likelihood of tamoxifen discontinuation due to treatment related side
effects. These data may explain part of the current controversy over
CYP2D6 genotype predicting response to tamoxifen and suggest that
patients most likely to bene¿t from tamoxifen are paradoxically most
likely to stop their tamoxifen therapy prematurely. Genetic testing to
identify patients likely not to comply with tamoxifen therapy could
help identify patients a priori who will bene¿t most from the effective
use of co-medications that ameliorate the side effects of tamoxifen and
could signi¿cantly impact response to therapy. This knowledge may
provide an ef¿cient means of improving tamoxifen ef¿cacy relative
to other treatments.
78
Preliminary results of the UK Taxotere as Adjuvant
Chemotherapy (TACT) Trial.
Ellis PA, Barrett-Lee PJ, Bloom¿eld D, Cameron DA, Hall E, Johnson
L, Johnston SRD, Bliss JM. Guys, Kings & St Thomas’s Hospital,
London, United Kingdom; Velindre Hospital, Cardiff, Wales, United
Kingdom; Royal Sussex County Hospital, Brigton, Sussex, United
Kingdom; University of Leeds, Leeds, United Kingdom; Institute of
Cancer Research, Sutton, Surrey, United Kingdom; Royal Marsden
NHS Foundation Trust, London, United Kingdom
Introduction: Previously reported phase III adjuvant chemotherapy
trials suggest a modest survival bene¿t favoring taxane containing
regimens over anthracycline regimens. However, uncertainty remains
with regard to the bene¿t of taxanes compared with anthracycline
regimens of similar duration. The UK TACT Trial, a large multicentre
phase III randomised trial comparing sequential FEC-Taxotere to
standard UK anthracycline chemotherapy, will provide further evidence
with regard to overall bene¿t, as well as which sub-groups, if any, have
more or less to gain from this intervention.
S21
Patients & Methods: Between Feb 2001 and July 2003 4162 women
with operable histologically con¿rmed completely resected early
invasive breast cancer were recruited from 104 centres in the UK (103)
and Belgium (1). Centres chose FEC (600/60/600 mg/m2 q3wk x 8) or
E-CMF (Epirubicin 100mg/m2 q3wk x 4 → CMF 100mg/m2 PO d1-14
or 600mg/m2 IV d1&8 /40/600 mg/m2 q4wk x 4) as their control arm,
reÀecting standard UK practice. Pts were randomised to FEC-T (FEC
q3wk x 4 → T 100 mg/m2 q3wk x 4) or control. 2523 patients were from
centres using FEC (FEC=1265: FEC-T=1258) and 1639 from centres
using E-CMF (E-CMF=824; FEC-T=815) as their chosen control arm.
Tumor blocks were collected prospectively for central HER2 testing
and creation of tumor microarrays. The primary endpoint was diseasefree survival (DFS) de¿ned as time to loco-regional or distant relapse,
contralateral invasive breast cancer or death prior to relapse. Secondary
endpoints included overall survival (OS), tolerability of regimens and
quality of life. TACT has 80% power to detect a clinically meaningful
4% difference in DFS (from 71% to 75% at 5 yrs). Survival estimates
will be compared using strati¿ed log-rank tests and Cox regression.
Results: At May 1 2007, median follow up is 50 mths (interquartile
range: 45-59). 954 DFS events were reported, exceeding the threshold
set by the independent Data Monitoring & Ethics Committee for analysis
for presentation. Centrally con¿rmed HER2 status is available for 3565
(83%) pts; assessment of other biomarkers for taxane responsiveness
is ongoing. Data to be presented, by treatment group, are DFS, OS and
planned subgroup analyses by ER and HER2 status.
Discussion: TACT will provide further data to inform the use of
adjuvant taxanes in early breast cancer. Subgroup analyses will allow
further exploration of the potential interaction with ER and HER2.
79
Evaluating the ef¿cacy of capecitabine given concomitantly
or in sequence to epirubicin/cyclophosphamide → docetaxel
as neoadjuvant treatment for primary breast cancer.
First ef¿cacy analysis of the GBG/AGO intergroup-study
“GeparQuattro”.
von Minckwitz G, Rezai M, Loibl S, Fasching P, Huober J, Tesch
H, Bauerfeind I, Hilfrich J, Mehta K, Untch M. University Hospital
Frankfurt, Frankfurt, Germany; German Breast Group, NeuIsenburg, Germany; Senologie, Brustzentrum, Düsseldorf, Germany;
Frauenklinik mit Poliklinik, Erlangen, Germany; Senologiezentrum
Ostschweiz SENZO, St. Gallen, Switzerland; Onkologie Bethanien,
Frankfurt, Germany; Frauenklinik, München, Germany; Frauenklinik,
Hannover, Germany; Frauenklinik, Berlin, Germany
Background: Integration of new cytotoxic agents is possible by either
simultaneous or sequential addition to established regimens. Direct
comparison of these strategies is usually biased by differences in
treatment duration. A three-arm neoadjuvant study was designed to
address this question by adding capecitabine (X) to docetaxel (D) after
pretreatment with epirubicin/cyclophosphamide (EC).
Patients (Pts) and methods: Pts were eligible in whom adjuvant
chemotherapy would be considered otherwise. Therefore, either
large operable (T3) and locally advanced (T4), or estrogen (ER) and
progesterone (PR) negative receptor status, or ER/PR positive tumors
but clinically node-positive disease were recruited in 115 German
centers to receive 4 cycles of EC (90mg/m2 / 600mg/m2) and to be
than randomized to either 4 cycles of D (100mg/m2) or 4 cycles of DX
(75mg/m2 / 1800mg/m2) or 4 cycles of D (75mg/m2) followed by 4
cycles of X (1800mg/m2) (D→X). Pts with HER-2 positive tumors
received trastuzumab concomitantly with all regimens. The primary
endpoint was pathologic complete response (pCR) at surgery. The coprimary objectives were to assess the effect of X by comparing EC→
D vs. EC→DX + EC→D→X (effect of X) and to assess the effect of
time (24 vs 36 weeks) by comparing EC→D + EC→DX vs EC→Doc→
X. The trial was designed to detect an increase in pCR from 17% to
23.5% (OR 1.5) for each comparison.
Results: Between 08/05 and 12/06 1512 pts entered and after receiving
4 cycles EC, 1421 pts were randomized to D (N=471), DX (N=471),
and D→X (N=479). Complete response (N=102, 7.2%), partial response
(N=917; 64.5%), and no change (N=402; 28.3%) after 4xEC was used
to stratify randomization. Further strati¿cation factors were extent of
disease (1202 [84.6%] operable, 219 [15.4%] locally advanced), ER/
S22
PR status (523 [36.8%] ER and PR negative, 898 [63.2%] ER and/or
PR positive), and HER2 status (434 [30.5%] positive, 979 [68.9%]
negative, 8 not measurable). Surgery is planned for the last pt at the
end of August 2007.
Conclusions: Results of the primary endpoint from this ¿rst mature,
randomized trial evaluating capecitabine as treatment for primary breast
cancer will elucidate which strategy appears to be superior.
80
Characterizing the biology and response of locally advanced
breast cancer in women undergoing neoadjuvant therapy:
preliminary results from the I-SPY trial.
Hylton N, Carey L, DeMichele A, Blume J, Broadwater G, Madhavan
S, Rosen M, George S, Esserman L, ISPY Clinical, Research, Pathology
and Radiology Investigators. Univ of California San Francisco, San
Francisco, CA; Univ of North Carolina, Chapel Hill, Chapel Hill, NC;
Univ of Pennsylvania, Philadelphia, PA; ACRIN, Philadelphia, PA;
CALGB, Chapel Hill, NC; NCI-SPORE, Bethesda, MD
Background: The I-SPY Trial is a multi-institutional study of locally
advanced breast cancer integrating serial biopsy and MRI to measure
response of tumors to neoadjuvant chemotherapy. The primary
objective is to identify surrogate markers of response to neoadjuvant
chemotherapy that are predictive of pathologic remission and survival
in women with stage II/III breast cancer.
Methods: Eligible patients had histologically-con¿rmed primary breast
cancer measuring at least 3 cm within the breast following diagnostic
biopsy. Required initial treatment was an anthracycline (AC)-based
neoadjuvant chemotherapy regimen: AC followed by T (91%); ACbased regimen without T (6%);chemotherapy beyond AC +/- T (2%).
Surgical treatment was individualized based upon response, surgeon,
and patient preference. Serial MRI and core biopsies were performed
at baseline (T1), after one cycle of AC (T2), intra-regimen (T3) and
pre-surgery (T4) to identify markers of tumor response. Patients were
accrued at nine institutions from 2002-2006.
Results: 222 patients were available for analysis as of 4/17/07.
The median patient age was 49 years, with a range of 27-69. The
distribution by age was 20%, 35%, 36%, and 10% for women < 40,
41-50, 51-60, 61-70. The racial distribution was 74% Caucasian, 19%
African-American, 4% Asian, and 3% other. Median tumor size was
6 cm (0-25 cm); 70% had clinically positive nodes. Distribution by
grade was 22% low, 38% intermediate, and 39% high. 54% were ER
positive and 28% had Her-2/neu overexpression. Clinical complete
response (CR) rates (46%) were higher than pathologic CR (35%).
pCR rate in Her2/neu+ patients was double that of Her2/neu- (51% vs.
25%). MRI demonstrated residual disease in 27% compared to 15%
with clinical residual disease. Prede¿ned morphologic MRI patterns
have been assessed in 219 patients. More patients had mutlinodular
or diffuse disease (54%) than solitary masses (46%). Distribution by
phenotype showed: single unicentric mass with well-de¿ned margins
(16%), multilobulated but well-de¿ned mass (30%); multifocal (30%);
diffuse(14%), and septal pattern (8%). As we continue to explore and
dissect the heterogeneity of this disease, we will be aided by the analysis
of baseline biomarkers collected, including 120 Agilent expression
arrays; 159 cDNA microarrays, 59 BAC CGH arrays, 126 MIP arrays,
195 reverse phase protein lysate arrays and 195 IHC assays to date.
Conclusion: The I SPY Trial is a rich repository to study breast cancer
biology and therapeutic response that will enable more effective therapy
for non-responders in the future.
81
Elucidating the stem and progenitor cell hierarchy in breast
development and cancer – an essential role for GATA-3.
Lindeman GJ, Asselin-Labat M-L, Sutherland KD, Barker H, Thomas
R, Shackleton M, Hartley L, Robb L, Grosveld FG, van der Wees J,
Visvader JE. The Walter and Eliza Hall Institute of Medical Research,
Melbourne, Australia; The Royal Melbourne Hospital, Melbourne,
Australia; Erasmus University, Rotterdam, Netherlands
Background: We have previously isolated discrete populations of
mouse mammary cells on the basis of cell-surface markers and de¿ned
a population that expresses ‘basal’ markers and is highly enriched
for mammary stem cells. Expanded stem cell numbers were noted
in the pre-neoplastic phase in the MMTV-wnt-1 mammary tumor
model, consistent with tumors originating in stem cells in this model.
Interestingly, the stem cell-enriched basal population was ‘triple
negative’ for ER, PR and ErbB2. This phenotype is reminiscent of
human basal tumors, suggesting that the mammary stem cell is the
‘cell of origin’ for this poor prognosis subset.
Methods & Results: We now report that the luminal cell population can
be further subdivided on the basis of CD61 (β3-integrin) expression.
The CD61-positive subset contained luminal progenitors, as de¿ned by
2D and 3D colony formation assays. Intriguingly, the CD61+ luminal
progenitor was the earliest cell-type to express ER, with approximately
5% of progenitor cells expressing ER compared to 40% of mature
luminal (CD61-) cells. Since the GATA-3 transcription factor is a key
marker of ‘luminal’ breast tumors, we next studied its role in normal
mammary gland development. A gradient of expression was noted
within the epithelial hierarchy, with low levels in the stem cell-enriched
population and high levels in differentiated luminal cells. Utilising
knockout mice, Gata-3 was found to be essential for mammary gland
morphogenesis in both the embryo and adult. Gata-3 de¿ciency resulted
in an expansion of CD61+ luminal progenitors and a concomitant block
in differentiation in both nulliparous and pregnant mice. Remarkably,
introduction of Gata-3 into the stem cell-enriched population was
suf¿cient to induce maturation along the alveolar luminal lineage.
Discussion: Our studies provide evidence for the existence of an
epithelial hierarchy within the mammary gland and establish GATA-3
as a critical regulator of luminal cell differentiation. These ¿ndings
suggest that high expression of GATA-3 in luminal breast tumors confer
a favorable prognosis due to the promotion of differentiation, while
GATA-3 loss likely results in a more clinically aggressive phenotype.
82
Decrease in tumorigenic breast cancer stem cells in primary
breast cancers with neoadjuvant lapatinib.
Li X, Creighton C, Wong H, Hilsenbeck SG, Osborne CK, Rosen JM,
Lewis MT, Chang JC. Dan L Duncan Cancer Center at Baylor College
of Medicine, Houston, TX
Background: Previously, we have shown that tumorigenic breast cancer
cells (CD44+/CD24-/low) were resistant to conventional chemotherapy.
Residual cancers showed an increase in tumorigenic CD44+/CD24-/low
cells, enhanced tumor-initiation by mammosphere (MS) formation,
and increased new tumor formation by xenograft transplantation
assays. Molecular pathways like EGFR/HER2 have been shown to
be aberrant in CSCs. Methods: We performed a neoadjuvant clinical
trial in 30 patients with locally advanced HER-2 overexpressing breast
cancers who received lapatinib (EGFR/HER2 tyrosine kinase inhibitor)
given initially as a single agent for the ¿rst 6 weeks, followed by a
combination of weekly trastuzumab and 3-weekly docetaxel for 12
weeks before primary surgery. Pathologic response in the surgical
specimens after neoadjuvant therapy was assessed. Sequential core
biopsies of the primary cancers were taken in patients at time of
diagnosis and after week 6 of lapatinib, and assessed for tumorigenic
CD44+/CD24-/low cells by Àow cytometry, and MS formation. Global
gene expression differences between cancer cells bearing CD44+/
CD24-/low cells and all other sorted cells, and between cancer MS and
the primary bulk invasive cancers were analyzed. Results Signi¿cant
tumor regression in the product of bidimensional tumor measurements
with a median decrease of –60.8% (range 0, -86.5%, p=0.001)
was observed in primary tumors after only 6 weeks of single agent
lapatinib. Unlike with chemotherapy, lapatinib treatment decreased
tumorigenic CD44+/CD24-/low breast cancer cells from 10.6% to 4.7%,
and also reduced self-renewal capacity measured by MS assays (30
to 15 MS/10,000 cells, p=0.01). The pathologic complete response
rate after lapatinib and trastuzumab/docetaxel was much higher than
expected, at 63%(16/25). The gene transcription pathways that underlie
chemoresistant, MS-forming CD44+/CD24-/low cells involve genes
belonging to stem cell self-renewal, Notch (Jagged-2, Hes1, Lunatic
fringe, mastermind-like 2), Hedghog (Cyclin B1, CDC2), and Wnt
pathways, FOXP1, growth factor/PI3K/AKT signaling (AKT3, BCL2,
CTNNB1, FGFR2, FOXO1A, FOXO3A, PIK3R1, PTEN), and early
development pathways (JARID2, JMJD2C, and MBNL1), regardless
of HER2 expression in the primary tumor. Conclusion Contrary to
conventional chemotherapy, human breast cancer specimens obtained
from this prospective in vivo study has demonstrated for the ¿rst time,
that lapatinib decreases tumorigenic breast cancer stem cells in the
primary breast cancers of women receiving neoadjuvant treatment.
This data suggests that speci¿c signaling inhibitors of the pathways
responsible for stem cell self-renewal could provide a therapeutic
strategy for eliminating tumorigenic cells in order to achieve long-term
eradication of cancer.
S23
S24
Abstracts – Poster Discussion Sessions
101
Serial detection and characterization of circulating tumor
cells in an animal model.
Eliane JP, Luker KE, Brown M, Repollet M, Doyle GV, Hayes DF, Luker
GD. University of Michigan Medical School; Immunicon Corporation,
Huntingdon Valley, PA
Introduction: The ability to serially monitor tumor response in animal
models in the preclinical phase of drug development could substantially
advance translational studies. Recent publications have shown that
circulating tumor cells (CTC) measured at any point during treatment
of metastatic breast, colorectal, or prostate cancer patients indicate
therapeutic bene¿t. Patients with elevated CTC have shorter progression
free survival and overall survival than those with low levels. The
objectives of this project were to ¿rst adapt an existing automated human
CTC assay system for use in mice and then to optimize the performance
of the murine / CTC model as a tool for drug development.
Materials and methods: Spike-in models: using ∼170 µL of normal
mouse blood spiked with 100-5000 cultured breast cancer cells were
used to establish assay precision. 0.5 - 1 x 106 tumor cells from breast
cancer cell lines (MDA-MB-231, MCF7-FGF, SUM-159) or primary
cells from clinical breast cancer biopsies were used to established
an orthotopic xenograft in SCID NOD mice. The FDA cleared
immunomagnetic/immunoÀuorescence based automated CellTracks™
system (Immunicon Corporation) was used to isolate and enumerate
CTC in 75-100 µl blood samples from serial direct cardiac puncture
(26 gauge needle) of living mice. Normal SCID NOD mice functioned
as controls GFP transfected cell lines used to inoculate mice functioned
as an independent identi¿er for CTC in addition to the cytokeratin
cocktail used in the standard assay. Post-mortems were performed
when possible and results were correlated with site of mets, extent of
disease and CTC levels.
Results: Blood from controls as well as xenograft animals contained
background epithelial cells when blood was drawn from the retroorbital site. No contaminating epithelial cells were found in specimens
when tail vein, direct cardiac or jugular venepuncture methods
were performed. As anticipated, GFP was visible in enriched stably
transduced MDA-MB-231 cells con¿rming that CTC were derived from
human tumor xenografts. Mice bearing MDA-MB-231 or MCF-7-FGF
xenografts had detectable CTC as early as 7 days after implanting cells,
approximately 5 weeks before tumors became palpable. All animals
with detectable orthotopic tumors had CTC (n = 11).
Conclusion: Using an automated system, CTC can be accurately and
reproducible isolated and enumerated from volumes as low as 50 µl
of mouse blood. CTC represent a non-invasive real-time method of
serially monitoring tumor activity in animal systems. They are also
an effective means of optimizing a murine model of metastasis by
identifying the most effective cell line, inoculum site, timing and
method of phlebotomy. Most importantly, this system can be used in
pre-clinical and clinical studies and ultimately translated into actual use
in the clinical setting as currently cleared by the FDA.
102
A new system for enrichment and detection of circulating
tumor cells in the peripheral blood of patients with
Deng G, Burgess D, Manna E, Krag D, Herrler M. Applied Imaging
Corp., San Jose, CA; University of Vermont, College of Medicine, VT
Background: Circulating tumor cells (CTCs) may offer to meet an
existing medical need to monitor cancer patients during a course of
treatment and for helping to determine recurrent disease. Currently,
neither imaging nor blood tests meet the needs of the oncologist
treating the cancer patient in respect of sensitivity, speci¿city and time
to results. Beside the importance to understand the role of CTCs in the
metastatic process, CTCs might also be useful as biomarkers in the
design of clinical trials and to evaluate new potential drug candidates.
Relatively successful approaches for CTC enrichment and detection
are based on binding to anti-EpCAM antibodies. However, some tumor
cells are lacking or have low expression of EpCAM.
Materials and Methods: Here we report a new, highly sensitive and
reproducible method for CTC enrichment and detection and have
successfully applied it to metastatic breast cancer patient’s blood
samples. Anti-cytokeratin alone or in combination with anti-EpCAM
antibodies linked to microbeads is used for CTC enrichment.
Fluorescence labeled anti-cytokeratin (CK), anti-CD45 and DAPI are
used for CTC identi¿cation. Applied Imaging’s ARIOL® SL-50 was
used for image capture and analysis of CTCs on standard microscope
glass slides.
Results: In a method comparison, 37 blood samples from metastatic
breast cancer patients were processed with the CellSearch system and
in parallel by our method. Our method recovered equivalent numbers
of CTCs in the prognostically relevant range (≥5 CTCs) relative to
the CellSearch™ assay; however, our method showed a signi¿cantly
(p=0.04) higher detection rate in the low range (≥1 and ≤4 CTCs).
The Ariol® system achieved an overall higher CTC detection rate
(51% vs. 30%) and a wider dynamic range (1-571 vs. 1-270) than the
CellSearch™ system. No CTCs were detected in blood samples from
healthy individuals.
Conclusion: Our assay is detecting anti-CK enriched tumor cells
from breast cancer patient’s blood samples. Preliminary data indicate
that enrichment with anti-EpCAM and anti-CK may enhance assay
sensitivity. The ARIOL® system provides superior imaging quality
by combining fluorescent and brightfield images. This allows
discriminating between intact cells and cell fragments.
103
MagSweeper: an automated system for high ef¿ciency and
speci¿city capture of live circulating tumor cells.
Powell AA, Talasaz AAH, Mindrinos M, Carlson R, Pease FW, Davis
RW, Jeffrey SS. Stanford University, Stanford, CA
Our group has developed a novel automated robotic device that
ef¿ciently isolates circulating tumor cells (CTCs) while removing
all contaminating blood cells. Our device, the MagSweeper, uses
powerful magnetic rods covered in removable plastic sleeves. These
rods sweep through blood samples, capturing cancer cells labeled
with antibodies linked to magnetic nanoparticles. Upon completion
of the capturing protocol, the magnetic rods undergo several rounds
of washing, thereby removing all contaminating blood cells. Finally,
the cancer cells are released by removing the magnetic rods from the
sleeves, causing the captured cells to be gently dislodged. We have
tested our prototype using a buffered solution on patient blood spiked
with MCF7 breast cancer cells labeled with Epithelial Cell Adhesion
Molecule (EpCAM) antibodies and nanoparticles. In preliminary tests
using buffer, our capture rates averaged 96%. Using patient blood
we achieved capture rates up to 100%, without any contamination by
blood cells. Additionally, cells captured by our device show no reduced
viability when cultured after capture. The exceedingly high purity and
capturing ef¿ciency of CTCs isolated by the MagSweeper will allow
for a variety of genetic and growth assays to be preformed on these
important and poorly understood cells.
104
Circulating tumor cells as a reliable assessment of treatment
ef¿cacy in metastatic breast cancer.
Liu MC, Shields P, Isaacs CJD, Warren R, Cohen P, Wilkinson M,
Ottaviano Y, Zhang Y, Shen R, Jasti M, Gallagher A. Lombardi Cancer
Center, Georgetown University Hospital, Washington, DC; Franklin
Square Hospital, Baltimore, MD
BackgroundThe enumeration of >5 CTC/7.5 mL (CTC, circulating
tumor cells) has been associated with worse progression free survival
(PFS) and overall survival (OS) in metastatic breast cancer (MBC),
and the persistence of >5 CTC/7.5 mL appears to predict for treatment
failure (NEJM 2004; 351:781. Clin Cancer Res 2006; 12:4218.). We
are conducting a prospective clinical trial to validate the prognostic and
predictive signi¿cance of this serum biomarker in MBC. Methods Serial
CTC levels are obtained in patients starting a new systemic treatment
regimen for progressive, radiographically measurable MBC. 10 mL
of peripheral blood are collected before the start of treatment and then
at 3-4 week intervals. All subjects are followed for OS and offered
the opportunity to continue CTC testing upon disease progression.
CTC enumeration is performed on a 7.5 mL blood volume using the
CellSearch™ technology (Veridex, LLC; Warren, NJ). Epithelial cells
are immunomagnetically separated and Àuorescently labeled, and
nucleated (DAPI+) cells with the EpCAM+, cytokeratin 8/18/19+, and
CD45- phenotype are counted as CTC. Clinical outcomes are based
on radiographic studies and physical examination in accordance with
RECIST criteria. Results 54/100 subjects have been accrued to date
with a median follow-up of 28 weeks. 41 subjects have completed at
least one radiographic staging evaluation, with 120 pairs of concurrent
CTC values and imaging assessments. Treatment at study entry for
the 41 evaluable patients includes chemotherapy (34%), endocrine
therapy (36%), and combination therapy with a biologic agent (30%).
98% of subjects (40/41) had >1 CTC/7.5 mL (range 1-311), and 89%
(36/41) had >2 CTC/7.5 mL. Focusing on the pairs of CTC values and
radiographic assessments (irrespective of subject), disease progression
occurred in 33% of cases with <5 CTC/7.5 mL and 71% of cases
with >5 CTC/7.5 mL (p<0.0001). When considering the correlation
between CTC values and radiographic assessments from the same
patient, >5 CTC/7.5 mL is associated with a 4.9-fold higher risk of
disease progression (p=0.0003). Median PFS was 2.7 months and 4.9
months for subjects with >5 vs <5 CTC/7.5 mL at baseline, respectively
(p=0.10). Discussion Reporting PFS on the basis of CTC assessments
at baseline and/or ¿rst-follow-up is complex, as PFS estimates are
arti¿cially bound by timing of the imaging studies. Correlating CTC
levels with concurrent radiographic determinations of disease response
should therefore provide a clearer determination of the signi¿cance of
CTC relative to treatment ef¿cacy. Our preliminary analysis indicates
that the odds of disease progression are 4.9 fold higher for patients
with >5 vs <5 CTC/7.5 mL (p=0.0003). CTC levels may be useful as a
surrogate marker for treatment ef¿cacy, and therefore provide a reliable
means of assessing treatment response in the setting of radiographically
nonmeasurable disease.
105
Disseminated tumor cells correlate with estrogen receptor
positivity in operable breast cancer patients.
Alvarado MD, Brissaud C, Scott J, Magbanua M, Moore D, Ewing
CA, Hwang S, Esserman LJ, Park JW. University of California, San
Francisco, San Francisco, CA
Background: Disseminated tumor cells (DTC) in bone marrow (BM)
and circulating tumor cells (CTC) in peripheral blood have both shown
prognostic and/or predictive signi¿cance in early and advanced breast
cancer, respectively. However, in early breast cancer DTC have typically
been detected by nonquantitative IHC assays and CTC have been more
dif¿cult to detect. We hypothesize that quantitative analysis of these
cells may provide advantages in assessing impact on outcome.
Methods: Patients (pts) with operable breast cancer had BM and blood
sampled at the time of surgery. DTC/CTC were subjected to antiEpCAM immunomagnetic enrichment, followed by multiparameter
Àow cytometry (FC). Primary tumor characteristics included tumor
size, lymph node status, ER and Her-2-neu receptor status. Statistical
analysis was performed using Cox proportional hazard models and
chi square analysis.
Results: 220 pts have been prospectively accrued with a median followup of 58 months. There have been only 22(10%) recurrences and
9(4%) deaths, a lower than predicted event rate in this contemporary
treatment population. BM was sampled in 202 pts and blood in 208.
A positive result for DTC was identi¿ed in 65% of pts. A positive
result for CTC was identi¿ed in 39% of pts. For death, only LN status
is signi¿cantly prognostic (p=0.043) to date. For recurrence, only
tumor size is prognostic (p=0.019) to date. DTC or CTC are not yet
signi¿cantly prognostic for outcome. DTC showed correlation with
ER positivity (p=0.02).
Conclusion: Simultaneous analysis of DTC and CTC is feasible in early
breast cancer. These have not shown signi¿cant impact on outcome
in this patient population and may be related to the unexpectedly low
number of events to date. The presence of DTC appears to correlate
with ER positivity, suggesting the delineation of a subgroup of ER+ pts
at an increased risk of recurrence. However, longer follow-up is needed
to ascertain this possibility, given the prolonged time for recurrence in
the ER+ breast cancer patient.
Relationship Between Tumor Characterisitcs and DTC
All pts (n=202) BM+ pts (n=132)
Tumor size cm (p=0.66) 0 to <1 62
37
1 to <2 94
61
2 to <4 46
27
>4
11
7
ER (p=0.002)
pos
183
118
neg
18
14
Her2 (p=0.42)
pos
41
26
neg
169
103
Grade (p=0.83)
1
82
49
2
79
49
3
56
34
Node status (p=0.68)
pos
82
47
neg
120
85
Relationship Between Tumor Characteristics and CTC
Total pts (n=208) CTC+ pts (n=81)
Tumor size cm (p=0.26) 0 to <1 64
21
1 to <2
36
2 to <4
18
>=4
6
ER (p=0.13)
pos
72
neg
9
Her2 (p=0.55)
pos
13
neg
66
Grade (p=0.44)
1
36
2
24
3
21
Node status (p=0.56)
pos
28
neg
53
S25
BM- pts (n=70)
25
27
15
3
50
19
10
55
29
24
17
27
43
CTC- pts (n=127)
43
54
27
3
102
24
24
97
46
47
34
49
78
106
Features of patients (pts) with metastatic breast cancer
(mBC) and a circulating tumor cell count (CTCc) of 0.
Bubis JA, Marsland TA, Justice KM, Edwards D. Integrated Community
Oncology Network, Orange Park, FL
Background: Circulating tumor cells (CTCs) can be measured in the
peripheral blood of pts with breast cancer (BC). These cells likely
play a role in the dissemination of disease and may be present prior
to radiologic or clinical ¿ndings of metastatic disease. The Veridex
CellSearch assay is the only FDA approved method for detecting these
cells. A CTCc of 5 or greater per 7.5 mL of blood is predictive of a
decreased progression free survival and decreased overall survival
in pts with mBC. In pts receiving therapy, an increasing CTCc or a
persistent CTCc of 5 or greater may indicate the need to consider
changing therapies. While a CTCc of 0 is reassuring, some patients with
a CTCc of 0 have clearly measurable and/or progressive disease. We
have endeavored to review the characteristics of these patients.
Materials & Methods: This is a single institution, IRB-approved,
retrospective chart review. All CTCs were measuring in our laboratory
using the Veridex CellSearch assay.
Results: 24 pts were found to have a CTCc of 0 at various stages of
therapy. Including repeat studies, the total number of time points studied
with a CTCc of 0 = 48. CA27.29 correlates were obtained for 29/48.
Average CA27.29 = 112.3 (range 15.0-807.2). Average age = 67 (range
34-89). 17 pts were postmenopausal. ER+ =14/24. HER2+=13/24.
ER-/HER2- = 2. Stage IV at diagnosis = 3. Bone-only metastases =
4. Lung-only metastases = 1. Liver-only metastases = 3. Other sites
(includes pleural effusion, chest wall, thyroid, mediastinum, pelvis,
brain)= 9. Bone and visceral metastases = 5. 2 pts had CTCc of >5
and subsequently went to zero with continued evidence of persistent
disease and rising CA27.29s.
Discussion: CTCs can be a helpful test in predicting prognosis and
response to ongoing therapy. However, we have demonstrated that
a CTCc of 0 does not always correlate with the behavior of mBC.
Our data indicates that pts with a CTCc of 0 may still have active,
progressive disease; although the small number of patients prevents
us from drawing statistical conclusions. This study is ongoing; further
investigation of this patient population is indicated. Updated data will
be available for presentation.
S26
107
Bone marrow micrometastasis and circulating tumor
cells are respectively strong prognostic factors in early
and metastatic breast cancer, a comparative study on 759
patients.
Bidard F-C, Vincent-Salomon A, Sastre X, Sigal-Zafrani B, Nos C,
Mignot L, Dieras V, Asselah J, Thiery JP, Pierga J-Y. Institut Curie,
Paris, France; IMCB Biopolis, Singapore, Singapore
Background:
Disseminated cancer cells are bone marrow micrometastasis (MM) and
circulating tumor cells (CTC). Bone marrow MM has been reported
to be a pronostic factor for both early and metastatic breast cancers.
CTC have also a prognostic impact in the metastatic setting. With a
highly speci¿c method for MM and CTC detection, we analyzed the
pronostic impact of these disseminated tumors cells in stage I to III
and in stage IV breast cancers.
Material and Methods:
From 11/98 to 11/04, cytospun Ficoll fractions of bone marrow aspirates
from 759 breast cancer patients (621 stage I to III and 138 stage IV)
were screened by immunocytochemical (ICC) with the pancytokeratin
monoclonal antibody A45-B/B3. Morphologic criteria were used to
distinguish isolated cancer cells from other cytokeratin-positive cells
in BM. CTC were simultaneously in peripheral blood were screened
by ICC in 77 stage I to III and 37 stage IV patients. Bone marrow
status was correlated with clinical outcome after a median follow-up
of 51 months.
Results:
Bone marrow MM with tumoral morphologic features were detected in
15% of the patients with stage I to III. On multivariate analysis, MM
in BM was the strongest prognostic factor for overall survival (RR=
2.43, p<0.0001). Other prognostic factors were clinical stage (p=0.004),
tumor grade (p=0.011) and tumor emboli (p=0.02). MM detection
was also associated with a poorer distant metastasis-free survival
(DMFS, RR=2.03 p=0.002) with a trend for more liver than bone
metastasis. Surprisingly MM were also associated with a poorer local
relapse free survival (RR= 3.92, p=0.0001). In 138 stage IV patients,
MM detection (65%) in BM was highly associated with clinical or
radiological bone metastasis (p=0.0001) and lobular histology (p=0.05).
Presence of MM in BM was not associated with a poorer survival rate.
Adverse prognostic factors for overall survival were hormonal receptor
negativity (p <0.001), more than one line of chemotherapy (p=0.004),
and liver involvement. CTC detection in a subgroup of 37 metastatic
patients was associated with a shorter survival (p=0,01).
Conclusion
For early stage of breast cancer, MM detection in bone marrow is a
strong independent prognostic factor. MM in BM in stage IV breast
cancer patients did not have a prognostic signi¿cance. This study
¿nally suggest that CTC are a usefull marker of the tumor aggressivity
in metastatic patients, whereas bone marrow MM are a marker of the
primary tumor ability to metastasize.
108
Prognostic value of the detection of circulating tumor cells
using a multimarker RT-PCR (CK19, mammaglobin A,
HER2/neu) in early breast cancer.
Ignatiadis M, Kallergi G, Ntoulia M, Apostolaki S, Perraki M, Xenidis
N, Stathopoulou A, Lianidou E, Georgoulias V, Mavroudis D. University
General Hospital of Heraklion, Heraklion, Crete, Greece; School of
Medicine, University of Crete, Heraklion, Crete, Greece; University
of Athens, Athens, Greece
Objective: To investigate the prognostic value of the molecular detection
of Circulating Tumor Cells using 3 markers (CK19, MammaglobinA
and Her2/neu) in early breast cancer
Patients and methods: CK19 mRNA-, MammaglobinA mRNA-, and
HER2 mRNA- positive cells, were detected using real-time (CK19)
and nested (MammaglobinA and HER2) RT-PCR, in 140 women with
stage I-III breast cancer before the initiation of adjuvant chemotherapy.
Their detection was correlated with clinical outcome. In 10 breast
cancer patients, double immunofluoresence staining experiments
were performed to investigate the co-expression of Cytokeratin (CK),
MammaglobinA and HER2 in CTCs.
Results: Among the 140 patients, 32.9% were premenopausal, 75.7%
had tumors > 2cm, 49.3% were histological grade III, 38.6% were
ER negative and 70.7% had in¿ltrated axillary lymph nodes. CK19
mRNA, MammaglobinA mRNA- and HER2 mRNA-positive cells were
detected in 42.8%, 9.3% and 22.1% of patients, respectively. Patients
had one of the following molecular pro¿les: CK19+/MammaglobinA+/
HER2+ (n=6), CK19+/MammaglobinA+/HER2- (n=2), CK19+/
MammaglobinA-/HER2+ (n=25), CK19+/MammaglobinA-/
HER2- (n=27), CK19-/MammaglobinA+/HER2- (n=5), CK19/MammaglobinA-/HER2- (n=75). Immunofluorence experiments
con¿rmed the following CTC phenotypes: CK+/MammaglobinA+,
CK+/MammaglobinA-, CK-/MammaglobinA+, CK+/HER2+, CK+/
HER2-, MammaglobinA+/HER2- and MammaglobinA+/HER2+. In
univariate analysis, the molecular detection of CK19-, MammaglobinAand HER2-positive cells were all significantly associated with
shorter disease-free survival (DFS), (p<0.001, p=0.004 and p=0.017,
respectively), whereas only the detection of CK19-positive cells was
associated with worse overall survival (p=0.001). In multivariate
analysis, histological grade III tumors and the detection of CK19
mRNA- and mammaglobinA mRNA-positive cells were independently
associated with worse DFS.
Conclusion: This multimarker RT-PCR provides significant and
independent prognostic information regarding DFS in women with
early breast cancer.
109
Circulating CK-19 mRNA (+) cells in patients with stage
I and II breast cancer after the completion of adjuvant
chemotherapy: evaluation of their prognostic relevance.
Xenidis N, Apostolaki S, Perraki M, Politaki E, Kalbakis K, Ignatiadis
M, Kalykaki A, Agelaki S, Georgoulias V, Mavroudis D. University
General Hospital of Heraklion, Heraklion, Crete, Greece; School of
Medicine, University of Crete, Heraklion, Crete, Greece
Purpose: To evaluate the prognostic value of circulating CK-19 mRNA
(+) cells in patients with early stage breast cancer after the completion of
adjuvant chemotherapy. Patients and Methods: 450 patients with early
(stage I/II) breast cancer were included in the present study. All patients
received adjuvant chemotherapy (CMF= 43; FEC= 210; T/EC= 197).
Peripheral blood (20ml in EDTA) was obtained before the initiation
and after the completion of adjuvant chemotherapy. Circulating CK19 mRNA (+) cells were evaluated by real time RT-PCR. Results:
One hundred and forty-seven (32.7%) patients had detectable CK-19
mRNA (+) cells post-chemotherapy. Only the presence of >3 involved
axillary lymph nodes was associated with a higher incidence of CK-19
mRNA (+) cells post-chemotherapy. Detection of circulating CK-19
mRNA (+) cells post-chemotherapy was signi¿cantly associated with
either a clinical relapse (p= 0.002) or disease-related death (p= 0.001).
Multivariate analysis demonstrated that the detection of CK-19 mRNA
(+) cells after chemotherapy was an independent factor for early relapse
(H.R 1.726; 95% CI 1.146-2.598; p= 0.009) and overall survival (H.R
2.034; 95% CI 1.079-3.836; p= 0.028). Conclusions: These results
further support that the detection of circulating CK-19 mRNA (+) cells
after adjuvant chemotherapy is a prognostic factor associated with poor
clinical outcome.
110
Circulating epithelial tumor cells a new tool for therapy
monitoring in breast cancer: a more than tenfold increase
in numbers during systemic therapy is highly predictive
of relapse.
Pachmann K, Camara O, Cavallaris A, Krauspe S, Malarski N, Gajda
M, Kroll T, Runnebaum I, Hoeffken K. Friedrich Schiller-Universität
Jena, Jena, Germany
Background: To demonstrate the feasibility of the analysis of circulating
epithelial tumor cells (CETC) to monitor the response to adjuvant
therapy and to early detect patients at risk of relapse.
Patients and Methods: In 91 non-metastatic primary breast cancer
patients CETC were quanti¿ed using Laser Scanning cytometry of antiEpCAM stained epithelial cells from whole unseparated blood before
and during adjuvant chemotherapy consisting of adjuvant Epirubicin/
Cyclophosphamid, Fluorouracil/Epirubicin/Cyclophosphamid with
or without subsequent taxane, or Cyclophosphamid/ Methotrexate/
Fluorouracil therapy.
Results: Numbers of CETC were analyzed before each new cycle
and at the end of chemotherapy. 3 typical patterns of response were
observed: 1. a decline, 2. minor changes in cell numbers, 3. a (sometimes
saw-toothed) increase (more than tenfold), or an initial decline with
subsequent reincrease more than tenfold in numbers of CETC. 20
(22%) relapses were observed within the accrual time of 40 months, 1
among the 28 patients from response group 1; 5 among the 30 patients
from response group 2 and 14 among the 33 patients from response
group 3. Mean relapse free survival time was 537 days for patients
without increase of CETC and 479 days for patients with increase of
CETC. The difference in relapse free survival was highly signi¿cant
(p < 0.0001).
Conclusion: These results show that cell numbers are inÀuenced
differently by the different agents and even after initial response to
therapy, an increase at the end of therapy is a strong predictor of relapse
(hazard ratio = 250) and is a surrogate marker for the aggressiveness
of the tumor cells.
201
A unique model of estrogen receptor (ER) α-positive breast
cancer metastasis.
Fuqua SA, Beyer A, Selever J, Hilsenbeck SG, Tsimelzon A, Cui Y.
Background: Mortality from breast cancer results from the ability of
some tumors to metastasize to distant sites. Unfortunately, we only
have a few preclinical breast cancer cell lines which metastasize to
distant sites. But these models are from ERα-negative cell lines, and
are thus not representative of the majority of patients, since two-thirds
of patients have ERα-positive tumors.
Material and Methods: To identify genes whose expression was
associated with the development of treatment resistance and metastasis,
we employed expression microarray analyses comparing primary
tumors from patients treated with the antiestrogen tamoxifen (Tam) who
did not recur, vs. metastatic tumors from patients that progressed during
adjuvant Tam treatment. We identi¿ed Rho guanine disassociation
inhibitor (GDI) α as being signi¿cantly under expressed in the Tamresistant group. We engineered ERα-positive MCF-7 breast cancer
cells by stable transfection with a plasmid encoding a short hairpin
(sh) RNA to Rho GDIα. We used growth assays in vitro and in vivo to
examine the effects of Rho GDIα blockade on hormone responsiveness
and metastatic behavior.
Results: Rho GDIα knockdown cells exhibited hormone-independent
growth in soft agar. Vector control and knockdown cells were injected
into athymic nude mice supplemented with estrogen and were
randomized to estrogen treatment, or to have the estrogen withdrawn
and remain untreated, or to begin Tam treatment. The Rho GDIα
knockdown tumors were resistant to Tam treatment. Remarkably 3050% of the Rho GDIα knockdown Tam and estrogen-treated tumors
metastasized to the lung within three months. These metastases were
ERα and progesterone receptor positive using immunohistochemistry.
We found that knockdown of Rho GDIα with shRNA enhanced
estrogen-induced activity in vitro. Since p21 activated kinase (PAK1)
is an effector of Rho GDIα, and we and others have shown that protein
kinase A and PAK1 can signal to and phosphorylate ERα at serine
(S) 305, we performed an in vitro immune complex kinase assay and
found that knockdown of Rho GDIα led to PAK-1 phosphorylation
of S305.
Discussion: We have established for the ¿rst time an ef¿cient metastatic
model of ERα-positive breast cancer cells which will be useful for
preclinical testing of inhibitors to intervene in the distant metastatic
cascade in vivo. Furthermore, our preliminary data suggests that ERα
phosphorylation at S305 may be downstream of Rho GDIα’s effects.
S27
We hypothesize that loss of Rho GDIα function promotes distant
metastatic spread of hormone-resistant ERα-positive breast tumors
via crosstalk with ERα and/or by triggering downstream molecules
with metastasis-promoting activities.
202
Primary tumor heterogeneity and sentinel lymph node
metastases: understanding molecular processes of breast
cancer metastasis.
Ellsworth DL, Ellsworth RE, Patney HL, Becker TE, Deyarmin B,
Jordan RM, Hooke JA, Shriver CD. Windber Research Institute,
Windber, PA; Walter Reed Army Medical Center, Washington, DC
Background: Sentinel lymph node (SLN) status is a key prognostic
factor for breast cancer patients. Sentinel nodes are believed to receive
early disseminating cells from the primary tumor, but it is unclear
whether the timing of metastatic dissemination or heterogeneity among
cell lineages in the primary tumor de¿nes the genetic makeup and
ultimately the clinical behavior of lymph node metastases. This study
used allelic imbalance (AI) to examine genomic relationships among
metastases in the sentinel and non-sentinel axillary lymph nodes and
multiple microdissected areas of the primary carcinoma in 20 patients
with lymph node positive breast cancer.
Methods: Heterogeneity was assessed in three dimensions by laser
microdissection of 6-15 areas (each ∼2.86 sq mm in size) from
multiple sections of the primary tumor. Sentinel nodes were localized
by standard scintigraphic and gamma probe techniques using 1.0 mCi
technetium-99m sulfur colloid (Tc-99). Pathologically positive nodes
were identi¿ed by H&E histology/IHC and metastases were isolated
by microdissection. AI was assessed at 26 chromosomal regions and
used to examine molecular mechanisms and infer timing of metastatic
spread to the sentinel and axillary nodes.
Results:
A high level of discordance was observed in patterns and frequencies
of AI events between metastases in the sentinel versus the nonsentinel axillary nodes. Hierarchical clustering and phylogenetic
analyses suggest that (1) multiple genetically-divergent metastatic
cells independently colonize the lymph nodes with vastly different
patterns of genomic alterations; (2) genomic heterogeneity in the
primary tumor at the time of diagnosis may not fully explain patterns
of molecular changes in the corresponding metastases; and (3) the
genomic composition of sentinel node metastases varies considerably
and may reÀect timing of metastatic dissemination rather than primary
tumor heterogeneity.
Conclusions: Genomic diversity and timing of metastatic nodal spread
may be important factors in determining outcomes of breast cancer
patients. Metastases successfully colonizing the sentinel nodes have
different patterns of molecular alterations not completely explained by
primary tumor heterogeneity, suggesting that these metastases arise at
different times during disease progression. Early growth of metastases
in the sentinel nodes thus may be a consequence of stimulating factors
that affect proliferation of previously disseminated cells rather than the
timing of metastatic spread.
203
Identi¿cation of genetic predisposition to development of
lymph node metastasis in breast cancer patients.
Callaghan KA, Weyandt JD, Ellsworth RE, Shriver CD. Windber
Research Institute, Windber, PA; Walter Reed Army Medical Center,
Washington, DC
Background: Breast cancer metastasis to ipsilateral axillary nodes is
one of the most important predictors of poor outcome in breast cancer
cases, and signi¿cantly inÀuences the recommendations for adjuvant
treatment such as chemotherapy. There is currently no way to predict
which patients will develop lymph node metastases despite multiple
studies examining the potential impact of primary tumor characteristics
on this phenomenon. Here we attempt to identify DNA variants that
potentially predispose individuals with breast cancer to the development
of lymph node metastases.
Methods: Genomic DNA was obtained from blood samples from
node-positive (n=37) and node-negative (n=40) Caucasian female
S28
breast cancer patients under 50 years of age. Following digestion,
ligation, and PCR, the biotin-labeled DNA product was fragmented
and hybridized to GeneChip Human Mapping 100K single nucleotide
polymorphism (SNP) arrays (Affymetrix). Data was analyzed using
Exemplar software and signi¿cance was evaluated using a P value
of <0.001. Results were compared between node-positive and nodenegative samples to identify signi¿cant differences in polymorphisms
between the two groups.
Results: Association studies using Fisher’s exact test revealed that
allele frequencies from 39 SNP markers representing 31 chromosomal
regions were signi¿cantly different between the two groups (P<0.001).
Additional model building analysis supported 36 of these markers,
with each of these regions demonstrating a difference in two or more
statistical tests when comparing node-negative to node-positive
samples. Of note, there were six chromosomal regions (5p13.2,
6q22.31, 8q13.3, 9p24.1, 14q32.2, and Xq23) in which multiple SNP
markers exhibited signi¿cance in both association analysis and model
building algorithms.
Conclusions: Identi¿cation of SNPs within six chromosomal regions
with signi¿cant differences between node-negative and node-positive
breast cancer patients suggests that the propensity to develop metastases
may be inÀuenced by genetic factors. Of the potential candidate genes
that have been discovered in these regions, several have been found
to function in immuno-modulation, cell growth regulation, and lipid
metabolism, thus polymorphisms within these genes may either confer
a protective effect by enhancing the host’s immuno-surveillance or
render individuals susceptible to metastatic spread by creating a host
tissue environment favorable to metastatic colonization.
204
Identi¿cation of new candidate breast cancer metastasis
genes.
Geradts J, Desouki MM, Liao S. Duke University Medical Center,
Durham, NC; Medical University of South Carolina, Charleston, SC
Background: We recently reported our results of a study identifying a
number of DNA copy number changes that distinguished small, high
grade, ER-positive breast carcinomas with and without associated
nodal metastases, as well as primary breast carcinomas and their paired
nodal deposits. We now describe a series of validation experiments that
support the role of six genes in breast cancer progression, most of which
were not previously implicated in mammary neoplasia.
Materials and Methods: DNA was extracted from macrodissected
paraf¿n sections (tumor cellularity >50%) of formalin ¿xed invasive
ductal carcinomas and their paired lymph node deposits (n=29), as
well as matched primary breast carcinomas without associated nodal
metastases within at least 5 years (n=24). The DNA was used for
comparative PCR, and the frequency of copy number gains and losses
was determined for each candidate gene. Additional validation studies
employed immunohistochemistry and quantitative RT-PCR using
RNA extracted from another cohort of frozen breast carcinomas and
from cell lines.
Results: We con¿rmed that 5 genes were more commonly deleted in
primary carcinomas compaired to their nodal metastases: DNCLI1,
SOX6, BCL2-L10, DDX6, and TIAM1. DDX6 and TIAM1 were
further remarkable for amplification in 25-30% of lymph node
metastases, suggesting a possible role of these genes in breast cancer
progression. The novel tetraspanin TSPAN1 was ampli¿ed in almost
half of tumors without nodal deposits, but deleted in almost half of
breast cancers with metastases, suggesting a possible role of this
gene as a metastasis suppressor (similar to other tetraspanins). At
the mRNA expression level, TSPAN1 was markedly downregulated
in HER2-negative versus HER2-positive breast cancer cell lines.
Expression was also signi¿cantly lower in HER2-negative and ERnegative breast carcinomas. Interestingly, by far the lowest levels
were observed in ER-/HER2- (basal-like) tumors. Although we could
not con¿rm their differential ampli¿cation or deletion, we identi¿ed
a number of additional candidate metastasis genes including Claudin
10 that showed copy number losses in a signi¿cant subset of primary
breast carcinomas.
Discussion: Our validation experiments have provided additional
evidence for the role of several novel genes in breast cancer metastasis.
Of these, TSPAN1, DDX6 and TIAM1 may be particularly relevant.
205
ALDH1 positive stem cells in inÀammatory breast cancer
mediate metastasis and are associated with a poor clinical
outcome.
Charafe-Jauffret E, Ginestier C, Tarpin C, Iovino F, Esterni B,
Jacquemier J, Xerri L, Merajver S, Dontu G, Birnbaum D, Wicha M,
Viens P. Institut Paoli-Calmettes, Marseille, France; Comprehensive
Cancer Center, University of Michigan Medical Center, Ann Arbor,
MI, France
Inflammatory breast cancer (IBC) is a relatively rare aggressive
form of breast cancer with a poor prognosis associated with a high
propensity to develop systemic metastasis. The molecular mechanisms
which mediate metastasis in this cancer and markers to predict its
occurrence remain unde¿ned. There is accumulating evidence that
breast cancers may contain a small «cancer stem cell» population
which drives tumorogenesis and contributes to therapeutic resistance.
In order to determine whether inÀammatory breast carcinoma contains
cancer stem cell populations which mediate metastasis, we utilize a
cell line SUM 149, derived from a primary IBC. Cells expressing the
stem cell maker aldehyde dehydrogenase were isolated from this cell
line utilizing the ALDEFLOUR assay. Utilizing Àow cytometry, we
isolated an ALDEFLUOR-positive component composing 3-5% of the
total population which displayed stem cell properties. ALDEFLUORpositive but not ALDEFLUOR-negative cells were tumorigenic in
NOD/SCID mice and were able to reconstitute the global heterogeneity
of the initial cell line upon serial passage in mice. In order to examine
the metastatic capacity of these cells they were labeled with a luciferase
containing lentivirus and introduced via intracardiac injection into
NOD/SCID mice. Only the ALDEFLUOR-positive cells were able to
form metastasis.
In order to investigate the clinical relevance of ALDH1 expression in
IBC, we examined the expression of ALDH1 utilizing a monoclonal
antibody in a series of 109 IBC specimens. ALDH1 was found to
be expressed in 31% of these tumors, ALDH1 expression did not
correlate with other clinical pathologic markers including estrogen and
progesterone receptor, BCL2, ERBB2, MUC1, or E-cadherin. However,
ALDH1 expression was found to be a strong predictor of patient
outcome and was associated with poor overall survival p=0.0337, as
well as metastasis-free survival p=0.0152. Metastasis-free survival was
49 months in patients with ALDH1-negative tumors as compared to 20
months in patients with ALDH-positive tumors. Multi-variant analysis
using Cox proportional hazard models showed that ALDH1 is the most
powerful marker of speci¿c survival (p=0.0012 and the only marker of
metastasis-free survival HR=2.81, 95% CI [1.355-5.815], p=0.0055).
These studies suggest that a subset of IBC contain ALDH1 positive
«cancer stem cells» which are responsible for tumor metastasis. In
addition, the expression of ALDH1 in patient specimens is a strong
predictor of metastasis and poor clinical outcome. The measurement
of ALDH1 in pretreatment biopsies may help to de¿ne those patients
needing particularly aggressive therapy. Furthermore, successful
treatment of these patients may require development of strategies which
selectively target this cell population.
206
Programmed cell death 4, a novel inhibitor of breast cancer
invasion.
Nieves-Alicea R, Simeone AM, Colburn NH, Tari AM. The University
of Texas M.D. Anderson Cancer Center, Houston, TX; National Cancer
Institute, Frederick, MD
High expression of the cyclooxygenase-2 (COX-2) protein is found in
36-63% of human breast tumors, and is associated with tumor invasion
and metastasis. Previously we demonstrated that COX-2 increases
the invasion of breast cancer cells by increasing the production of
prostaglandin E2 (PGE2), which results in increased protein kinase C
(PKC) activity and increased interleukin-8 (IL-8) production. Here we
expand our studies to determine speci¿cally what downstream factors
are inhibited by the COX-2/PGE2/PKC/IL-8 pathway for breast cancer
invasion. Microarray analysis revealed that the mRNA expression of
Programmed Cell Death 4 (PDCD4) is 2-fold lower in MCF-7 breast
cancer cells stably transfected with COX-2 (MCF-7/COX-2) than
parental MCF-7 cells. PDCD4 is a tumor suppressor protein whose
expression is decreased in many tumor types, including breast tumors.
Western blot analysis of MCF-7/COX-2 cells showed decreased
PDCD4 expression, in comparison to the parental MCF-7 cells, thus
corroborating our microarray results. In addition, PDCD4 protein
levels were decreased when MCF-7 cells were treated with PGE2,
the PKC activator phorbol-12-myristate-13-acetate (PMA), or IL-8.
We hypothesized that COX-2 utilizes the PGE2/PKC/IL-8 pathway
to suppress PDCD4 expression to induce breast cancer invasion, and
that overexpression of PDCD4 would reverse the invasive activity of
COX-2. Plasmids encoding the human PDCD4 cDNA were stably
transfected into MCF-7 cells (MCF-7/PDCD4). Matrigel invasion assay
was used to investigate the invasiveness of MCF-7/PDCD4 cells. PGE2,
PMA, and IL-8 all failed to induce the invasion of MCF-7/PDCD4
cells, indicating that high levels of PDCD4 suppress breast cancer
invasion. Furthermore, MCF-7/PDCD4 cells were found to produce
4-fold higher levels of the Tissue Inhibitor of Metalloproteinases-2
(TIMP-2) than the parental MCF-7 cells. To determine whether TIMP-2
is essential for PDCD4 to inhibit invasion, we used siRNA to knock
down TIMP-2 expression in MCF-7/PDCD4 cells. Pretreatment of
MCF-7/PDCD4 cells with TIMP-2 siRNA allowed PGE2, PMA, and
IL-8 to induce the invasion of MCF-7/PDCD4 cells, indicating that
knocking down the expression of TIMP-2 reversed the anti-invasive
effects of PDCD4. Here we report the novel ¿ndings that COX-2
decreases PDCD4 expression via the PGE2/PKC/IL-8 pathway, and
that PDCD4 increases TIMP-2 production to inhibit breast cancer cell
invasion. Bone metastasis occurs in 3 out of 4 patients with advanced
breast cancer. COX-2 has been indicated as a determinant of breast
cancer bone metastasis. We are currently conducting experiments to
determine whether PDCD4 overexpression could block COX-2 driven
breast cancer bone metastasis.
207
TROP2 is a novel, major determinant in breast cancer
growth and metastatization.
Alberti S, Trerotola M, Vacca G, Zappacosta R, Rossi C, Guerra E,
Bonasera V, Lasorda R, Lattanzio R, Piantelli M. Foundation University
of Chieti, Chieti Scalo, Chieti, Italy
Background: TROP2 is an intronless gene that encodes a transmembrane
calcium signal transducer, that contains an EGF-like and a thyroglobulin
domain in its extracellular portion and a HIKE motif / PKC
phosphorylation site in its cytoplasmic region.
Material and Methods: A relationship between expression patterns of
TROP2 and differentiation / tumor progression stages was explored
with DNA array, SAGE, Northern and Western blotting, Àow cytometry,
confocal microscopy and IHC analysis of normal and transformed
tissues. The functional role of Trop-2 in breast cancer was analysed
in vitro and in vivo by transfection of the gene or down-regulation
of endogenous expresssion. Mutagenesis of the Trop-2 cytoplasmic
tail was used to identify signaling pathways in tumor growth and
metastatization in vivo.
Results: The TROP2 gene was found upregulated in most breast cancers
by DNA microarray, EST, SAGE, RT-PCR and Northern blot analysis.
IHC analysis of 1231 breast cancer cases demonstrated a dramatic
overexpression of the Trop-2 protein. Trop-2 potently stimulated the
growth of tumor cells, whereas TROP2 siRNA inhibited the growth of
breast cancer cell lines. Trop-2 transfectants demonstrated a reduced
cell-cell and cell-substrate adhesion, that correlated with changes in
cell shape and cell aggregate geometry and orientation. Deletion of the
cytoplasmic region of Trop-2 abolished its growth stimulatory capacity,
as did mutagenesis of the S303 PKC phosphorylation site. Proteomic
and phosphoproteomic analysis indicated PKCα as a downstream
effector of Trop-2. In vivo imaging showed dynamic colocalization of
PKCα and Trop-2 in vivo in membrane rufÀes and podosomes. DN
PKCα and PKCα siRNA abolished the Trop-2-induced growth. The
increase in cell growth correlated with cell surface levels of Trop-2,
and IHC analysis revealed up-regulation of Trop-2 in breast cancer
metastases compared with primary tumors. To assess if Trop-2 played
a direct role in metastatic spreading, TROP2-transfected KM12SM
cells were orthotopically injected in nude mice. TROP2-overexpressing
transfectants demonstrated increased metastatic potential to the liver.
Deletion of the HIKE domain of Trop-2 severely diminished, whereas
S29
that of the whole cytoplasmic region vastly increased metastatic
diffusion, indicating the existence of both metastatic enhancers and
silencers in the Trop-2 cytoplasmic tail.
Discussion: Our findings candidate Trop-2 as a novel, critical
determinant of breast tumor growth, as well as of metastatic cancer.
Novel diagnostic and therapeutic procedures are being targeted to
Trop-2.
208
Osteoblasts and their progenitors stimulate breast cancer
cell migration through chemokine secretion.
Molloy AP, Dwyer RM, Kerin MJ. National University of Ireland,
Galway, Ireland
Introduction
Although breast cancer mortality is decreasing, in patients with
advanced disease over 80% will develop bone metastases for which
there is no cure. Bone is a very dynamic environment with continuous
cell turnover, which may play an important role in directing the homing
and engraftment of circulating breast cancer cells. Mesenchymal Stem
Cells (MSCs) and osteoblasts are two subpopulations of cells that exist
within bone. MSCs have the potential to differentiate into a range of
cell types, and when cultured under appropriate conditions will develop
into osteoblasts. Chemokines secreted from bone derived cells are
believed to create a favourable microenvironment for development
of metastases.
Aim
The aim of this project was to investigate chemokine secretion by bone
derived cells and elucidate the potential role of MSCs and NHOst
(osteoblast progenitor) cells in breast cancer cell migration.
Methods
Migration of breast cancer cells (BT-474 and MDA-MB-231) in
response to MSCs and NHOst cells was investigated using Transwell™
migration inserts. Chemokines secreted by the bone derived cells
were detected using ChemiArray™ & ELISA®. The potential role
of Monocyte Chemotactic Protein -1 (MCP-1) in breast cancer cell
migration was investigated using a monoclonal antibody to the
chemokine. Differentiation of cells into mature osteoblasts was induced
in the presence of appropriate media supplements and con¿rmed using
Von Kossa staining. The level of MCP-1 secreted was quanti¿ed at
various stages of differentiation.
Results
There was a signi¿cant increase in migration of both breast cancer
cell lines in response to factors secreted by the bone derived cells
(5-10 fold increase). MSCs and NHOst cells were shown to secrete a
range of chemokines including IL-6 & 8, TIMP 1 & 2 and MCP-1. A
monoclonal antibody to MCP-1 resulted in inhibition of MDA-MB-231
(20% reduction) and BT-474 (30% reduction) migration in response
to bone derived cells. Differentiation of cells into mature osteoblasts
was con¿rmed by the presence of calcium deposits following Von
Kossa staining. When cultured in differentiating conditions the levels
of MCP-1 rose signi¿cantly from 319 pg/ml on day 3 to 12,280 pg/ml
on Day 21, which was signi¿cantly higher than that seen in control
cells (p<0.05).
Conclusion
Bone derived MSCs and NHOst cells secrete varying levels of
chemokines, including MCP-1, that play a potentially important
role in mediating breast cancer cell migration. This variation in both
type and level of chemokines detected during differentiation may aid
the development of a favourable premetastatic niche, and inÀuence
subsequent homing and engraftment of circulating cancer cells.
209
Signi¿cance of PELP1/MNAR-mediated ER-nongenotropic
actions in cytoskeleton signaling.
Chakravarty D, Chandrasekharan Nair B, Rajhans R, Cortez V, Nair
SS, Tekmal RR, deGraffenried LA, Sun LZ, Vadlamudi RK. UTHSCSA,
San Antonio, TX
Background: Emerging evidence suggests that in addition to wellstudied nuclear functions, the estrogen receptor (ER) also participates
in nongenotropic (cytoplasmic and membrane-mediated) signaling via
S30
formation of a multiprotein complex collectively called as “signalsome”.
The role of ER-nongenotopic signaling in the progression and metastasis
of breast cancer is not known and the identity of the molecular targets in
the ER-signalsome is elusive. Recent studies identi¿ed Proline, glutamic
acid, and leucine-rich protein-1 (PELP1) as one of the component of
ER signalsome. PELP1 participates in ER nongenotropic signaling
and its expression is deregulated in breast tumors. In this study we
examined the signi¿cance of PELP1-mediated nongenotropic signals
in the cytoskeleton signaling.
Methods: To mimic ER nongenotropic signaling seen in tumors, we
created breast cancer cells that express PELP1 exclusively in cytoplasm
and that excessively activates ER-nongenotropic signaling via ER
sequestration. We have used ligands and shRNA that activate or block
nongenotropic signaling. Yeast 2-hybrid screen was performed to
identify other components of signalsome. Using confocal microscopy,
migration, wound healing and western analysis, we studied the
significance of PELP1-mediated nongenotropic signaling in ER
mediated cytoskeleton signaling.
Results: Activation of nongenotropic signaling uniquely enhanced E2mediated rufÀes and ¿lopodia-like structures. Our results indicate that
PELP1 play a key role in facilitating ER nongenotropic signaling in the
cytoskeleton remodeling. MCF7 cells stably expressing PELP1-shRNA
showed diminished ER-nongenotropic signaling and exhibited defects
in cytoskeletal reorganization. Yeast 2-hybrid screen identi¿ed ILK as
a binding protein of PELP1. We have con¿rmed PELP1 interactions
with ILK using invitro and in vivo assays. ILK functions as down
stream effector of ER- nongenotropic signaling leading to cytoskeletal
reorganization and PELP1 mediates ER interactions with ILK. PELP1
interaction with ILK enhances its activity and ER-PELP1-ILK signaling
appears to contribute to activation of AKT pathway in part in nongenomic manner.
Conclusions: Our results suggest that ER-nongenotropic actions play
a role in cell motility/metastasis and establishes that PELP1/MNAR
as a critical component of ER-nongenotropic actions leading to cell
motility. The findings of this study suggest that ER-PELP1-ILK
pathway represent a novel target for preventing the emergence of
ER+ve metastatic cells via blockage of ER-nongenotropic signals in
210
Lapatinib prevents the metastatic colonization of EGFR+
and Her-2+ breast cancer cells in the brain.
Palmieri D, Gril BM, Herring J, Vega-Valle E, Hua EK, Leiwehr D,
Steinberg SM, Gilmer TM, Rubin SD, Steeg PS. National Cancer
Institute, Bethesda, MD; SAIC-NCI, Fredrick, MD; GlaxoSmithKline,
Collegeville, PA
Central nervous system or brain metastases occur in approximately
20% of metastatic breast cancer patients and are associated with a dire
prognosis. The incidence of brain metastases appears to be higher in
metastatic patients with Her-2 ampli¿ed tumors. The ef¿cacy of the dual
EGFR/Her-2 tyrosine kinase inhibitor, lapatinib, on brain metastatic
colonization of a human breast carcinoma cell line was determined.
An EGFP labeled brain-seeking derivative of the human MDA-MB231 cell line (231-BR) endogenously overexpressed EGFR. When
231-BR cells were transfected with a control vector or Her-2 cDNA,
the Her-2 over expressing clones produced 2.5-3-fold greater large
(>50 µm²) metastases in the brains of Balb/c nude mice following
intracardiac injection (p=0.0001). In vitro, using siRNA knockdown of
endogeneous EGFR, lapatinib equally inhibited the growth of 231-BR
cells that overexpressed either Her-2 or EGFR. However, when both
receptors were overexpressed lapatinib increased growth inhibition
approximately 30% compared to cells that overexpressed either Her2 or EGFR. To determine the effect of lapatinib on brain metastatic
colonization in vivo, mice received intracardiac injections of either
the control or the Her-2 transfected 231-BR cells. Five days later
mice were randomized to vehicle, 30 or 100 mg/kg lapatinib by twice
daily oral gavage. Histologic analysis was conducted to quantify both
micrometastases and large metastases from 10 step sagittal sections in
one hemisphere of the brain. For the control transfectant mean (95%
CI) large metastases were 3.36 (2.73-3.98) per section in the vehicle
controls, were unaffected by 30 mg/kg lapatinib but declined 54% to
1.56 (0.94-2.17) when treated with 100 mg/kg lapatinib (p=0.0001).
The Her-2 transfectant produced 6.83 (5.86-7.79) large metastases per
section. Treatment with 30 mg/kg resulted in a 53% decline to 3.21
(2.31-4.11) large metastases (p<0.0001), while treatment with 100
mg/kg resulted in a 50% decline to 3.44 (2.55-4.32) large metastases
(P<0.0001). The data indicate that lapatinib can inhibit the brain
colonization of dual EGFR-Her-2+ breast cancer cells.
301
Optimal dose and schedule of a HER2/QHX peptide (E75)
vaccine in disease-free breast cancer patients: results from
two phase I/II clinical trials.
Holmes JP, Patil R, Amin A, Jama YH, McNeill A, Hueman MT, Craig
D, Ponniah S, Peoples GE. National Naval Medical Center, Bethesda,
MD; Windber Medical Center, Windber, PA; USUHS, Bethesda, MD;
Brooke Army Medical Center, Ft. Sam Houston, TX
Background: We have administered the HER2/neu-derived peptide E75
as a preventive vaccine in disease-free breast cancer (BrCa) patients.
The combined results of two clinical trials showed the vaccine is safe,
immunogenic and may reduce recurrences. In this study, we have
assessed the clinical results based on the different doses and schedules
of the vaccine to to determine the optimal biologic dose (OBD).
Materials and Methods: Disease-free node-positive (NP) and nodenegative (NN) BrCa patients were vaccinated over six months either
3, 4 or 6 times with E75 + GM-CSF in different dose/schedule groups.
Toxicities were graded per NCI Common Terminology Criteria. GMCSF was reduced for signi¿cant toxicity. Immunologic response was
measured by local reactions, delayed type hypersensitivity test (DTH)
and E75-speci¿c CD8+ T-cells quanti¿ed with HLA-A2:IgG dimer
and Àow cytometry.
Results: 96 patients (45 NP and 51 NN) were vaccinated over 6 months
in one of seven dose groups [peptide(µg).GM-CSF(µg).#doses]:
100.250.6, 500.125.3, 500.125.4, 500.250.4, 1000.250.4, 500.250.6,
1000.250.6. Twenty patients required GM-CSF dose reduction. Patients
receiving GM-CSF 250µg for six doses were more frequently reduced
than patients on <250µg or <6 doses (33% vs 8%, p<0.01). The majority
of dose reductions were due to local toxicity (75%). The OBD was
was found to be 1000.250.6. Patients in the OBD dose group (n=27)
experienced similar toxicities to the 69 sub-optimally dosed patients
(SUB). Mean E75-speci¿c CD8+ T-cells were similar in the OBD and
SUB groups at all time points post-vaccination (OBD±SE vs SUB±SE):
post-vaccination average (0.89±0.1% vs 0.71±0.1%); maximum
(1.8±0.3% vs 1.99±0.2%); and long-term response (0.79±0.2% vs
0.79±0.1%). Despite similar quantitative T-cell responses, the OBD
patients had signi¿cantly larger post-vaccination DTH responses to
E75 compared to SUB patients (22±2.7mm vs 11±1.3mm, p=0.0008).
OBD patients had worse prognostic factors than SUB patients with
larger tumors (≥T2 52% vs 22%, p=0.006), more NP patients (NP
74% vs 36%, p=0.001) and higher grade tumors (grade 3 48% vs 29%,
p=0.1). Recurrence rates in the OBD patients were lower (3.7%) than
SUB patients (10.1%, p=0.4) although the OBD has a shorter median
follow-up time.
Discussion: In our trials, the OBD of E75 in disease-free BrCa patients
is 1000.250.6. However, some patients required dose reduction of
the GM-CSF. Using this dosing strategy, a robust local reaction to
successive inoculations was maintained, while limiting cumulative
toxicity, and resulted in the best in vivo immune response (DTH). Of the
8 recurrences in all of the E75-vaccinated patients, only one occurred
in the optimally dosed group.
302
Clinical results of a phase I trial of a HER2/QHX-derived
peptide (GP2) vaccine in disease-free, node-negative breast
cancer patients.
Carmichael M, Holmes JP, Mittendorf EA, Amin A, Hueman MT,
Ponniah S, Peoples GE. USUHS, Bethesda, MD; National Naval
Medical Center, Bethesda, MD; UTMD Anderson Cancer Center,
Houston, TX; Brooke Army Medical Center, Ft. Sam Houston, TX
Background: E75 and GP2 are HER2/neu-derived immunogenic
peptides. Pre-clinical studies demonstrated epitope spreading to
GP2 in disease-free breast cancer (BrCa) patients receiving E75 as a
preventive vaccine, and GP2-stimulated CD8+ T-cells lyse HER2/neuexpressing cancer cells in vitro. Here, we describe the results of a
phase I dose escalation study of GP2 used as a vaccine in disease-free
BrCa patients.
Materials and Methods: Disease-free node-negative HLA-A2+
BrCa patients were vaccinated in a dose escalation study of GP2
+ GM-CSF. Vaccinations were given monthly for 6 months. Dose
groups consisted of 3 patients each and were as follows [GP2(µg).
GM-CSF(µg)]: 100.250, 500.250, 1000.250, 500.125. Toxicities
were graded per NCI Common Terminology Criteria. GM-CSF was
reduced 50% for signi¿cant toxicity and large local reactions. Immune
response was measured with pre- and post-vaccination delayed-type
hypersensitivity test (DTH). GP2-speci¿c CD8+ T-cells were measured
by Àow cytometry utilizing HLA-A2:IgG dimer.
Results: Twelve patients have been enrolled. Maximum local toxicities
were grade 1 (33%) and grade 2 (67%). Maximum systemic toxicities
were grade 1 (67%) and grade 2 (33%). All of the patients (n=9)
vaccinated with 250µg GM-CSF required dose reduction for large local
reactions. Median post-vaccination DTH response to GP2 (34mm, range
18-115mm) was signi¿cantly larger than pre-vaccination DTH (0mm, 019mm; p<0.0001). Maximum levels of post-vaccine GP2 speci¿c CD8+
T-cells (median 0.81%, range 0.44-2.35%) were higher than pre-vaccine
(0.12%, range 0-0.98%, p=0.001). Median long-term (6 month postvaccine) levels of GP2-speci¿c CD8+ T-cells in 5 patients was 0.44%
(0.04-0.65%) suggesting durable though waning immunity.
Discussion: GP2 can be safely and effectively administered to BrCa
patients in combination with GM-CSF with minimal toxicity. The GP2
peptide appears to be very immunogenic requiring lower doses and less
GM-CSF than the E75 vaccine. A randomized study of GP2 + GM-CSF
vs GM-CSF is underway in node-positive breast cancer patients to
further delineate the clinical effects of this immunogenic peptide.
The views expressed herein are those of the authors and do not represent
the policy of the Department of Army, Department of Navy, Department
of Defense or the US Government.
303
Immunotherapy against metastatic breast cancer with a
twist.
Demaria S, Wang B, Yang AM, Santori F, Kawashima N, Matsumura
S. New York University School of Medicine, New York, NY
Background: Effective loco-regional treatments are available for
breast cancer, but metastatic disease remains a therapeutic challenge.
The effectiveness of immunotherapy (IT) will depend on the ability to
target antigens that are essential for the metastatic process. Expression
of the transcriptional regulator Twist is required for the metastatic
behavior of 4T1 cells, an experimental mouse model of metastatic
breast cancer (Yang, et al., Cell 2004, 117: 927-939). Here we show
that Twist behaves as a tumor associated antigen (TAA) that can be
recognized by tumor-speci¿c CD8+ T cells.
Methods: H2 d haplotype-restricted CD8+ T cell epitopes were
identified within Twist protein using the SYFPEITHI Epitope
Prediction computer-based algorithm. The top scoring peptides were
tested for binding to H2-Ld or H2-Kd in a major histocompatibility
complex (MHC) stabilization assay using RMA-S cells expressing
the appropriate MHC class I allele. Next, the stability of peptideMHC complexes was measured by determining the time required for
loss of 50% (DC50) of peptide-H2-Kd or H2-Ld complexes at 37°C.
Binders were further tested for the ability to sensitize P815 cells to
lysis by 4T1 tumor-speci¿c cytolytic T cells (CTL) in a standard 51Cr
release assay. γ-interferon production was determined by intracellular
cytokine staining.
Results: One out of ¿ve candidate peptides bound to H2-Ld, and four
out of ¿ve candidate peptides bound to H2-Kd. Among them, only
peptide #9 (pTw9) formed stable complexes with H2-Kd with a half
live of >6 hours on the cell surface. pTw9-speci¿c CTL precursors
were expanded in vitro from mice previously cured of metastatic
4T1 tumors with a combination of local radiation and IT (Demaria et
al., Clin. Cancer Res. 2005, 11:728-34). pTw9-speci¿c CTL showed
peptide-speci¿c anti-tumor effector functions such as killing and γinterferon production in vitro. Vaccination experiments indicated that
S31
pTw9 peptide is immunogenic in naïve mice.
Discussion: These data indicate that Twist, a gene normally expressed
during embryonic development, and playing a critical role in metastasis
of breast cancer cells, can be a target of the anti-tumor immune response.
IT approaches targeting Twist could be effective for the treatment of
cancers with high expression of Twist such as human lobular carcinoma
of the breast.
Supported, in part, by Department of Defense grant W81XWH-051-0436.
304
10 years follow up of pilot phase III immunotherapy
study in early stage breast cancer patients using oxidized
mannan-MUC1.
Vassilaros S, Tsibanis A, Tsikkinhs A, McKenzie IF, Apostolopoulos
V. PROLIPSIS – Diagnostic Breast Center, Athens, Greece; Burnet
Institute at Austin, Heidelberg, Victoria, Australia
Introduction. We report the 10 year follow up of a pilot phase III
immunotherapy study, in stage II adenocarcinoma of the breast, by
injecting subcutaneously oxidated Mannan-MUC1. MUC1 is a high
molecular weight glycoprotein overexpressed on adenocarcinoma cells
and is the target of this immunotherapy protocol.
Method. The study is a randomized double blind. 31 (16 in the study
group and 15 in the placebo group) patients, operated for stage II
adenocarcinoma of the breast, were enrolled and followed from
December 1997 to May 2007, in order to evaluate any difference in
the length of the disease free period. Disease free period, survival and
immunological assays, were assessed.
Results. From December 1997 to May 2007 in the study group of 16
patients who were injected with oxidated MUC1, only one developed
metastatic disease, 96 months after the initial surgery. In the placebo
group of 15 patients, the disease was relapsed in 6 patients at 8, 18,
34, 78, 89 and 102 months after the initial surgery. These ¿nding
was statistically signi¿cant (p=0,0247). Nine out of 13 patients had
measurable antibodies to MUC1 and 4 out of 10 had MUC1-speci¿c
Tcell response; None of the placebo group exhibited any immune
response to MUC1. Ten years passed after the ¿rst enrolment in the
study and the mean period of follow up is 8,5 years.
Conclusion. The results suggest that in early breast cancer MUC1
immunotherapy is bene¿cial and that a larger phase III study should
be undertaken.
305
Circulating immature myeloid cells in breast cancer patients
correlate with clinical cancer stage and cyclophosphamide
treatment: implications for cancer immunotherapy.
Montero AJ, Dewaay DJ, Salem M, Cole DJ, Diaz-Montero CM.
Medical University of South Carolina, Charleston, SC
Background: Tumor-associated immune suppression is known to
be an important contributor to cancer progression. One important
mechanism is the abnormal accumulation of immune suppressive
immature myeloid cells (ImC) in the peripheral blood. Although both
tumor burden and cyclophosphamide (CTX) induced accumulation of
ImC are well described in animal studies, human studies have been
limited. Thus, the goal of our study was to determine whether levels
of ImC in whole blood correlate with clinical cancer stage in patients
(pts) with breast cancer and determine whether standard dose dense
(dd) chemotherapy with doxorubicin and cyclophosphamide (ddAC)
results in greater increases in ImC than paclitaxel (ddT).
Methods: Flow cytometry analyses were performed on whole peripheral
blood from 14 normal healthy volunteers and 57 newly diagnosed cancer
pts including 27 patients with breast cancer (stages: I/II n=15; III, n=11;
IV, n=31) prior to therapy. ImC population was de¿ned as lineage-,
CD33+, HLA-DR-, CD11b+. In 16 pts with stage II-III breast cancer
receiving (ddAC→ddT) blood was collected on day 1 of each cycle of
chemotherapy prior to receiving the subsequent cycle.
Results: Greater circulating levels of ImC in cancer pts vs. normal were
noted (4.02% vs. 1.46%; P=6.37x10-5). Stage IV pts had the highest
percentage and absolute number of ImC (Table 1). Moreover, ddAC was
S32
associated with signi¿cant increases in circulating ImC compared with
pretreatment levels (2.51% vs. 13.17%; P=1.6x10-12), and also when
compared to ddT (4.6%; P=2.76x10 –9). This increase was sustained
throughout ddAC chemotherapy.
Conclusions: Overall elevated levels of ImC correlated with advanced
clinical breast cancer stage. ddAC chemotherapy was associated with
signi¿cant and sustained increases in ImC in breast cancer pts. This
has important implications for breast cancer vaccine therapy because
vaccine-elicited anti-tumor responses can be signi¿cantly dampened
by this cell type. Novel pharmacologic means to decrease levels of
circulating ImC or to modify them to acquire an immunoenhancing
rather than an immunosuppressive phenotype have the potential to
signi¿cantly enhance the effectiveness of immunotherapy in breast
cancer and other solid tumors. Finally, although CTX is currently
used in adoptive immunotherapy protocols in part because it can
decrease numbers of regulatory T-cells, our study shows that CTX is
also associated with signi¿cant rises in ImC which could antagonize
development of tumor speci¿c immunity.
Table 1. Circulating Levels of ImC by Clinical Cancer Tumor Stage
Clinical Cancer Stage
% ImC
Total ImC (cells/microliter)
Normal Volunteers
1.46*
I/II
2.46*
163.74*
III
2.89*
205.72*
IV
5.17*
414.21*
*P<0.04
306
Targeting of the chemokine receptor CXCR4 in acquired
trastuzumab resistance.
Tripathy D, Mukhopadhyay P, Verma U, Mukhopadhyay C, Shelton J,
Story M, Ding L. University of Texas Southwestern Medical Center,
Dallas, TX
Background: The anti-HER2 antibody trastuzumab is effective in
HER2-expressing breast cancer, yet clinical resistance develops in
almost all cases of advanced disease. Acquired trastuzumab resistance
is not well understood, although it has been shown that expression of
the HER2 target is preserved, suggesting alterations in downstream or
interacting signaling pathways. We describe a novel speci¿c alteration
in a cell line model of acquired trastuzumab resistance, the targeting of
which reverses resistance. The chemokine receptor CXCR4 has been
implicated in increased metastatic potential in breast and colon cancer
and as a scaffolding protein required for optimal HER2 function.
Methods: A trastuzumab-resistant subclone (BT 474HR) of the HER2positive breast cancer line BT 474 was developed by serial passage in
trastuzumab for about 1 year. Gene expression pro¿les before and after
trastuzumab exposure were assessed using Affymetrix HG-U133A/B
human gene arrays. siRNA mediated knockdown of CXCR4 in BT
474 and BT 474HR cells was performed and con¿rmed by real timePCR and Western blotting (fusin antibody, Santa Cruz), and effects on
cell viability were assessed using the CellTiter-Glo luminescent cell
viability assay (Promega). Subcellular localization of CXCR4 was
assessed by immunoÀuorescence and gradient centrifugation. The effect
of the CXCR4 inhibitor AMD3100 (Sigma) on sensitive and resistant
cells was measured. Effects of CXCR4 ligand SDF-1 (R&D Systems)
on HER2 phosphorylation was assessed using anti-pHER2 antibody
(2247 Cell Signaling).
Results: BT 474HR cells exhibited upregulation of several genes
including CXCR4 (con¿rmed by real-time PCR), CSTA (cysteine
protease inhibitor) and mitotic checkpoint regulators. Gene-speci¿c
knock down of CXCR4 was con¿rmed by real-time PCR and Western
blotting, and led to re-sensitization of BT 474HR to trastuzumab,
with a >60% reduction in cell number in both resistant and sensitive
cells. CXCR4 inhibitor AMD3100 treatment led to partial reversal of
trastuzumab resistance in resistant cells. BT474HR cells demonstrated
nuclear compared to membrane distribution of CXCR4. Treatment of
both cell lines with SDF-1 led to rapid HER2 phosphorylation.
Conclusions: In this cell line model, acquired resistance to trastuzumab
is associated with CXCR4 is upregulation and nuclear redistribution.
Stimulation of CXCR4 leads to HER2 phosphorylation and may
represent a bypass pathway for the activation of the HER2 signaling
pathway that is augmented with trastuzumab resistance. Inhibition of
CXCR4 reverses acquired trastuzumab resistance. This phenomenon
needs to be validated in other cell line and in xenograft models as
well as in breast tumor tissue from patients prior to and after clinical
trastuzumab resistance. CXCR4 antagonists may be useful in preventing
or reversing trastuzumab resistance.
307
TBCRC 001: EGFR inhibition with cetuximab in metastatic
triple negative (basal-like) breast cancer.
Carey LA, Mayer E, Marcom PK, Rugo H, Liu M, Ma C, Rimawi M,
Storniolo A, Forero A, Esteva F, Wolff A, Ingle J, Ferraro M, Sawyer
L, Davidson N, Perou CM, Winer EP. University of North Carolina;
Dana Farber; Duke; UCSF; Georgetown; Washington University;
Baylor; Indiana University; University of Alabama-Birmingham; M.D.
Anderson; Johns Hopkins; Mayo
Background: Basal-like breast cancer (BBC) has low expression of
ER, PR, and HER2, and is thus often called “triple negative” (TN)
BrCa. Preclinical studies suggest that BBC may be EGFR (HER1)dependent for proliferation. TBCRC 001 is a multicenter randomized
phase II study of cetuximab with carboplatin in TN BrCa. In 3/07, Arm
1 (cetuximab alone) was closed according to prespeci¿ed response
criteria. This report summarizes the interim analysis of cetuximab
alone in stage IV TN BrCa.
Methods: Eligible patients (pts) had measurable TN metastatic BrCa,
</= 3 prior chemotherapies, no prior platinum or EGFR inhibitor. Pts
randomized to Arm 1 received cetuximab alone (400 mg/m2, then
250 mg/m2 weekly) with carboplatin (AUC 2 weekly, 3 of 4 weeks)
added upon progression (PD). Pts on Arm 2 receive cetuximab +
carboplatin throughout. The primary endpoint is objective response
(RR, CR+PR).
Results: Of 21 evaluable pts in Arm 1: mean age 48.6 (range 33-67),
33% African-American, 10% Hispanic, 62% PS=0. 86% had received
prior (neo)adjuvant chemotherapy, usually anthracycline/taxane-based;
62% had also received at least 1 regimen for metastatic disease. Single
agent cetuximab was well-tolerated; grade 3 drug-related AEs: rash (4
pts), fatigue (1), cellulitis (1), back pain (1), irregular menses (1), and
elevated LFTs (1). One grade 4 anaphylaxis occurred. There is 1 PR
(4%) that has lasted over 40 weeks, 4 SD (19%), and 16 PD (76%) in
Arm 1. Most progressed quickly; 5 (24%) PD 4 weeks into therapy,
and 10 (48%) by 8 weeks. 19 pts had carboplatin added to cetuximab
after PD; 14 are currently evaluable, 4 (28%) have uncon¿rmed PR and
4 (28%) have SD. Molecular subtyping on 10 tumors from the overall
study con¿rmed BBC in 9 (1 claudin subtype). Further subtyping and
preliminary studies of the biologic effects of EGFR inhibition will be
presented.
Conclusion: Cetuximab alone was well-tolerated but had a low
single agent response rate so failed criteria for ongoing study. Rapid
progression in this population may have limited evaluation of ef¿cacy.
Cetuximab + carboplatin Arm 2 is ongoing, expecting completion
in mid-2007. Translational studies con¿rming molecular subtype,
identifying biologic effects of EGFR inhibition and platinum, evaluating
circulating tumor cells, and studying the BRCA1 pathway are ongoing.
Support: Translational Breast Cancer Research Consortium; AVON PFP
award; NCI Breast Cancer SPOREs at UNC (CA58223) and other sites;
NIH (M01RR00046, LAC).
308
Preliminary results of a randomized phase II study of
weekly irinotecan/carboplatin with or without cetuximab
in patients with metastatic breast cancer.
O’Shaughnessy J, Weckstein DJ, Vukelja SJ, McIntyre K, Krekow L,
Holmes FA, Asmar L, Blum JL. US Oncology Research, Inc., Houston,
TX; Baylor-Charles A. Sammons Cancer Center, Dallas, TX; Texas
Oncology, P.A. – Dallas Presbyterian, Dallas, TX; New Hampshire
Oncology-Hematology, Hookset, NH; Tyler Cancer Center, Tyler, TX;
The Breast Care Center of North Texas, Bedford, TX; Texas Oncology,
P.A., Houston, TX
Background: Irinotecan and carboplatin (ICb) is a synergistic
antineoplastic combination in several cancers. Weekly irinotecan is
active in metastatic breast cancer (MBC) and has proven activity in
combination with cetuximab in colorectal cancer. The primary objective
of this study was to determine the objective response rates produced by
irinotecan and carboplatin therapy ± cetuximab; secondary objectives
were progression-free survival (PFS), overall survival, and safety.
Subjects and Methods: 163 pts with measurable disease were
randomly assigned to either (Arm 1) irinotecan (I) 90 mg/m2 followed
by carboplatin (Cb) area AUC=2 Days 1 and 8 of each 21-day cycle or
(Arm 2) same as Arm 1 except C 400 mg/m2 IV dose 1, then 250 mg/m2
weekly thereafter. Pts who progressed on Arm 1 could cross-over to
single-agent cetuximab (Arm 1b).
Results: Enrollment to this study has been completed. In this preliminary
analysis reporting on 103 patients who have been on study >4 months,
49 pts and 54 pts were enrolled in Arms 1 and 2, with a median age
of 54 years. 76 pts had received prior adjuvant chemotherapy and 33
pts had received 1 prior chemotherapy for metastatic disease. Of 36
pts on Arm 1 currently evaluable for response, 19% had an objective
response compared with 39% of the 31 pts evaluable for response on
Arm 2. Grade 3-4 toxicities for Arm 1/Arm2 were: fatigue 6%/18.5%,
diarrhea 18%/50%, vomiting 12%/17%, neutropenia 50%/91%, and
thrombocytopenia 12%/20%.
Conclusions: This preliminary assessment suggests that the addition
of cetuximab to ICb may improve antitumor activity but is associated
with greater toxicity. A complete analysis of all patients and all study
endpoints will be available for SABCS 2007.
This research was supported, in part, by research grants from BristolMyers Squibb, Plainsboro, NJ, and P¿zer, Inc., New York, NY.
FINAL ABSTRACT WITH FINAL RESPONSE DATA WILL BE
SUBMITTED NO LATER THAN NOVEMBER 12, 2007.
309
Evaluation of trastuzumab, docetaxel and capecitabine as
¿rst-line therapy for HER2-positive locally advanced or
Wardley A, Antón-Torres A, Pivot X, Morales-Vasquez F, Zetina L, Dias
Gaui M, Otero Reyes D, Jassem J, Button P, Bell R. Christie Hospital
NHS Foundation Trust, Manchester, United Kingdom; Hospital
Universitario Miguel Servet, Zaragoza, Spain; CHU Jean Minjoz,
Besançon, France; Instituto Nacional de Cancerología, Mexico City,
Mexico; Hospital Roosevelt, Guatemala City, Guatemala; Instituto
Nacional do Câncer, Rio de Janeiro, Brazil; Hospital CIMA, San José,
Costa Rica; Akademia Medyczna, Gdansk, Poland; Roche Products
Pty Ltd, Dee Why, New South Wales, Australia; Andrew Love Cancer
Centre, Geelong Hospital, Geelong, Victoria, Australia
Background: Trastuzumab (Herceptin®; H) in combination with
docetaxel (T) is standard ¿rst-line therapy for HER2-positive metastatic
breast cancer (MBC). The Phase II international, open-label CHAT
(Capecitabine, Herceptin And Taxotere) study evaluated the addition of
capecitabine (X) to the HT combination as ¿rst-line therapy for HER2positive locally advanced breast cancer (LABC)/MBC.
Materials and Methods: Patients with HER2-positive (IHC 3+ and/or
FISH+) LABC/MBC were randomised to receive H (8 mg/kg loading
dose, then 6 mg/kg q3w) + T (75 mg/m2 in HTX arm and 100 mg/m2 in
HT arm, q3w) +/- X (950 mg/m2 bid on Days 1-14 q3w). Primary end
point was overall response rate (ORR); secondary end points included
duration of response (DoR), progression-free survival (PFS), time to
progression (TTP), overall survival (OS) and safety.
Results: In total, 222 patients were randomised and received study
medication. Baseline characteristics were reasonably well balanced.
Median follow-up for the 2 arms was 25.5 (HTX) and 23.5 (HT) months.
Key ef¿cacy and safety results are shown in the tables.
Discussion: High response rates were displayed by both regimens, with
HTX achieving signi¿cant improvement in TTP and PFS compared with
HT in HER2-positive LABC/MBC. Both regimens were generally well
tolerated and cardiac safety was consistent with other H-based trials.
ORR, %
Complete response, %
Partial response, %
Stable disease, %
Progressive disease, %
Missing, %
Median DoR, months
Median PFS, months
Median TTP, months
Median OS, months
HTX (n=112)
71
23
47
25
4
1
15.9
17.9
18.6
43.5
HT (n=110)
73
16
56
16
9
2
13.4
12.8
13.6
47.3
p value
0.717
0.0402
0.029
0.485
S33
HTX (n=112)
HT (n=110)
Grade 3/4 neutropenia, %
27
24
Grade 3/4 febrile neutropenia, %
15
27
Grade 3/4 neutropenic sepsis, %
4
<1
LVEF absolute drop, 15%, %
19
17
LVEF decline to <40%, %
2
2
Symptomatic congestive heart failure,a %
<1
<1
Grade 3 hand-foot syndrome, %
17
<1
Grade 3/4 diarrhoea, %
11
4
Treatment-related deaths, %
<1
3
a
New York Heart Association class II; LVEF, left ventricular ejection fraction.
310
A phase I study of trastuzumab-DM1, a ¿rst-in-class HER2
antibody-drug conjugate, in patients with advanced HER2+
breast cancer.
Krop IE, Beeram M, Modi S, Rabbee N, Girish S, Tibbitts J, Holden
SN, Lutzker SG, Burris HA. Dana-Farber Cancer Institute, Boston,
MA; Institute for Drug Development, San Antonio, TX; Memorial
Sloan-Kettering Cancer Center, New York, NY; Genentech, South San
Francisco, CA; Sarah Cannon Research Institute, Nashville, TN
Rationale
Trastuzumab-DM1 (T-DM1) is a ¿rst-in-class HER2 antibody-drug
conjugate (ADC) in development for HER2-positive breast cancer (BC).
T-DM1 is designed to combine the biological activity of trastuzumab
(T) with the targeted delivery of a highly potent antimicrotubule agent
(DM1) to HER2-expressing cells. Focusing such chemotherapeutic
agents on tumor cells via high-speci¿city monoclonal antibodies that
bind unique and/or over-expressed cell-surface tumor antigens is
intended to improve the therapeutic window for such agents, allowing
their potential to be applied to the clinic.
DM1 binds to tubulin competitively with vinca alkaloids, but 20-100
times more potently than vincristine. Its parent molecule, maytansine,
has induced responses in patients (pts) with breast and lung cancer,
with principal adverse events (AEs) of nausea, vomiting, diarrhea, and
sensory neuropathy. The stable MCC linker molecule was engineered
to potentially enhance the therapeutic window of DM1 by improving
exposure to T-DM1 and minimizing exposure to free DM1. T-DM1 is
the ¿rst ADC with an MCC linker in clinical trials.
T-DM1 binds to HER2 with affinity similar to that of T and is
internalized via the normal ongoing HER2 internalization process.
T-DM1 has activity in both T-sensitive and T-insensitive HER2+ BC
xenografts; its principal preclinical AEs were reversible transaminase
(TA) elevations, reversible decreases in platelets, and neuropathy.
Objectives
This ongoing ¿rst-in-human phase I study is evaluating the safety and
pharmacokinetics (PK) of T-DM1 given IV to pts with advanced HER2+
BC who have progressed on a T-containing regimen.
Results
Nineteen pts (median age 50 (range 35-70); all PS 0-1); median number
prior chemo regimens 8 (range 2-18) have received 83 doses of T-DM1
at 6 dose levels (0.3-4.8 mg/kg) on a q3 wk schedule. Related mildmoderate AEs include TA elevations (grade (gr) 1, 4 pts; gr 2, 1 pt),
thrombocytopenia (TCP; gr 1, 5 pts), fatigue (gr 1, 5 pts; gr 2, 1 pt),
anemia (gr 2, 2 pts), and peripheral neuropathy (gr 1; 1 pt). Related gr
3-4 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt; gr 4,
2 pts). There has been no cardiac toxicity. T-DM1 clearance decreased
with increasing dose as predicted by preclinical modeling. Four of 16
pts treated at or below the MTD have had partial responses; three are
con¿rmed and ongoing after 1.7-5.5 months.
Conclusions
The MTD of T-DM1 given IV q3 wks is 3.6 mg/kg; TCP was doselimiting at 4.8 mg/kg. At the MTD, gr ≥2 AEs related to T-DM1 have
been infrequent and manageable. T-DM1 PK is consistent with q3-week
dosing. Objective tumor responses have been observed at doses at or
below the MTD. Phase II trials in advanced HER2+ BC are being
initiated; weekly dosing is also being explored.
S34
401
Patterns of estrogen receptor alpha (ER) protein expression
and ESR1 gene ampli¿cation in primary and metastatic
breast cancer.
Holst F, Haas H, Nottbohm AK, Sauter G, Simon R. University Medical
Center Hamburg-Eppendorf, Hamburg, Germany
Background: Estrogen receptor alpha (ESR1) gene ampli¿cations
belong to the most frequent genetic alterations in breast cancer. In a
recent study we found ESR1 alterations in more than 30% of tumors.
Ampli¿cation was linked to low grade and early stage cancers, and
predicted response to tamoxifen therapy. These ¿ndings raise the
question whether possible differences of the ESR1 ampli¿cation status
between primary tumors and metastases might contrubute to failure of,
or resistence to hormone therapy in breast cancer.
Materials and Methods: Two sets of primary and metastatic breast
cancer tissues were analyzed by means of immunohistochemistry (IHC)
and Àuorescence in-situ hybridization (FISH) to compare patterns of
ER expression and ESR1 ampli¿cation. The ¿rst set of samles included
192 primary tumors, each with three matched lymph node metastases.
The second set consisted of 59 primary tumors with multiple (range
1-15) matched distant metastases from the lungs, liver, brain, and bone
marrow. To study possible intratumoral heterogenetity, three punches
were compared from every individual tissue sample.
Results: As expected, strong ER expression was signi¿cantly linked
to ESR1 gene ampli¿cation in all samples (p<0.0001). Comparison of
three punch cores from the same tissue sample showed a high degree
of concordance with respect to both ER expression (1341/1525, 88%)
as well as ESR1ampli¿cation (810/933, 87%), strongly arguing against
presence of signi¿cant intratumoral heterogeneity. Comparison between
primary tumors and matched metastases yielded identical results in the
majority of cases.
In ER positive primary cancers, 92% (92/100) of the nodal metastases
and 94% (27/29) of the distant metastases were also ER positive.
For ESR1 ampli¿cation, the concordance was 86% (12/14) for nodal
metastases and 75% (3/4) for distant metastases.
Discussion: Intratumoral heterogeneity is infrequent for both ER
expression and ESR1 ampli¿cation in breast cancer, and might be
¿rst of all related to technical issues. Our data do also not suggest
major differences of ER/ESR1 between primary cancers and both
nodal or distant metastases. It is therefore unlike that heterogeneity
of ER/ESR1 has major contribution to failure of hormone therapy in
breast cancer.
402
Ampli¿cation of (65 may predict resistance to adjuvant
tamoxifen in postmenopausal patients with hormone
receptor positive breast cancer.
Ejlertsen B, Nielsen KV, Rasmussen BB, Balslev E, Müller S, Møller
S, Mouridsen HT. Rigshospitalet, Copenhagen, Denmark; Dako A/S,
Glostrup, Denmark
Background: The estrogen receptor (ER) is the target of tamoxifen,
and patients with ER negative breast cancer are unlikely to bene¿t
from tamoxifen. Unfortunately, endocrine therapies do not bene¿t all
patients with ER positive tumors and we therefore hypothesized that
copy number changes in the ESR1 gene, encoding the estrogen receptor,
confer resistance.
Material and Methods: Within a consecutive series of postmenopausal
patients allocated to tamoxifen 20 mg daily for 5 years following radical
surgery for early hormone receptor positive breast cancer, we identi¿ed
61 patients with recurrence less than 4 years and 48 patients with
recurrence more than 7 years after initiation of adjuvant tamoxifen.
Archival tissue from the primary tumor was collected from 100 of the
109 patients (92%). The tumor samples were analyzed for ESR1 copy
number changes using FISH with a probe covering the ESR1 gene at
6q25 and a reference probe covering the centromere of chromosome 6.
FISH was performed with Dako Histology FISH accessory kit.
Results: The FISH analysis for ESR1 was successful in 94 of the 100
patients (94%). Ampli¿cation (ratio ESR1/CEN-6 > 2) was observed
in 11 of 52 (21%) with an early recurrence (< 4 years), compared to
2 of 42 (5%) patients who still were recurrence free after more than
7 years (p=0.03). In both groups 2 patients with ESR1 deletion (ratio
ESR1/CEN-6 <0.8) were identi¿ed.
Discussion: In accordance with our hypothesis, this pilot study supports
that ampli¿cation of ESR1 might be a marker for tamoxifen resistance
in patients with operable and ER positive breast cancer. This study
also revealed the existence of ESR1 deletions. The prognostic and
predictive impact of ESR1 copy number changes is being further
analyzed in clinical trials.
403
Relationship between (65 copy number and ER expression
in the DBCG 89D trial.
Ejlertsen B, Nielsen KV, Rasmussen BB, Jensen M-B, Møller S, Balslev
E, Müller S, Mouridsen HT. Rigshospitalet, Copenhagen, Denmark;
Dako A/S, Glostrup, Denmark
Background: The ESR1 gene located on chromosome 6q25 encodes
the estrogen receptor alpha (ER). The present study explores the
prognostic impact and relationship between ESR1 and ER in the
DBCG 89-D trial.
Material and Methods: The DBCG 89-D trial randomized 980 high-risk
Danish breast cancer patients to nine series of CMF or CEF, without
endocrine therapy. Overall CEF was superior to CMF in terms of
DFS and OS. TMA’s were constructed and analyzed centrally for
ER expression and ESR1 copy number changes using FISH (Dako
Histology FISH accessory kit) with a probe covering the ESR1 gene at
6q25 and a reference probe covering the centromere of chromosome 6.
Relationships between DFS, OS and biomarkers were analyzed using
uni- and multivariate statistics.
Results: Cut sections from 41 TMA blocks with 707 patient samples
(72% of total eligible) were available and the ESR1 test was successful
in 607 (86%). Eight patients (1%) had ESR1 ampli¿cation (ratio ESR1/
CEN-6 > 2) and 162 (27%) had ESR1 deletion (ratio ESR1/CEN-6 <
0.8). Central ER was successful in 633 (90%) and 427 patients (67%)
had ER negative (< 10% positive stained cells) tumors. ER expression
was associated with (p=0.02) ESR1 aberrations. In this material of
predominantly ER negative patients the proportion of patients with
ESR1 ampli¿cation was too small to enable a statistical analysis.
ESR1 deletion was not signi¿cantly associated with other established
prognostic factors including positive nodes, tumor size, grade, ER,
HER2 or TOP2A. ESR1 deletion was not a signi¿cant independent
prognostic factor for DFS (p=0.13) or OS (p=0.26).
Discussion: Deletions in ESR1 were demonstrated in a high proportion
of predominantly ER negative patients in the DBCG 89D trial, but
an independent prognostic value of ESR1 deletion could not be
demonstrated.
404
Gene copy number variability of oestrogen receptor-α in
breast cancer.
Drury S, Lambros M, Marchio C, Johnson N, Salter J, Levey P, Fletcher
O, Peto J, Reis-Filho JS, Dowsett M. The Breakthrough Breast Cancer
Research Centre, London, United Kingdom; CR-UK Epidemiology &
Genetics, LSHTM, London, United Kingdom
Background: Approaching 80% of breast cancers (br ca) are ER+ and
ER status provides a guide to therapy. It has recently been reported
(Nat. Gen. 19:655-660) that the ER-α (ESR1) gene is ampli¿ed in
approximately 20% of ER+ br ca. However, c.20% of normal subjects
are reported to have ESR1 copy number polymorphisms, usually as
copy number gains. We have sought to con¿rm the reports of ESR1
ampli¿cation using quantitative real-time PCR (qRT-PCR) and in situ
hybridisation, using two sets of invasive primary br ca and germline
gDNA from br ca patients.
Methods: DNA was extracted from 35 microdissected, formalin-¿xed
and paraf¿n-embedded, invasive br ca (91% ER+; grade 2 46%, grade
3 40%) using the DNeasy Blood and Tissue kit. DNA was isolated
from circulating lymphocytes of 30 patients with synchronous, bilateral
breast cancer using the QIAamp DNA Blood Kit. ESR1 (exon 2 and
8) and the reference genes FAM38B and ASXL2 were detected using
qRT-PCR. Reference genes were selected based on not being affected
by copy number polymorphisms (http://projects.tcag.ca/variation/)
and not being targeted by copy number aberrations in br ca. ESR2 was
measured in the tumours. Ampli¿cations and gains were de¿ned as
normalised values between >2 and 1.5-2, respectively. ESR1-speci¿c
CISH was performed using biotin-labelled, in-house generated probes
on 13/35 of the invasive tumours analysed by qPCR, in addition to a
further 148 invasive breast cancers, 85.1% of which were ERα-positive.
CISH was analysed by JSR-F and CM. Ampli¿cation was de¿ned as
>50% of neoplastic cells harbouring > 5 ESR1 gene signals/ nucleus
or large ESR1 gene clusters.
Results: Using qRT-PCR on the cohort of 35 invasive breast cancers,
when ESR1 was normalised to ESR2, 2/35 samples (5.7%) showed
gain and 2/35 samples (5.7%) showed ampli¿cation of ESR1. When
normalised to both reference genes (ASXL2 and FAM38B), 0/35 samples
showed gain and 1/35 (2.8%) showed ampli¿cation. This ampli¿ed
sample had the highest EIA score (500fmol/mg versus a mean of
82fmol/mg) and second highest H-score (248.6 versus a mean of 138).
CISH did not con¿rm the single ampli¿cation detected by comparison
to the combined reference genes, but in conjunction with Àuorescent
in situ hybridisation (FISH) con¿rmed one gain and one ampli¿cation
as judged by normalisation to FAM38B alone. CISH analysis of an
independent 148 samples of invasive breast cancers con¿rmed that
the frequency of ESR1 ampli¿cation is uncommon; only 2 tumours
(1.6%) harboured ESR1 gene ampli¿cation as de¿ned by the presence
of large gene clusters. All ampli¿cations were con¿rmed with FISH.
To assess whether the high prevalence of ESR1 ampli¿cation observed
in previous studies could be due to a copy number polymorphic gain
in germline DNA, germline DNA from br ca patients was assessed
by qRT-PCR as described above. No increase in ESR1 copy numbers
could be identi¿ed.
Conclusion: The notion of copy number gain of ESR1 in breast cancer
is an important route of investigation given the applicability and wide
use of this marker in guiding br ca therapy. However, in our hands,
de¿nite ESR1 ampli¿cation in ERα-positive invasive br ca and ESR1
gene copy number variation in germline DNA was uncommon.
405
Serine118 phosphorylation of estrogen receptor: correlation
with kinase pathways and evolution after preoperative
endocrine therapy.
Zoubir M, Mathieu M-C, Simmans F, Bouaziz J, Geha S, Drusch F,
Liedtke C, Spielmann M, Delaloge S, Andre F. Institut Gustave Roussy,
Paris, France; MD Anderson Cancer Center, Houston, TX
Background: Serine (ser) 118 phosphorylation has been reported to
be involved in the activation of Estrogen Receptor (ER). In the present
study, we evaluated whether kinase pathways correlated with the level
of ER phosphorylation on ser118 and assessed the evolution of ER
phosphorylation under endocrine therapy.
Patients and Methods: We constructed a tissue microarray that
included 68 localized primary breast tumors before the administration
of endocrine therapy. A second tissue microarray was performed
that included 38 tumors obtained after endocrine therapy from the
same patients. Immunostainings for ER (anti-ER 6F11antibody),
phosphoSer118-ER (P-Ser118 antibody), Her2, IGFR, PAK1, pMAPK
were performed. The level expression of pER was determined
as a composite score that include percentage of stained cells and
intensity.
Results: 68 patients received endocrine therapy for a median duration
of 211 days. The median age at diagnosis was 79 years (64-93). Median
tumor size was 53 mm (15-90). 27 patients received tamoxifen while 41
received aromatase inhibitors. A clinical objective tumor response was
observed in 36 patients (54%). Immunostaining for PhosphoSer118-ER
was higher in Her2-, IGFR- and pMAPK-expressing tumors (p<0.0001
for all markers, t-test), but did not correlate with ER expression (p=0.16,
t-test), nor PAK1 expression (p=0.15, t-test). ER phosphorylation
at baseline did not signi¿cantly correlate with the occurrence of a
clinical tumor response (p=0.16). PhosphoSer118 ER expression was
signi¿cantly reduced by endocrine therapy (n=38 paired samples). The
mean score was 160 (range:0-300) and 80 (range:0-300) in pre- and
post-endocrine therapy samples respectively (p<0.0001, t-test). At the
opposite, ER expression was not signi¿cantly modulated by endocrine
therapy (p=0.18, t-test). Interestingly, the occurrence of a phospho-
S35
ER downregulation after endocrine therapy was associated with the
occurrence of clinical response. The clinical response rates were 36%
(7 out of 19 patients) and 63% (12 out of 19 patients) in patients with
stable or downregulated phosphoSer118 ER expression respectively
(p=0.10, Khi-square test).
Conclusion: Phosphorylation of ER on ser118 correlated with Her2,
IGFR and pMAK expressions and was downregulated by endocrine
therapy. The decrease of ER phosphorylation on ser118 was associated
with ef¿cacy of endocrine therapy.
406
Induction of a novel estrogen receptor (ERα) phosphoserine (S154) in human breast cancer cells identi¿ed by
mass spectrometry.
Britton D, Scott G, Schilling B, Held J, Atsriku C, Baldwin M, Gibson
B, Benz C. Buck Institute for Age Research, Novato, CA
While crystallographic and nuclear magnetic resonance structures
have provided critical understanding of the C-terminal ligand-binding
domain of ERα, lack of structural information about the N-terminal
region of ERα and limited availability of suf¿ciently powerful analytical
tools to catalog ERα post-translational modi¿cations have hampered
our understanding of ligand-dependent and ligand-independent ERα
activation. In particular, the N-terminal 184 amino acids of ERα,
predicted to be highly disordered, encompass its critical AF1 activation
function domain (aa 38-149) and contain 14 serine (S) residues of
which only ¿ve are known to be phosphorylated (S102, S104, S106,
S118, S167) in response to ligands (e.g. E2) or growth factors (e.g.
EGF, IGF-1, TGF-α) and their receptor-activated downstream serine/
threonine kinases. We employed high precision mass spectrometry
(MS), including HPLC-ESI-MS/MS (Q-STAR) and vMALDI-MSn
(vMALDI-LTQ), to look for novel N-terminal phospho-serine
modi¿cations in ERα immunoprecipitated from E2 (vs. serum-stripped
control) or EGF (vs. serum-free control) stimulated MCF7 cells.
Commercially obtained recombinant human ERα (expressed in insect
cells) was used to optimize immunoaf¿nity puri¿cation, in-gel protease
digestions, and MSn procedures; immunoaf¿nity enriched extracts
were also immunoblotted for ERα phospho-S118 and phospho-S167 to
assure preservation of phosphorylation status. MS analysis of peptides
from the N-terminal region resulting from ERα trypsin digestion
revealed a 5-fold increase in phospho-S154 content following E2 (30
min) stimulation of MCF7 cells, with no detectable phospho-S173 or
phospho-S178. Immunoblotting with a newly produced rabbit antiserum
generated against a synthetic ERα phospho-S154 peptide con¿rmed
this MS observation. Unlike ERα phospho-S118 and phospho-S167
induction, phospho-S154 was equally stimulated by either E2 (30 min)
or EGF (10 min) treatment of MCF7 cells. Following E2 exposure,
phospho-S154 induction exceeded that of phospho-S167 but not that
of phospho-S118. Following EGF exposure, phospho-S167 induction
exceeded that of both phospho-S118 and phospho-S154. This ¿nding of
phospho-S154 illustrates the analytical power and potential biological
impact of applying comprehensive proteomic and MS strategies for
unbiased interrogation of endogenous ERα to identify novel posttranslational modi¿cations. Hopefully, these ¿ndings will also shed
new light on breast cancer serine/threonine kinase pathways thought
to modify receptor function and the clinical behavior of ERα-positive
breast cancers.
407
Withdrawn by author
408
Mitogen activated protein kinase (MAPK) regulation of
estrogen receptor (ER) α and tamoxifen resistance.
Cui Y, Fuqua SAW. Baylor College of Medicine, Houston, TX
Background: Tamoxifen (Tam) has been the most widely prescribed
antiestrogen for the treatment of women with ERα-positive breast
cancer. While Tam is initially useful for many patients, acquired
tamoxifen resistance can develop. Increasing evidence from both the
laboratory and the clinic suggest that crosstalk between the MAPK and
S36
ERα pathways may play a role in the development of resistance. We
have previously demonstrated that MAPK phosphatase 3 (MKP3) levels
were signi¿cantly higher in tamoxifen-resistant breast tumors, and that
its overexpression conferred resistance both in vivo and in vitro1.
Materials and Methods: In an effort to explore the potential mechanisms
underlying MKP3-mediated tamoxifen resistance, we utilized gene
reporter transactivation assays, and performed binding studies between
ERα, MAPK, and MKP3.
Results: We discovered that MKP3 overexpression augmented estrogeninduced ERα activity in a number of breast cancer cell lines, and that
MKP3 phosphatase activity was not essential for this coactivator effect
because a phosphatase dead MKP3 mutant exerted a similar effect as
wild-type MKP3 on ERα activity. We found that MKP3 enhanced
the activity of a number of other steroid receptors, including the
receptors for androgen, progesterone, and retinoic acid. ERα activity
could also be increased by MKP5 which belongs to the same MAPK
phosphatses family as MKP3, but not by the unrelated phosphatase,
pp2B. This result suggests that MAPK phosphatases might regulate
ERα through their target MAPK. Overexpression of ERK2 MAPK
or a dominant negative mutant of ERK2 dramatically repressed both
ligand-independent and estrogen-induced ERα activity. This suggests
that repression of ERα activity by MAPK might not be dependent on
its activation. Overexpression of MKP3 relieved ERK2 repression
of ERα activity. Using GST-pulldown assays, we demonstrated that
ERα directly interacts with ERK2 MAPK in a ligand-independent
manner. All of the ERα functional domains bound to ERK2, except
for the amino-terminal, ligand-independent AF1 domain which harbors
the MAPK phosphorylation site within ERα (serine 118). This was
unexpected since it has been generally considered that S118 was the
structural determinant for MAPK and ERα cross-talk.
Conlusion: Our data suggests a novel mechanism underlying MAPK
modulation of ERα and tamoxifen resistance in breast cancer cells.
1
Cui,Y. et al. Cancer Res, 66:5959, 2006.
409
Single nucleotide polymorphism 3814 C>T (P1272S)
in steroid receptor coactivator-1 alters its coactivation
activity.
Richter AS, Hartmaier RJ, Lee AV, Skaar T, Rae J, Li L, Flockhart D,
Tchatchou S, Hemminki K, Schmutzler RK, Meindl A, Bartram CR,
Burwinkel B, Oesterreich S. Baylor College of Medicine, Houston,
TX; Indiana University, Indianapolis, IN; University of Michigan,
Ann Arbor, MI; DKFZ, Heidelberg, Germany; University of Cologne,
Cologne, Germany; Klinikum Rechts der Isar TU, Munich, Germany;
University of Heidelberg, Heidelberg, Germany
Introduction: Genetic alterations as single nucleotide polymorphisms
(SNPs) can contribute to alterations in breast cancer risk, outcome,
and treatment ef¿ciency. Since the steroid receptor coactivator (SRC)
family, speci¿cally SRC1, has been implicated in disease recurrence/
progression as well as response to hormonal therapy, we hypothesize
that SNPs in SRC1 alter the transcriptional activity of estrogen
and progesterone receptor, and could impact breast cancer risk and
Tamoxifen response.
Methods: ERE-LUC-Reporter and DBD-Gal4-tethering assays were
conducted in MCF7, T47D, Ishikawa, or HEK293 cells, and PRE-LUCReporter assays in Ishikawa cells. To determine changes in protein half
live, pulse-chase experiments were performed. The genotype effect on
bone mineral density (BMD) change was tested by Wilcoxon-signed
rank test.
Results: To con¿rm SNPs from databases we sequenced the SRC1 gene
from 48 African American and 48 Caucasian healthy subjects from the
Coriell DNA diversity panel. We found the 3814C>T SNP causing a
P1272S amino acid change located in the activation domain-2 (AD2)
of SRC1. We observed a signi¿cant loss of coactivation due to this
SNP compared to WT in ERE- as well as PRE-LUC assays. A similar
loss of activity was also seen using the AD2 in DBD-Gal4-tethering
assay suggesting that causative changes are inherent to the domain
between amino acids 1241 and 1385. Further, we compared turnover
rates of SRC1 WT and SNP. Treatment with cycloheximide followed
by immunoblotting as well as pulse chase experiments revealed that
SRC1 SNP is degraded faster than WT. To determine whether these in
vitro ¿ndings may play a role in breast cancer etiology and response to
endocrine therapy, clinical samples were genotyped. In a case-control
study with 759 healthy controls and 857 familiar breast cancer patients
(negative for BRCA1/2 mutations), the SNP was not associated with
breast cancer risk. We genotyped 258 samples from patients treated only
with Tamoxifen after tumor resection. BMD change at 12 months after
treatment was used as a surrogate endpoint. Lumbar and hip BMD were
found to be signi¿cantly lower in patients carrying the SNP compared
to WT. According to these preliminary results, the SRC1 3814C>T
genotype is associated with a detrimental effect on BMD change after
Tamoxifen treatment.
Summary: We have, for the ¿rst time, identi¿ed a SNP in a coactivator
that alters ERα activity. The mechanism includes increased turnover
rate. There was no significant association with risk, however,
preliminary results suggests that the SNP alters tamoxifen effects
in bone. Studies are ongoing to con¿rm these results, and further
understand the mechanism.
501
The ZO-FAST trial: zoledronic acid effectively inhibits
aromatase inhibitor associated bone loss in postmenopausal
women with early breast cancer receiving adjuvant
letrozole: 24 month BMD results.
De Boer R, Eidtmann H, Lluch A, Pinotti G, Miller J, Schenk N, Dias R,
Coleman R. Royal Melbourne Hospital, Parkville, Victoria, Australia;
Universitaetsklinikum, Kiel, Germany; Hospital Clinico Universitario
de Valencia, Valcenia, Spain; Ospedale di Circolo Fondazione Macchi,
Varese, Italy; Novartis, East Hanover, NJ; Weston Park Hospital,
Shef¿eld, United Kingdom
Background: Letrozole is safe and effective in the treatment of receptor
positive early breast cancer (EBC) in postmenopausal women (PMW).
But like other aromatase inhibitors, long-term letrozole is associated
with loss of bone mineral density (BMD) and a higher incidence of
fractures. This multicenter open-label randomized study evaluates
an immediate or delayed strategy of bone protection therapy with
zoledronic acid (ZA) in preventing aromatase inhibitor induced bone
loss (AIBL) in PMW with EBC who are receiving adjuvant Letrozole
(Let) therapy.
Material and Methods: 1065 PMW with stage I-IIIa ER+/PR+ EBC
starting Let (2.5 mg qd x 5 yrs) were randomized to immediate ZA (4
mg IV infusion q 6 mos) vs delayed ZA in 112 centers in 28 countries.
The delayed group will receive ZA when either post-baseline T-score
decreases to less than -2.0 SD or if a non-trauma fracture occurs. The
primary endpoint, the percent change in lumbar spine (LS) BMD at 12
mos was reported at the 2006 European Breast Cancer Conference. The
results of longer term (24 mos) follow up are reported here.
Results: Baseline characteristics were similar between the two groups.
730 of 1065 pts are evaluable for 24 mos LS BMD. Immediate ZA
group shows a mean increase of 3.7%, the delayed group shows a mean
decrease of 4.5%, resulting in a signi¿cant difference of 8.2% between
groups (p<0.0001). 718 of 1065 pts were evaluable for 24 mos total hip
(TH) BMD. Immediate ZA group shows a mean increase of 1.7%, the
delayed group shows a mean decrease of 3%, resulting in a signi¿cant
difference of 4.7% between groups (p<0.0001). The median duration
of Let therapy was similar in both arms (31.7 vs 31.5 mos). Patients on
the immediate arm received a median of 5 doses of ZA. 100 patients on
the delayed arm had started ZA at the time of the 24 month analysis.
21 patients in the immediate arm had a breast cancer recurrence versus
32 in the delayed arm. At month 24, the most common adverse event
was arthralgia with a similar incidence (40.2% vs 37.2%). 30 patients
had a clinical fracture (13-immediate, 17-delayed). Two patients on the
delayed arm had reported episodes of renal failure. Neither patient had
received ZA. There were two cases of suspected osteonecrosis of the
jaw. These cases will be independently adjudicated.
Conclusion: These results show the continuing ef¿cacy of Zometa in
preventing AIBL. The 24 mos data shows an even greater difference
in the LS and TH BMD between the immediate and the delayed arms
than was seen at 12 mos. Overall, the incidence of adverse events was
not different between the two arms, con¿rming the safety of Zometa
in this setting.
502
The SABRE (Study of Anastrozole with the Bisphosphonate
RisedronatE) study: 12-month analysis.
Van Poznak C, Hannon RA, Clack G, Campone M, Mackey JR,
Apffelstaedt J, Eastell R. University of Michigan, Ann Arbor, MI;
University of Shef¿eld, Shef¿eld, United Kingdom; AstraZeneca,
Maccles¿eld, Cheshire, United Kingdom; Site Hospitalier Nord de
Nantes, Nantes, France; University of Alberta, Edmonton, AB, Canada;
University of Stellenbosch, Tygerberg, South Africa
Background: The SABRE trial (NCT00082277) evaluated the effects
of the bisphosphonate risedronate on bone mineral density (BMD)
and bone turnover in postmenopausal women with hormone receptorpositive early breast cancer treated with anastrozole. Materials and
methods: Lumbar spine and hip T-scores were used to assess baseline
risk of fracture, and pts were strati¿ed into treatment groups accordingly.
Pts with a T-score <-2.0 for either spine or hip, or those pts deemed
by the investigator to be at increased risk of fracture, were designated
higher-risk (H), and received anastrozole 1 mg/day plus risedronate 35
mg/week orally. Moderate-risk (M) pts (T-score <-1.0 for spine or hip
but ≥-2.0 at both sites) were randomized in a double-blind manner to
receive anastrozole plus risedronate (A+R) or anastrozole plus placebo
(A+P). Pts with T-scores ≥-1.0 at both spine and hip were designated
lower-risk (L), and received anastrozole alone. All pts received calcium
and vitamin D. Levels of serum C-terminal crosslinking telopeptide
of type I collagen (sCTX), serum procollagen type I amino terminal
peptide (PINP) and bone alkaline phosphatase (bALP) were used to
assess bone turnover. Lipid pro¿les were also assessed before and during
treatment. Results of the 12-month analysis are now available. Results:
The table shows percentage change in BMD. In H, BMD increased
signi¿cantly, while in L, a numeric decrease was observed. A signi¿cant
difference was seen between M treatment groups for total hip (p=0.002)
and lumbar spine (p<0.0001, analysis of covariance) in favor of A+R.
In M, percentage changes in bone markers were signi¿cantly different
between the A+R and A+P treatment groups (sCTX -43.73 vs 5.18, PINP
-47.56 vs -7.65, bALP -23.91 vs 1.61, respectively; p<0.0001 for all).
Incidences of adverse events (AEs) and serious AEs were comparable
between M treatment groups (A+R 88%; A+P 86%), as were serious
AEs (A+R 5%; A+P 5%). Discussion: In postmenopausal women with
breast cancer who are scheduled for treatment with adjuvant anastrozole
and are already at moderate to high risk of fragility fracture, BMD can
be managed with risedronate at the licensed dose and bone health can
be managed according to established guidelines.
Stratum/treatment
Lumbar spine L / A only
M / A+P
Total hip
N
35
65
Estimated % change in BMD from
baseline to 12 months (95% CI)
-0.62 (-1.93, 0.71)
-0.41 (-1.11, 0.29)
M / A+R
73
+1.71 (0.85, 2.58)
H / A+R
L / A only
M / A+P
36
35
65
+3.36 (2.05, 4.69)
-0.35 (-1.37, 0.68)
-0.09 (-0.66, 0.47)
M / A+R
73
+1.29 (0.69, 1.90)
H / A+R
37
+1.53 (0.37, 2.71)
A, anastrozole; CI, con¿dence intervals; P, placebo; R, risedronate
503
The effect of risedronate on hip structural geometry in
chemotherapy-induced postmenopausal women on SERMS
versus aromatase inhibitors: a 2 year trial.
van Londen G, Perera S, Vujevich K, Sereika S, Bhattacharya R, Vogel
V, Brufsky A, Lembersky B, Greenspan S. University of Pittsburgh,
Pittsburgh, PA; University of Kansas, Kansas City, Kansas
Background: Although aromatase inhibitors (AIs) cause signi¿cant
loss of bone mineral density (BMD), little is known about their
effect on bone structure, a signi¿cant contributor to fracture risk.
Our objectives were 1) to examine the impact of AIs versus Selective
Estrogen Receptor Modulators (SERMs) and no hormone therapy on
hip structural geometry, and 2) to determine if bisphosphonates could
affect these changes.
Methods: This sub-analysis of a 2 year, double-blind trial of 72
chemotherapy-induced postmenopausal women with nonmetastatic
S37
breast cancer who were randomized to risedronate, 35 mg once weekly
(RIS), or placebo (PBO). Outcomes included changes in Beck’s hip
structure analysis (HSA) derived BMD and structural indices measured
at the intertrochanteric region, femoral neck, and proximal shaft [i.e.
cross sectional area (CSA), section modulus (SM: measure of bending
strength), and buckling ratio (BR: index of cortical bone stability)].
Results: Twenty women did not receive adjuvant hormone therapy,
while 28 women received SERMs and 24 received AIs (distributed
similarly between RIS and PBO). Compared to PBO, RIS improved
BMD and several HSA indices in women on no hormonal therapy or AIs
at the intertrochanteric site. In the RIS group, BMD and indices were
poorer in women on AIs than those on no hormonal treatment. Changes
at the narrow neck and femoral shaft revealed similar ¿ndings.
Discussion: In addition to decreases of BMD, AIs cause a deterioration
of hip structural indices. Weekly RIS was able to attenuate these
effects. These ¿ndings provide an important insight into AI-induced
changes in bone geometry, which deserve further exploration to allow
individualized management.
Absolute changes over 24 months for HSA-derived BMD and structural parameters at the
intertrochanteric site [Mean (SE)]
RIS
PBO
BMD (g/cm2) §‡
None †
0.059 (0.026)*
-0.000 (0.013)
SERMs
0.030 (0.019)
0.018 (0.014)
CSA (cm2) §
SM (cm3) § ¨
BR §‡
AIs
0.006 (0.013)
-0.034 (0.013)*
None †
SERMs
0.311 (0.127)*
0.180 (0.083)*
0.022 (0.054)
0.111 (0.061)
AIs
0.018 (0.058)
-0.085 (0.053)
None †
SERMs
0.305 (0.115)*
0.166 (0.076)*
0.013 (0.046)
0.138 (0.052)*
AIs
0.004 (0.057)
0.029 (0.059)
None †
SERMs
-0.660 (0.278)*
-0.218 (0.223)
0.175 (0.145)
-0.128 (0.146)
AIs †
-0.006 (0.174)
0.503 (0.181)*
* P < 0.05 Difference from baseline. † P < 0.05 RIS vs. PBO. § P < 0.05 AIs vs. none in
RIS. ¨ P < 0.05 AIs vs. SERMs in RIS. ‡ P < 0.05 AIs vs. SERMs in PBO.
504
Practical guidance for the prevention of aromatase inhibitorassociated bone loss in women with breast cancer.
Hadji P, Appro M, Brufsky A, Tubiana-Hulin M, Guise T, Body
JJ. Philipps-University of Marburg, Marburg, Germany; Institut
Multidisciplinaire d’Oncology, Genolier, Switzerland; University of
Pittsburgh, Pittsburgh, PA; Centre René Huguenin, St. Cloud, France;
University of Virginia, Charlottesville, Virginia; Université Libre de
Bruxelles, Brussels, Belgium
Background: American Society of Clinical Oncology guidelines on
bone health issues in women with breast cancer recommend that women
with osteoporosis (T-score <–2.5) receive bisphosphonate therapy to
increase bone mineral density (BMD) and reduce the risk of fracture
and that osteopenic women (T-score –1 to –2.5) receive individualized
therapy. Because the majority of fractures occur in osteopenic women,
this threshold appears inadequate for averting fractures in patients with
breast cancer, particularly those receiving aromatase inhibitor (AI)
therapy. Given that BMD testing is not readily available to all patients,
our goal was to provide additional evidence-based guidance to assess
fracture risk and direct treatment with or without BMD scores.
Material and Methods: A systematic literature review was performed to
identify factors that contribute to the increased fracture risk observed
in women with breast cancer. Risk factors were evaluated using an
evidence-based medicine approach to identify patients at high risk, to
determine when to initiate bisphosphonate treatment, and to identify
the appropriate bisphosphonate for treatment.
Results: With the exception of AI treatment, fracture risk factors were
chosen based on their validation in large, prospective, population-based
studies. Risk factors in patients with breast cancer were AI therapy, Tscore <–1.5, age >65, family history of hip fracture, history of personal
fragility fracture after age 50, oral corticosteroid use >6 months, or low
body mass index (<20). Additional risk factors were identi¿ed for which
S38
guidance could not be provided because available data were insuf¿cient:
a diagnosis of breast cancer, chemotherapy, radiotherapy, low weight,
and smoking. Available data clearly suggest that combined risk factors
contribute to fracture risk independent of BMD and that some women
receiving AIs do not become osteoporotic before experiencing a
fracture; therefore, BMD measurement should not be the sole criterion
to assess fracture risk in this patient population. Randomized clinical
trials support zoledronic acid 4 mg every 6 months for prevention of
AI-associated bone loss when a patient is identi¿ed to be at risk, and
data with other bisphosphonates are emerging.
Discussion: Our recommendations for treatment and prevention of
AI-associated bone loss are as follows: In addition to calcium and
vitamin D, any patient initiating AI therapy with a T-score <–2.0 should
receive zoledronic acid 4 mg twice yearly. Any patient receiving AI
therapy with any 2 of the following risk factors, T-score <–1.5, age
>65 years, family history of hip fracture, personal history of fragility
fracture after age 50, or oral corticosteroid use >6 months, should
receive zoledronic acid.
505
Effect of zoledronic acid on bone loss in women undergoing
chemotherapy for breast cancer.
Aft R, Chavez-MacGregor M, Trinkaus K, Naughton M, Weilbaecher
K. Washington University, Siteman Cancer Center, St. Louis, MO; John
Cochran Veterans Administration Hospital, St. Louis, MO
Background: Ovarian failure secondary to adjuvant chemotherapy
is known to have an adverse effect on bone mineral density and to
increase bone turnover markers. The effect of chemotherapy with
growth factor support in the absence of hormonal changes on bone loss
has not been described. We conducted a randomized Phase II study to
determine the effect of zoledronic acid on bone loss related to breast
cancer therapy.
Methods: 120 women with localized stage II/III breast cancer
were randomized to either zoledronic acid 4 mg IV every 3 weeks
for 1 year starting with the first cycle of chemotherapy or no
bisphosphonate therapy. All women received chemotherapy with
epirubicin (75 mg/m2) and docetaxel (75 mg/m2). Four cycles were
given prior to surgical resection and 2 cycles in the adjuvant setting.
Prophylactic dexamethasone and G-CSF was given during all cycles of
chemotherapy. Bone turnover markers (urinary N-telopeptide, serum
speci¿c alkaline phosphatase, and osteocalcin) were measured at
baseline, 3 months, and 1 year after initiation of chemotherapy. Bone
mineral density (BMD) was measured by dual-x-ray absorptiometry
(DEXA) of the hip, lumbar spine, and wrist at baseline and at 1 year.
Eligible patients received aromatase inhibitors or tamoxifen after
chemotherapy. Data was analyzed using Wilcoxon Signed rank tests
or Mann-Whitney tests.
Results: Between March 2003 and March 2006 120 patients were
enrolled in the trial. The groups were well balanced for stage, grade,
menopausal status, ER positivity, baseline BMD and bone turnover
markers. Baseline and 1 year DEXA results are available for 62 women.
The percentage change in the bone turnover markers were signi¿cantly
less in the zoledronic treated group for all markers (p<.001). Both
pre- and post-menopausal women in the control group experienced
a signi¿cant decrease in BMD (p<0.001); whereas women receiving
zoledronic acid experienced a statistically signi¿cant increase in BMD
from baseline (p=0.001). More women with normal BMD at baseline
developed osteopenia and osteoporosis in the no treatment group
compared to the zoledronic acid group (p=0.025).
Discussion: Our study evaluated the effect of zoledronic acid on bone
loss in women undergoing chemotherapy for breast cancer. This is the
¿rst demonstration that anthracycline-taxane chemotherapy with growth
factor support increased bone resorption markers in both pre- and
post-menopausal women independent of endocrine therapy, radiation
therapy, and surgery. We found that both pre- and post-menopausal
women experienced signi¿cant decreases in bone mineral density
related to breast cancer therapy. A signi¿cant proportion (42%) of
these women with normal BMD at baseline developed osteopenia or
osteoporosis at 1 year. The addition of zoledronic acid to systemic
chemotherapy resulted in signi¿cant improvement in bone mass at 1
year following the initiation of systemic chemotherapy.
506
Zoledronic acid prevents bone loss in premenopausal women
undergoing adjuvant chemotherapy for early stage breast
cancer.
Hershman DL, McMahon D, Crew K, Cremers S, Irani D, Cucchiara
G, Brafman L, Siarra A, Shane E. Columbia University Medical Center,
New York, NY
Background:
Adjuvant therapy for breast cancer may be associated with increased
rates of bone loss and decreased bone mineral density (BMD) that may
contribute to early onset osteoporosis and increased risk of fracture.
This study examined whether zoledronic acid can prevent bone loss
associated with adjuvant chemotherapy in premenopausal women with
early stage breast cancer.
Methods:
This study is a randomized, double-blind, multi-center, phase III trial
comparing zoledronic acid (4 mg intravenously every 3 months) versus
placebo for 1 year in premenopausal women with invasive breast cancer
undergoing adjuvant chemotherapy. Patients underwent serial BMD
measurements at 0 (after surgery and before initiating therapy), 6 and
12 months. Patients were strati¿ed by presence or absence of hormone
sensitive tumors. Fasting morning blood was analyzed at week 0, 6,
12, 18, 26, 36 and 52. Serum was archived, stored at -70o and analyzed
in batches in a research laboratory for markers of bone turnover.
Information on demographic, clinical and tumor characteristics, and
quality of life were collected. The primary outcome variable was lumbar
spine (LS) BMD at 6 months. Secondary outcomes were LS spine
BMD at 12 months, other BMD sites, markers of bone resorption and
formation, and predictors of bone loss. A linear mixed model analysis
was performed with SAS version 9.
Results:
Of 122 women randomized, 104 completed the 6 month and 94 the
12 month evaluations (retention 85% and 77%, respectively). The
remaining women withdrew before completion, but none due to toxicity.
Baseline characteristics were evenly distributed between groups. Mean
age was 42 years. No renal or other toxicities were observed in either
group. Chemotherapy without zoledronic acid was associated with
signi¿cant decline in LS BMD after both 6 (2.4%) and 12 (4.1%)
months. Similarly total hip (TH) BMD declined by 0.8% at 6 months and
2.6% by 12 months.in In contrast, BMD remained stable in zoledronic
acid-treated patients (P<.0001 compared with chemotherapy alone).
Markers of bone turnover are being analyzed and will be presented.
Conclusions:
Chemotherapy was associated with signi¿cant bone loss in the lumbar
spine and total hip in premenopausal women with breast cancer.
Zoledronic acid 4 mg every 3 months effectively prevented bone loss.
Additional analyses are planned to determine whether the onset of
chemotherapy-induced menopause inÀuences which patients bene¿t
the most from early initiation of concomitant bisphosphonate therapy
for prevention of bone loss. Regular BMD measurements should be
considered for premenopausal women undergoing chemotherapy for
invasive early stage breast cancer.
507
Differential effects of doxorubicin and zoledronic acid on
intra-osseous vs extra-osseous breast tumour growth LQ
YLYR.
Ottewell PD, Deux B, Monkkonen H, Cross SS, Coleman RE, Clezardin
P, Holen I. University of Shef¿eld, Shef¿eld, Yorkshire, United Kingdom;
Faculte de Medicine Laennec, Lyon, France
Introduction: Breast cancer patients with bone metastases are
commonly treated with chemotherapeutic agents such as doxorubicin
(dox), as well as zoledronic acid (zol) to control their bone disease.
Sequential administration of dox followed by zol has been shown to
increase tumour cell apoptosis in vitro . We have, therefore, investigated
the antitumour effects of clinically relevant doses of these drugs in a
mouse model of breast cancer bone metastasis.
Methods: MDA-MB-231/BO2 (BO2) cells were injected via the
tail vein into athymic mice. Tumour-induced osteolytic lesions were
detected in all animals following x-ray analysis 18 days after tumour
cell inoculation (day 18). Mice were then administered saline, 100?g/kg
zol, 2mg/kg dox, dox and zol simultaneously, or dox followed 24h
later by zol. Dox treated animals received a second injection on day
25, and all animals were sacri¿ced on day 32. Tumour growth in the
marrow cavity and on the outside surface of the bone was measured
on 4 non-serial histological sections. Apoptosis and proliferation were
assessed at both sites following immunohistochemistry for caspase 3
and BrdUrd, respectively. Effects of treatments on bone were evaluated
following X-ray and µCT analysis.
Results: Animals treated with zol, alone or in combination with dox,
had signi¿cantly smaller tumour-induced osteolytic lesions compared
with control (saline) or dox treated animals. In addition, sequential
treatment with dox then zol caused a signi¿cant inhibition of intraosseous tumour growth compared with control, either drug alone, or
simultaneous treatment with dox and zol. The reduced intra-osseous
tumour volume was associated with an increase in tumour cell apoptosis,
and a decrease in tumour cell proliferation. Extra-osseous tumour
growth was unaffected in all treatment groups.
Conclusions: Sequential treatment with clinically relevant doses of
dox followed by zol reduces intra-osseous but not extra-osseous growth
of BO2 breast tumours in long bones of immunocompromised mice.
508
Survival in breast cancer patients with bone metastases and
reductions in markers of bone resorption during zoledronic
acid treatment.
Lipton A, Cook R, Major P, Smith M, Coleman R. Milton S. Hershey
Medical Center, Hershey, PA; University of Waterloo, Waterloo,
ON, Canada; Juravinski Cancer Centre, Hamilton, ON, Canada;
Massachusetts General Hospital Cancer Center, Boston, MA;
University of Shef¿eld, Shef¿eld, United Kingdom
Background: Most breast cancer patients (pts) with bone metastases
receive bisphosphonates, which can lower their levels of biochemical
markers of bone metabolism. Pts with bone metastases and high levels of
N-telopeptide of type I collagen (NTX) are likely to experience skeletalrelated events (SREs) and reduced survival. The purpose of this study
was to assess whether zoledronic acid (ZOL)-mediated reductions in
NTX levels correlate with long-term bene¿ts. This post hoc analysis
investigated whether early (3-mo) suppression of NTX levels during
ZOL therapy correlate with prolonged survival and a reduced risk of
SREs in pts with breast cancer.
Material and Methods: This was a subset analysis of breast cancer pts
enrolled in a phase III randomized trial comparing intravenous ZOL
with pamidronate in pts with bone lesions from breast cancer or multiple
myeloma. Urine was obtained as a morning second-void sample, and
NTX levels were corrected according to creatinine (CRE) levels. NTX
levels ≥64 nmol/mmol CRE were considered elevated. Pts with breast
cancer who received ZOL and had NTX assessments at baseline and
mo 1 and 3 (n=328) were included in this analysis. The correlation
between changes from baseline NTX level at 3 mo and the following
time-dependent variables were modeled: bone lesion progression,
skeletal-related events (SRE), and survival.
Results: Median NTX level at baseline was 77 nmol/mmol CRE (25th
S39
percentile = 50 nmol/mmol CRE and 75th percentile = 127 nmol/mmol
CRE). Baseline NTX was elevated in 196 (60%) pts. Of these pts, 149
(76%) normalized NTX after 3 mo of ZOL, and 31 (16%) pts still had
elevated NTX at 3 mo. Median survival was approximately 50% longer
and the risk of SREs approximately 50% lower for pts whose NTX
normalized compared with pts whose NTX remained elevated (P=.0004
and P=.0034, respectively). In all pts, the percentage reduction in NTX
level versus baseline corresponded with continuous decreases in the
risk of SREs, death, and bone lesion progression. ZOL decreased NTX
levels by ≥40% versus baseline at the 3-mo assessment in 80% of pts.
In models correlating NTX reductions with bone lesion progression
for patients with different baseline NTX levels, a ≥40% reduction was
associated with a signi¿cant 32% (25th percentile baseline NTX),
34% (median baseline NTX), or 39% (75th percentile baseline NTX)
decrease in risk of bone lesion progression compared with similar pts
without a 40% reduction (P<.05 for each).
Discussion: These results suggest that early normalization or reduction
of elevated baseline NTX while receiving ZOL is associated with
improved SRE-free and overall survival compared with persistently
elevated NTX. Further analyses of NTX kinetics in patients with breast
cancer are warranted.
509
Effects of zoledronic acid on wnt inhibition by dickkopf1 and
frizzled-related protein in patients with bone metastases.
Helsten TL, Mortimer JE, Corr M. Moores UCSD Cancer Center, La
Jolla, CA; University of California, San Diego, CA
Background: Data from mice and humans suggest that wnt/frizzled
signaling is important for skeletal development and regulation of adult
bone mass. There are two types of soluble inhibitors of wnt signaling:
dickkopf1 (DKK1) and frizzled-related proteins (FRP). In multiple
myeloma, serum DKK1 levels correlate with the burden of lytic bone
lesions, but no such data are known for solid tumors. Breast cancer is
primarily osteolytic, but may be osteoblastic or mixed, while prostate
cancer is osteoblastic. We explored the wnt antagonists DKK1 and FRP
as potential biomarkers in patients with bone metastasis from breast
or prostate cancer and their response to treatment with zoledronic
acid (ZA).
Methods: This is a cohort study of bisphosphonate naïve breast and
prostate cancer patients with bone metastases. Anti-cancer therapy
was not speci¿ed. Sera were collected at baseline and at day 60 after
treatment with 2 monthly doses of ZA (4 mg IV) for measurement of
DKK1, FRP, and bone-speci¿c alkaline phosphatase (BAP, a standard
marker of bone turnover and osteoblast activity) using standard ELISA
protocols. Primary endpoints: mean changes in serum DKK1 and
FRP. Secondary endpoints: correlation of markers with each other and
comparison of breast vs. prostate cancer patients. Statistics: two-tailed
student t-tests and Pearson correlation coef¿cients.
Results: The cohort included 20 patients: 11 with breast and 9 with
prostate cancer. Mean age = 61 years (range 42-79). Three breast
cancer patients were premenopausal. Four breast and 4 prostate cancer
patients received chemotherapy; all others were treated hormonally.
Pretreatment BAP was higher in prostate than breast cancer patients
(mean 107.0 mg/dl vs. 35.5 mg/dl). As expected, ZA decreased BAP in
all but one patient (mean decrease 24.83 mg/dl, 95%CI -3.71 to 53.37).
There was no clear trend in DKK1 (mean change -0.08 mg/dl, 95%CI
-8.38 to 8.21) or FRP (mean change -6.31 mg/dl, 95%CI -14.85 to 2.23),
nor any apparent difference between breast and prostate cancer. DKK1
and FRP tended to change in the same direction (15/20 patients), but not
linearly (p = 0.1). Pretreatment DKK1 and FRP correlated with each
other (r2 = 0.26, p = 0.02), but not with BAP. Post-treatment DKK1
correlated with BAP (r2 = 0.41, p = 0.002), while FRP did not (r2 =
0.01, p = 0.7). ZA treatment abrogated the correlation between DKK1
and FRP (r2 = 0.19, p = 0.06).
Conclusions: Both DKK1 and FRP are present in the sera of patients
with bone metastases and treatment with ZA has measurable effects
on their levels. While DKK1 and FRP correlated with each other
moderately well at baseline and tended to change in the same direction
after ZA, DKK1 more than FRP seems to correlate with bone turnover
S40
after ZA treatment (as measured by BAP). These pilot data suggest
that bisphosphonates may have an effect on wnt inhibition, though the
effects of concurrent anti-cancer treatment and disease response are
not known. Further studies are needed.
510
Zoledronic acid as adjuvant therapy for women with
early stage breast cancer and occult tumor cells in bone
marrow.
Lin A, Park J, Melisko M, Goga A, Moasser M, Moore D, Brissaud
C, Rugo H. University of California-San Francisco, Comprehensive
Cancer Center, San Francisco, CA
Background: The presence of occult tumor cells (OTC) in the bone
marrow (BM) is associated with an increased risk of distant recurrence
and death from cancer in women with early stage breast cancer (BC),
particularly when these cells are detected after completion of adjuvant
systemic therapy. Bisphosphonates have the potential to act as antitumor agents by a variety of mechanisms including induction of
tumor cell apoptosis. Adjuvant clodronate in women with OTC at BC
diagnosis reduced the incidence of osseous and non-osseous metastasis
and improved survival. Zoledronic acid is signi¿cantly more potent that
clodronate in inhibiting bone resorption. We are conducting a pilot study
to evaluate the effects of zoledronic acid in women with early stage BC
with OTC following systemic chemotherapy (CTX). We hypothesize
that treatment with zoledronic acid will result in decrease in OTC which
could serve as a surrogate marker of anti-tumor effect.
Methods: OTCs are detected by immunomagnetic enrichment + Àow
cytometry (FC) as follows: 4 ml of BM aspirate was subjected to
anti-EpCAM-conjugated iron particles, followed by FC for EpCAM,
CD45, and nucleic acid content for quantitative analysis of OTC per
ml. Patients (pts) with stage I-III BC are evaluated for OTC with a
unilateral BM aspiration following neoadjuvant or adjuvant CTX;
eligibility was de¿ned as >4 OTC/ml within 12 weeks of study entry.
This cutoff is de¿ned as > 2.5 standard deviations above that found in
50 normal BM samples (Park, Proc ASCO 2002). Pts receive 4 mg of
zoledronic acid IV monthly for 2 years. Concomitant hormone therapy
was allowed. Serum creatinine and toxicity are evaluated monthly and
urinary n-telopeptide is measured at 0, 2, 4, 6, 12, and 24 months (mos).
Repeat BM aspirations are performed at 1 and 2 years.
Results: 44 pts are enrolled in this study. We report an interim analysis
of baseline and one year BM results. The mean OTC at baseline is 25.6
OTC/ml (range 5-332 OTC/ml), and the mean follow-up period is 16.2
mos (range: 1 to 31 mos). Baseline OTC >30 OTC/ml predicts for
distant recurrence (p=0.007). 26 pts have received more than 12 mos
of zoledronic acid and 22 have had BM aspirations at 1 year. 16/22 pts
(73%) had a decrease in OTC from baseline to 1 year (p=0.013). To
date, only 9 pts have had BM aspirations at 2 years. Five breast cancer
recurrences occurred during the ¿rst year of study enrollment (average
time to recurrence 5.2 mos); all pts were node positive, and negative
for ER, PR, Her2/neu. Zoledronic acid was well tolerated with only 1
pt discontinuing study treatment due to side effects.
Discussion: Serial detection of OTC in BM is feasible in women with
early stage BC. High baseline BM OTCs predicted for early recurrence
in women with high risk disease. This preliminary data suggests that
zoledronic acid may decrease the number of OTC at one year, and this
treatment was well tolerated. The study is ongoing, updated data will
be presented.
511
Effect of zoledronate on persisting isolated tumor cells in
the bone marrow of patients without recurrence of early
breast cancer.
Rack BK, Jueckstock J, Genss E-M, Schoberth A, Schindlbeck C, Strobl
B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese K, Janni W.
Ludwig-Maximilians-University, Munich, Germany; Laboratory Drs.
Tiller and Partners, Munich, Germany; Estimate GmbH, Augsburg,
Germany
3XUSRVH
Recently, the highest level of evidence was reached for the prognostic
impact of isolated tumor cells (ITC) in bone marrow of breast cancer
pts both at primary diagnosis and during recurrence-free follow-up.
Chemotherapy seems to have only limited effect on ITC in dormant
state. The goal of the present study is to investigate the therapeutic
ef¿cacy of zoledronate on the persistence of ITC in the bone marrow
of breast cancer pts after completion of primary therapy.
0HWKRG
We followed 172 breast cancer pts without evidence for distant
recurrence but detection of ITC in bone marrow. As part of an
interventional pilot study, zoledronate was applied at 4mg q4wx6mon
(loading dose 8mg) to 31 pts who had completed surgery, leading to
R0 resection of their tumor, and adjuvant chemotherapy for at least 6
months. In a matched pair analysis, these pts were compared to those
141 pts, who were treated according to standard guidelines but did
not receive additional zoledronate treatment. The bone marrow was
re-examined after a median of 7.9 months (std .89) in the treatment
group and 11.5 months (std 12.41; P=.11) in the control group. ITC
were detected by immunocytochemical staining using the monoclonal
pan-cytokeratin antibody A45-B/B3 and the APAAP technique. Pts
were followed prospectively for a median of 39 months following the
¿rst aspiration.
5HVXOWV
Primary tumor characteristics, i.e. tumor size (P=.09), axillary nodal
status (P=.85), hormone receptor status (P=.67) and grading (P=.35),
as well as surgical (P=.22), adjuvant systemic (P=.18) and irradiation
treatment (P=.51) were well balanced between both pt groups. While
ITC were detected in all 172 pts at the time of ¿rst bone marrow
aspiration, four pts (13%) showed ITC following 6 months of
zoledronate therapy. In contrast, persisting ITC were detected in 38 pts
(27%) of the control group without zoledronate treatment (P=.099). The
reduction in cell numbers between ¿rst and second aspiration reached
statistical signi¿cance in the zoledronate group (P=.02) in contrast to
control pts (P=.14). Persistent ITC at the follow-up aspiration were
associated with reduced RFS (P=.05). Among 12 pts without detection
of ITC in bone marrow after treatment who underwent additional
aspirations, 10 pts showed a persistently negative bone marrow status
after a median of 19 months (range 4.7-38.7 mon) following treatment.
Zoledronate treatment was well tolerated with mild bone pain as the
most common side effect in 45% of pts (n=14).
&RQFOXVLRQ
These results indicate a potential antineoplastic effect of the cell-cycle
independent agent zoledronate on persisting ITC in dormant state. Our
data provide a hypothesis generating basis to investigate the therapeutic
ef¿cacy of zoledronate on ITC in the secondary adjuvant setting by
prospectively randomized trials.
Abstracts – Poster Session I
1001
Effect of magnetic resonance imaging on the clinical
management of women with newly diagnosed breast
cancer.
Newstead GM, Abe H, Jansen SA, Shimauchi A, Sennett CA, Schmidt
RA, Zak L, Olopade O, Jaskowiak N. University of Chicago; University
of Chicago, Chicago, IL
Background: Magnetic resonance imaging (MRI) has been shown to
identify multifocal, multicentric and contralateral breast cancer, not
identi¿ed by clinical examination, mammography and ultrasound.
Although the biological importance of additional areas of disease
identi¿ed by histopathology has been questioned, we sought to evaluate
the contribution of MRI to the initial staging of newly diagnosed breast
cancer patients, and to document the effect of MRI assessment on
patient management.
Materials and Methods: MRI has been routinely and non-selectively
used for breast cancer staging at our institution since 2002. We identi¿ed
459 consecutive patients with 465 newly diagnosed breast cancers who
underwent MRI between July 1 2002 and December 31 2006. Excluded
were patients with clinical ¿ndings of inÀammatory cancer. All patients
were assessed by clinical examination, bilateral mammography (MG)
and ultrasound (US) of the affected breast. Location, number and size
of the cancers were documented. Mean patient age was 56.5 yrs (range
26-82). Histology of the index lesion: invasive duct carcinoma (IDC)
n=201 (43.2%), invasive lobular carcinoma (ILC) n=40 (8.6%), ductal
carcinoma-in-situ (DCIS) n=69 (14.8%) and IDC with DCIS n=155
(33.3%). Dynamic bilateral MR contrast-enhanced protocol:1 pre and
4-6 post-contrast images acquired in the coronal or axial plane, with
60-75 s timing. Analysis of lesion morphology and kinetic curve shape
was classi¿ed according to the BIRADS lexicon. Location, number
and size of unsuspected areas of additional tumor were documented,
and classi¿ed according to their location: within the same quadrant
(multifocal), within a different quadrant and at least 3 cms away
(multicentric), and in the contralateral breast. Patients with positive MR
for additional lesions underwent “second look” directed MG and US
to search for additional tumor, and selected patients underwent biopsy
and/or localization of additional tumor under US or MR guidance. All
imaging and histologic ¿ndings were discussed at an interdisciplinary
treatment conference.
Results: Analysis of the MRI staging data with pathology review,
demonstrated secondary disease to be present in 106 (23.1%) patients,
mean age 51.2 years (5 years younger than mean age of all). Distribution
of additional disease: multifocal n=58 (12.6%), multicentric n=27
(5.9%), contralateral breast n=21(4.5%). Additional cancer histology:
IDC n=36 (33.9%), IDC + DCIS n=26 (24.5%), DCIS n=29 (27.4%),
ILC n=15 (14.2%). Management change: More extensive cancer
surgery with breast conservation n= 86 (81.1%), mastectomy rather
than conservation n=10 (9.4%) and Neoadjuvant chemotherapy n=5
(4.7%).
Conclusion: MR imaging offers more precise assessment of tumor
extent than mammography or ultrasound imaging. Therapeutic
management was changed in 23.1% patients (n=106), resulting in a
change from breast conservation to mastectomy in 9.4% patients.
1002
Deconvolution-based dynamic contrast enhanced MRI
of breast cancer: correlation of tumor blood Àow with
pathologic and molecular markers.
Makkat S, Fontaine C, Stadnik T, Luypaert R, Bourgain C, De Greve J,
De Mey J. UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
Purpose: Characterization of angiogenesis has been performed mostly
by in-vitro immunohistochemical evaluation of angiogenic tumor
markers. Non-invasive measurement of blood Àow in tumors has
potential for assessing changes in angiogenic vasculature because the
blood Àow in tumors is usually abnormal. The aim of our study was to
test whether breast carcinomas possess characteristic values of tumor
blood Àow that correlate with pathologic and molecular prognostic
markers. Materials and Methods: 57 patients with carcinoma of the
breast (31–80 years; mean 51 years) who underwent mastectomy or
wide excision after MR imaging were studied by in-vivo perfusion
S41
measurements on a 1.5 T scanner (Philips Intera). The routine MR
protocol was ¿rst applied, which included whole breast dynamic
contrast enhanced (DCE MR) sequence. The slice in which the
lesion enhanced maximally was located by visual inspection of the
subtracted DCE MR images. A second bolus of 0.1 mmol/kg Gd-DTPA
was injected and a dynamic single slice inversion prepared FLASH
acquisition (400 dynamics with a temporal resolution of 0.3s) was
performed at that slice position. The relative enhancement time courses
of this second bolus sequence were deconvolved pixel wise, to generate
the impulse response function, the maximum of which corresponds
to tumor blood Àow (TBF). Quantitative value for each patient was
derived as the median value of all the pixels in the ROI covering the
lesion. Formalin-¿xed, paraf¿n-embedded slides were evaluated for
histological size and grade. Tumor samples were stained for estrogen
receptor (ER), progesterone receptor (PR) and HER-2 protein by
IHC. For an HER-2 protein score of 2+ and 3+, HER-2 gene status
was assessed by FISH. For ER, PR and HER-2 gene status, median
TBF was compared between positive and negative groups. Results:
Signi¿cantly higher TBF was observed in tumors larger than 2 cm
in size and in PR negative tumors (p <0.05). In addition, the median
TBF values were signi¿cantly higher in the HER-2 positive group (98
± 37 ml/100ml/min) compared with the HER-2 negative group (71
± 43 ml/100ml/min) (p <0.05). In both the HER-2 positive and the
negative groups, the ER+/PR+ had a lower median TBF compared to
the ER-&PR-. This difference was statistically signi¿cant in the HER-2
positive group (p <0.05). Conclusion: Our preliminary results support
the hypothesis that there is increased blood Àow in poor prognostic
(HER-2 positive and hormone receptor negative) tumors. Moreover, our
results also show that a pixel wise deconvolution analysis of DCE MR
data in malignant breast tumors can provide pre-operative information
regarding the angiogenic status as assessed by the blood Àow. Further
validation of perfusion data against clinical and biological parameters
could enable TBF to become a noninvasive angiogenic marker that
could also be explored in the context of anti-angiogenic therapies for
which in vivo biomarkers are currently lacking.
1003
A new approach to studying the progression of mammary
gland carcinoma in mice: high resolution MRI of early
cancer and DCIS.
Jansen SA, Conzen S, Zamora M, Krausz T, Newstead GM, Karczmar
GS. University of Chicago
Background: Longitudinal studies of the progression of mammary
gland carcinoma in mice usually involve large, palpable tumors.
For example, in many preclinical evaluations of therapies, a drug is
administered to mice with palpable tumors, and subsequent changes in
tumor size are measured using calipers. However, these xenografted or
transgenic tumors are not necessarily realistic models of human breast
carcinoma presentation: 64% of breast cancer patients present with
localized cancer, and 15-25% have preinvasive ductal carcinoma in situ
(DCIS). Improved imaging is needed to study the full progression from
hyperplasia to DCIS to invasive cancerin animals. Thus, the purpose of
this study was to develop techniques to study very early breast cancer
and its progression in vivo with histopathologic correlation.
Materials and Methods: Twelve C3(1) SV40 TAg transgenic mice
between 10-18 weeks of age were used. A pair of inguinal mammary
glands in each mouse was imaged using a T1-weighted gradient echo
(GE) sequence, with and without fat suppression, with 117 micron
in plane resolution. H&E sections of the glands were obtained. We
used a polyethylene grid embedded in partially deuterated agar to
register tissue sections and MR images. On one representative H&E
section from each mouse, the tumors and ducts distended with DCIS
were identi¿ed by an experienced pathologist. The MR images were
examined to see if correlative structures were discernable.
Results: GE images were able to detect 1/1 large (∼5mm) tumor, 17/18
small (∼1mm) tumors, and 13/16 ducts distended with DCIS greater than
300 microns (please see ¿gure below). There were no false positives—a
clear MR ¿nding corresponded to cancer in all glands. The morphology
of DCIS lesions was either linear ductal or stippled, while small invasive
tumors appeared as round masses with smooth margins.
Discussion: This is the ¿rst report demonstrating in vivo, high resolution
S42
imaging of early cancers in mice, including DCIS, with high sensitivity
and speci¿city. With these techniques, MRI could be used to study the
natural history of experimental breast cancer, and evaluate effects of
therapies on localized, non-palpable and spontaneous cancers. These
cancers are more realistic models of clinical disease than the larger,
often palpable tumors measurable and imaged in pre-clinical studies.
Use of MRI to assess the in vivo ef¿cacy of therapies on earlier cancers
may in turn lead to more clinically effective therapies. Advances in
non-invasive imaging methods, such as those described here, will shift
the paradigm for pre-clinical research to detecting and preventing early
cancer from progressing.
-0.05 to 0.96). A moderate positive linear relationship between MRI and
pathologic size was identi¿ed (r=0.665, p<0.001, Figure 1).
Discussion: A moderate correlation between post-PIC MRI and
pathologic size was identi¿ed, with a trend for MRI to over-estimate
pathologic size.
1005
How does ER/PR and Her2/Neu status affect the MR
characteristics of invasive ductal carcinoma?
1004
Magnetic resonance imaging in predicting pathologic
residual disease after primary induction chemotherapy.
Anderson CM, Patrick RJ, Rybicki LA, Chellman-Jeffers M, Obi B,
Crowe JP. Cleveland Clinic, Cleveland, OH
Background: Magnetic resonance imaging (MRI) is useful to assess
response to primary induction chemotherapy (PIC) and to assist in
surgical planning. This report assesses the ability of MRI to predict
pathologic residual disease after PIC.
Materials and Methods: Data were available in our institutional review
board approved registry for patients who underwent MRI before and
after PIC between April 2004 and December 2006. MRI were performed
using the same scanner (HARMONY, Siemens Medical Systems;
Erlangen, Germany) with a dedicated breast coil, operating at 1.0 Tesla.
Breast radiologists interpreted all MRI using computer-aided detection
(Cadstream, Con¿rma, Inc, Kirkland, WA, USA). Radiographic tumor
response was assessed using Response Evaluation Criteria in Solid
Tumors (RECIST). Longest diameter of the largest lesion on postPIC MRI was compared to subsequent pathologic size of the largest
remaining tumor. Data were analyzed using Spearmans correlation (r)
and Wilcoxon signed-rank test; a p-value of <0.05 was signi¿cant.
Results: Data were available for 30 patients. A majority of patients were
premenopausal (67%), TNM Stage IIB-IIIA (70%), and diagnosed with
in¿ltrating ductal histology (90%). Most patients (97%) received four
cycles of either doxorubicin/cyclophosphamide or epirubicin, either
with or without a taxane. Median diameter of largest tumor on pre-PIC
MRI was 4.4 cm (range 2.4-14.0). Median diameter of largest tumor on
post-PIC MRI was 1.9 cm (range 0-7.4). Evaluation of tumor response
on post-PIC MRI showed complete response (rCR) for ¿ve (17%)
patients, partial response (PR) for 16 (53%) and stable disease (SD)
for nine (30%). Of the ¿ve patients achieving rCR, one had pathologic
CR (pCR), three had residual microscopic nests of tumor (near pCR),
and one had 0.4 cm residual tumor. Surgery was completed a median
of 23 days (range 2-50) after post-PIC MRI. Eighteen (60%) patients
underwent modi¿ed radical mastectomy and 12 underwent lumpectomy.
Median diameter of largest tumor pathologically was 1.0 cm (range 09.5). Six patients achieved pCR, of whom one had rCR, four had PR,
and one had SD on post-PIC MRI. Four patients achieved near pCR,
of whom three had rCR and one had SD on post-PIC MRI.
Post-PIC MRI measurement over-estimated pathologic size for 57% of
tumors; median over-estimation was 0.2 cm (95% con¿dence interval
Jansen SA, Abe H, Shimauchi A, Karczmar GS, Newstead GM.
University of Chicago, Chicago, IL
Background: Dynamic contrast enhanced MRI (DCEMRI) is being
used increasingly due to its high sensitivity to breast cancer. DCEMRI
provides both morphologic and functional characterization of lesions
via contrast media uptake and washout (or ‘kinetic’) curves. Prior
reports have linked kinetic curves to underlying lesion vasculature
and biology. Molecular markers, such as estrogen receptor (ER),
progesterone receptor (PR) and Her2/Neu gene ampli¿cation status,
are important for selection of appropriate therapy. They are also
related to tumor biology, with Her2/Neu positive and ER negative
lesions showing less favorable prognosis. The purpose of our study
was to perform a systematic evaluation of the kinetic characteristics
of 145 invasive ductal carcinoma (IDC) lesions classi¿ed by ER, PR,
and Her2/Neu status.
Materials and Methods: 138 patients with 145 histologically proven
IDC lesions with known ER, PR and Her2/Neu status were selected
for IRB approved review. These lesions were classi¿ed as: ER positive
(n=101), ER negative (n=44), PR positive (n=76), PR negative (n=69),
Her2/Neu positive (n=25) and Her2/Neu negative (n=120). Dynamic
MR protocol: 1 pre and 3-5 post-contrast T1-weighted SPGR sequence
with 68 s timing. Analysis of kinetic curve shape was made according
to the BiRads lexicon: initial rise (rapid, medium, slow) and delayed
phase (persistent, plateau, washout). In addition, several quantitative
parameters were derived from the kinetic curves: initial enhancement
percentage (E1), the signal enhancement ratio (SER), and the time to
peak enhancement (Tpeak).
Results: Overall, 92% of lesions showed rapid initial enhancement, and
74% exhibited washout curves. ER negative lesions had a stronger initial
enhancement, stronger washout and a shorter time to peak enhancement
(E1=351%, SER=1.36, Tpeak=94 seconds) compared with ER positive
lesions (E1=286%, SER=1.02, Tpeak=142 seconds), with p values
< 0.03 for all parameters. PR negative lesions exhibited a stronger
washout (SER=1.25) compared with PR positive lesions (SER=1.01),
with p value < 0.01. Kinetic parameters did not differ for Her2/Neu
negative and positive lesions.
Discussion: The kinetic characteristics of ER and PR positive and
negative lesions showed some statistically signi¿cant differences
(p <0.03), with ER negative lesions showing the strongest initial
enhancement, shortest time to peak enhancement and strongest washout.
This suggests that PR and in particular ER status may be related
vasculature in a way that Her2/Neu status is not.
1006
Breast density assessment using magnetic tesonance imaging
and diffuse optical spectroscopy.
Klifa CS, Shah NS, Watkins M, Li A, Hattangadi J, Tromberg B,
Hylton N. University of California, San Francisco, CA; University of
California, Irvine, CA
Background:
We studied breast density using Magnetic Resonance Imaging
(MRI) and Near Infra-Red Broadband Diffuse Optical Spectroscopy
(DOS) to obtain unique information about breast tissue structure and
function that may be complementary to mammographic breast density.
Breast MRI provides high tissue contrast and three-dimensional
characterization of tissue structures. Near-infrared Broadband Diffuse
Optical Spectroscopy is a new non-invasive modality that characterizes
breast tissue composition and function. The DOS probe is a handheld device that is applied on the breast at several locations. Light
absorption and scattering are quanti¿ed at each measurement, at a
maximum depth of 2cm. DOS parameters including concentrations of
breast total hemoglobin, water, lipid, as well as scatter power (related
to the distribution of scatter particle size in tissue) are extracted at
each location.
The overall goal of our research is to provide a reproducible quantitative
technique that could lead to a better understanding of the biological basis
of the relation between breast density and cancer risk. If we can explain
what biological components in the breast are linked to breast density,
using our combination of MRI and DOS, then we may be able to better
monitor breast cancer risk by monitoring these components.
Method:
Twenty nine normal female volunteers were recruited and underwent
one DOS scan immediately before or after a non-contrast enhanced
breast MRI exam. All volunteers were scanned in the prone position
for all scans, in order to facilitate coregistration of both modalities. MR
parameters such as Apparent Diffusion Coef¿cient (ADC) and measures
of breast density and breast tissue patterns were extracted from all
volunteers MRI data. DOS measures were obtained at 8 locations on
the surface of the breast, for all volunteers.
Results:
We evaluated MRI/DOS parameters that may contribute to radiological
breast density in the 29 volunteers’ data and found that 1) MR apparent
diffusion coef¿cient, 2) MR morphology components related to fat
involvement in breast tissue and 3) DOS measures such as Total
Hemoglobin and Water contents were very closely correlated with
MR breast density, suggesting an association between underlying
physiological tissue properties and breast density.
Conclusion:
The MR quantitative index of tissue patterns strongly translated
differences in fat/tissue composition in women with similar MR breast
densities, providing a potentially powerful strati¿cation tool. This novel
MR index and the combined DOS/MRI measures translating breast
density will be further evaluated on larger populations of patients, in
particular women taking breast density changing treatments.
1007
MR imaging of tumor response in breast cancer patients
following neoadjuvant chemotherapy: correlated with
pathological ¿ndings.
Chen J-H, Agrawal G, Yu H, Carpenter P, Mehta R, Nalcioglu O, Su
M-Y. University of California Irvine, Irvine, CA
Background: This study aimed to evaluate the role of MRI in evaluating
tumor response of breast cancer following neoadjuvant chemotherapy
(NAC) and correlate with ¿nal pathological ¿ndings.
Materials and Methods: In a period of three years, ¿fty nine breast
cancer patients, including 28 HER-2 positive and 31 HER-2 negative
patients, were studied. For 25 HER-2 positive cancer patients , the
NAC protocol consisted of 2-4 cycles of bi-weekly AC (Anthracycline
(doxorubicin)-Cyclophosphamide), followed by Taxane regimen
(TCa ± H), including paclitaxel or Nab-paclitaxel (Abraxane) and
Carboplatin, with Trastuzumab (Herceptin), then surgery. For 26 HER-2
negative cancer, the protocol consisted of 2-4 cycles AC (Anthracycline
(doxorubicin)-Cyclophosphamide) followed by 3-4 cycles of TCa. Five
patients received AC followed by Taxane and three patients received
S43
AC regimen only. The clinical stages were stage II (N = 25), stage III
(N = 20), and stage IV (N = 14). The tumor size ranged from 0.9 cm
to 8.5 cm (median 2.4 cm). The tumor morphologies, divided into four
categories, in the baseline MRI and the imaging ¿ndings in the ¿nal
MRI after completion of NAC were studied and correlated with the
pathological ¿ndings after surgery.
Results: Complete clinical response on MRI was identi¿ed in 36
patients (61%). Pathological complete response (pCR) was achieved in
28 patients (47%) and MRI correctly diagnosed 27 pCR (27/36, 75%),
including 19 of 20 patients (95%) in HER-2 positive group and 8 of 16
patients (50%) in HER-2 negative group (P < 0.01). High correlation
of residual lesion size between ¿nal MRI and pathology was found
for the 23 patients showing partial response on MRI (r = 0.986). For
comparison of baseline tumor morphologies vs. pCR and non-pCR, and
baseline tumor morphologies vs. pathologically positive axillary lymph
nodes, they all showed non-signi¿cant difference (P = 0.44 – 1.0). When
comparing the pathologically positive axillary lymph nodes versus
pCR and non-pCR, a statistically signi¿cant difference was found in
the whole patient cohort (P < 0.01) and in Her-2 positive group (P <
0.05) but not in HER-2 negative group (P = 0.401).
Conclusion: MRI was an excellent imaging modality in predicting
pCR especially with a high accuracy in HER-2 positive patients. The
high correlation of lesion size between ¿nal MRI and pathology might
help breast surgeons in determining the breast conservation surgery.
The tumor morphology in the baseline MRI did not correlate with
pathological response after NAC.
1008
The utility of MRI in preoperative planning for breastconserving therapy.
Kaufman G, Guth AA, Singh B, Axelrod D, Moy L. NYU School of
Medicine, New York, NY
Introduction: The use of preoperative MRI is increasing for patients with
breast cancer to determine extent of disease and the appropriate surgical
approach. However, the impact of MRI on improving surgical outcome
is unknown. The goal of this study was to compare the re-excision rates
for patients with breast cancer in those who underwent MRI, compared
to a matched control group who did not undergo preoperative MRI. The
conversion rate from BCT to mastectomy has been used as a surrogate
marker for ptient outcome. Objective criteria such as re-excision rates
and margin width have not been widely investigated.
Methods: Retrospective study of patients undergoing preoperative
MRI with initial plan for BCT, from 2002-2006. Re-excision rates
were compared to a control group selected from the same time period
undergoing evaluation for BCT.
Results: 70 patients underwent preoperative MRI. The re-excision
rates were similar for both groups (Table 1). The conversion rate from
BCT to mastectomy was higher in the control group: 14% vs. 9%.
Negative margin rates were similar between the two groups, however
the MRI group had a lower incidence of close surgical margins. The
percentage of patients who ultimately underwent mastectomy was the
same in both groups.
Conclusions: Women undergoing preoperative MRI in this study had an
increased rate of successful BCT, and a decreased incidence of multiple
re-excisions followed by mastectomy.
Pre-operative MRI in planned breast-conserving therapy
Characteristic
MRI Group
Study group(# patients)
70
Initial # patients undergoing BCT/mastectomy 52(74%)/18(26%)
No. undergoing re-excision
14(30%)
Re-excision/DCIS
5(35%)
Re-excision/invasive cancer
1(8%)
Re-excision/mix DCIS-invasive cancer
8(57%)
Conversion BCT to mastectomy
4(9%)
Total # mastecomies
22(30%)
Control Group
57
48(84%)/9(16%)
21(37%)
6(31%)
3(16%)
11(52%)
8(14%)
17(30%)
S44
1009
Does MRI improve chances of obtaining negative surgical
margins after localized excision? A retrospective study.
Kulkarni K, Newstead GM, Jansen SA, Abe H, Shimauchi A, Schmidt
RA, Jaskowiak N. University of Chicago, Chicago, IL
Background: Dynamic contrast enhanced MR imaging (DCE-MRI) of
the breast has been shown to have high sensitivity to breast cancer, with
lower speci¿city. The role of DCE-MRI in patient management is not
well-established. Some advocate DCE-MRI for every cancer patient,
while others favor use of breast MRI in more restricted circumstances,
such as evaluation of treatment response. Here, the purpose was to
determine the role of DCE-MRI in achieving negative surgical margins.
The study was designed to compare positive surgical margin rate in
patients who underwent DCE- MRI in conjunction with conventional
mammography and ultrasound to the positive surgical margin rate
published in the surgical literature using conventional imaging alone.
Materials and Methods: A retrospective analysis of 168 women (mean
age 60.3 yrs, range 35-92) with breast cancer presenting to evaluate
for extent of malignant disease from September 2002 to June 2006
was performed. A total of 64 women that underwent modi¿ed radical
mastectomy were excluded from the study. The remaining 104 women
underwent localized excision of breast cancer following DCE-MRI
evaluation. Surgical margins were assessed by dedicated pathologists
and were categorized using the same criteria as in the literature: free
(>2mm), very close (>0≤1mm), close (>1≤2mm) and positive. These
cases were further classi¿ed based on their histological subtypes as: 33%
in¿ltrating ductal carcinoma (IDC), 46% IDC with ductal carcinoma
in situ (DCIS), 12% DCIS, 8% in¿ltrating lobular carcinoma (ILC)
and 1% ILC with DCIS. The size of the index lesion obtained from
mammogram and breast MRI were compared to assess the total extent
of disease.
Results: The surgical margins were positive in 5% (n=5), very close
(>0≤1mm) in 13.4% (n=14), close (>1≤2mm) in 9% (n=9) and free
in 73% (n=76) of cases. Out of the 5 cases with positive margins, the
histological subtypes were: 1 ILC only, 3 IDC with DCIS and 1 ILC
with DCIS. Out of the14 cases with very close (>0≤1mm) margins, 7%
(n=1) were DCIS only, 43% (n=6) were IDC with DCIS, 36% (n=5)
were IDC, 14% were (n=2) ILC. At our institution, one of the criteria
for re-excision in cases of DCIS alone is distance from the tumor margin
≤1mm, and thereby the true re-excision rate is 6% (5 with positive
margins + 1 with very close margin with DCIS alone, out of 104). The
extent of disease was larger on the MRI than the mammogram in 61%,
comparable in 9%, and smaller on MRI in 23% of cases.
Conclusion: The true re-excision rate was 6% which is signi¿cantly
less than previously published values that range from to 15 to 63%
in the surgical literature. These results demonstrate a pivotal role of
DCE-MRI in effective patient management by signi¿cantly reducing
re-excision surgeries for residual disease. An effort to compare the
current re-excision rate at University of Chicago with the re-excision
rate before the advent of routine preoperative DCE-MRI at the same
institution will be made in near future.
1010
The role of breast MRI in the preoperative evaluation of
patients with newly diagnosed breast cancer.
Schell AM, Kaufman PA, Lewis PJ. Dartmouth-Hitchcock Medical
Center, Lebanon, NH
Introduction: MRI is being increasingly used in the preoperative
evaluation of patients with biopsy-proven breast cancer. We performed
a prospective study of the diagnostic utility of breast MRI in a rural
tertiary referral setting.
Methods: All patients between September 2005 and December 2006
with a new diagnosis of invasive breast cancer who underwent bilateral
breast MRI preoperatively at a single institution were enrolled in the
study. All gadolinium-enhanced breast MRI scans were performed on
a 1.5T magnet; during the initial six months of the study contralateral
and ipsilateral breasts were scanned on separate days, in the remaining
patients both breasts were scanned on one occasion. All studies were
interpreted by 4 experienced mammographers and image data entered
into a Filemaker Pro® database at the time of the scan. Patients were
managed according to imaging and clinical data. Analyzed data included
additional imaging and biopsies performed based on the MRI scan
¿ndings, ¿nal surgical management, and pathological correlation on
a lesion by lesion basis.
Results:Two hundred and thirteen patients had ipsilateral breast MRI,
206 of these also had contralateral scans.
Ipsilateral breast: One hundred and ¿ve BIRADS category 3,4 or 5
lesions were found in addition to the known malignancy in 83 patients
(39%). Thirteen percent of patients required an additional ipsilateral
biopsy as a result of the MRI, some additional lesions were excised
at the time of the primary lesion excision. Fifty-eight lesions in 46
(22%) patients were found to be malignant. An additional two lesions
were isolated high risk. Twenty percent of lesions were not biopsied
or follow up is not available.
Contralateral breast: Fifty-two BIRADS category 3,4 or 5 lesions
were found in 41 (21%) patients. Twenty-nine (15%) patients had
33 contralateral lesions biopsied, and of these, 11 lesions in 9 (5%)
patients were malignant and 5 lesions were high risk. No pathology is
available on 29 lesions.
In total, 20% of patients needed additional (mammographic/ultrasound)
imaging as a result of the MRI. MRI detected 69 additional cancers in
53 (23%) patients. 80% of these malignancies were invasive. The false
negative rate is not currently known, only one BIRADS 3 lesion was
found at a biopsy after the six- month follow up to be DCIS.
Conclusion: Breast MRI clearly detects unsuspected malignant lesions
in both the ipsilateral and contralateral breasts in patients with a new
diagnosis of breast cancer in this single instutional study. How this,
and how the signi¿cant false positive rate impacts the ¿nal surgical and
medical management, is currently being investigated.
1011
Comparative accuracy of MRI and ultrasound for predicting
breast cancer extent after neoadjuvant chemotherapy.
Karuna ST, Wechter DG. Virginia Mason Medical Center, Seattle,
WA
Background: Neoadjuvant chemotherapy is utilized to reduce breast
cancer size and allow a patient to undergo a lesser procedure, either
partial mastectomy instead of mastectomy, or a smaller excision with
partial mastectomy. There is little consensus regarding the best imaging
modality to predict the post-treatment extent of breast cancer. Various
imaging techniques such as MRI, mammography, and ultrasound have
been used. Although MRI sensitivity and speci¿city compare favorably
with clinical breast exam and mammography, its accuracy compared to
ultrasound is less clear. Operative planning depends upon the residual
tumor size, so accurate measurement with imaging is crucial.
Material and methods: A retrospective review from January 2001 to
October 2006 included 44 patients with invasive breast cancer treated
with neoadjuvant chemotherapy and imaged with post-treatment MRI,
ultrasound, or both. Most patients received four cycles of doxorubicin
and cyclophosphamide and four cycles of taxane-based therapy.
Operation was performed less than eight weeks after imaging.
Results: Thirty-nine tumors were evaluated with ultrasound, and 24
with MRI. For all tumors, correlation between tumor size on imaging
and pathology showed an r-value of +0.65 (p<0.005) for ultrasound and
+0.47 for MRI (p<0.005). For patients with invasive ductal carcinoma
only, r= +0.79 and +0.75 for MRI and ultrasound, respectively
(p<0.005 for both). Though the sample size was small, for patients
with invasive breast cancer with lobular features, MRI and ultrasound
both demonstrated poor correlation, r= -0.23 (p=0.5517) and r= +0.31
(p=0.3537) respectively.
Conclusion: Ultrasound may be more accurate than MRI in prediction
of residual tumor size after neoadjuvant chemotherapy. Although the
data cannot support eliminating the use of post-treatment MRI, in cases
of discrepancy between MRI and ultrasound, perhaps more attention
should be paid to the ultrasound prediction in surgical planning.
Further study of a larger group of patients is needed to better assess
the comparative accuracy of ultrasound and MRI in patients who have
received neoadjuvant chemotherapy, especially those with lobular
features.
Assessment of Breast Cancer Extent Post-Neoadjuvant Chemotherapy:
Correlation Between Breast Imaging and Final Pathology
PATIENT POPULATION
IMAGING MODALITY R-VALUE
All study patients
MRI
+0.47
All study patients
Ultrasound
+0.65
Study patients with invasive
MRI
+0.79
ductal carcinoma only
ductal carcinoma only
breast cancer with lobular features
breast cancer with lobular features
P-VALUE
<0.005
<0.005
<0.005
Ultrasound
+0.75
<0.005
MRI
-0.23
0.5517
Ultrasound
+0.31
0.3537
1012
Accuracy of preoperative evaluation of the axilla with MRI
in breast cancer.
Kaufman G, Guth AA, Axelrod D, Moy L. NYU School of Medicine,
New York, NY
Background
The ability to assess axillary lymph node involvement in patients
undergoing surgery for invasive breast cancer can lead to changes in
their surgical management. Traditional imaging modalities such as
ultrasound have been used with increasing success in the preoperative
evaluation of the axilla. The increasing use of MRI in the preoperative
evaluation of patients undergoing surgery for breast cancer may impact
axillary evaluation and inÀuence surgical decision making. The ef¿cacy
of conventional MRI for this evaluation has not been fully evaluated.
The goal of this retrospective analysis was to determine the sensitivity
of breast MRI in the detection of metastatic lymph node involvement
and to determine if surgical management is altered.
Methodology
Patients undergoing preoperative MRI were identi¿ed from a radiology/
pathology database from 2002-2006. The rates of sentinel lymph node
and axillary dissection and conversion to axillary dissection in the
MRI group were compared to a control group selected from patients
undergoing breast conserving therapy during a similar time period.
Statistical analysis used Chi-square test.
Results
A total of 63 patients had preoperative MRI and underwent lymph
node dissection. The sensitivity and speci¿city of MRI for detecting
metastatic disease involving the lymph nodes was 33% and 94%
respectively. MRI had a positive predictive value of 80% and a negative
predictive value of 68%. A fewer number of patients in the MRI cohort
(6%) had initial axillary dissection compared to the control group (13%).
However, a greater percentage of patients in the MRI cohort (28%)
compared to control group (20%) converted from sentinel lymph node
biopsy to completion axillary dissection. Therefore the rates of axillary
dissection were similar in both groups. The rate of micrometastatic
disease approached 10%.
Conclusions
The evolving applications of MRI in the evaluation of patients with
breast cancer are increasing. The ability of MRI to accurately predict
size and detect synchronous lesions in patients with known invasive
cancer has been sufficiently demonstrated. The efficacy of MRI
to stage the axilla of patients with breast cancer has not yet been
demonstrated. Continued research involving speci¿c protocols for
axillary evaluation and the use of speci¿cally designed MRI breast
coils for this purpose may enhance its overall ef¿cacy. Although breast
MRI has a high speci¿city for the evaluation of axillary lymph nodes,
the poor sensitivity makes this modality unreliable for screening the
axilla for metastatic involvement prior to surgery. The lack of sensitivity
may be due to the subset of patients that present with micrometastatic
disease.
1013
Model selection for analysis of dynamic contrast enhanced
MRI (DCE-MRI) data.
Yankeelov T, Welch EB, Chakravarthy B, Lee R, Freehardt D, Mayer I,
Meszoely I, Kelley M, Means-Powell J, Gore J. Vanderbilt University,
Nashville, TN; Philips Medical Systems, Cleveland, OH
Background: DCE-MRI is the acquisition of MR images before
and after an intravenous injection of contrast agent (CA). By ¿tting
S45
DCE-MRI data to a model, physiological parameters such as vessel
perfusion (Ktrans) and extracellular volume fraction (ve) are extracted
[1]. In diagnosing breast cancer, DCE-MRI is shown high sensitivity
(77-100%), but moderate speci¿city (26-97%) [1]. A possible reason is
that the standard model used to analyze such data may not describe the
relevant physiology. The standard model relies on a linear dependence
between the MRI signal intensity and the concentration of CA in tissue
[2]. This model assumes that tissue is effectively one compartment;
in MRI, this assumption is referred to as the fast exchange limit
(FXL). Studies have shown this assumption is violated in vivo [2]. By
accounting for the effect of the intra- and extracellular compartments
a “fast exchange regime” (FXR) model is obtained which has revealed
errors of up to 200% in the FXL [2]. Through two common statistical
tests, we show that the FXR is the preferred model. As DCE-MRI
ultimately aims to positively impact clinical decisions, model choice
is important.
Methods: 10 patients with locally advanced breast cancer underwent
DCE-MRI (at 3.0T) prior to neoadjuvant chemotherapy. DCE-MRI data
were analyzed on a voxel basis by the (standard) FXL and (new) FXR
models to return estimates of Ktrans and ve. The Durbin-Watson statistic
(a well-known test for detecting serial correlation) was computed for
the residuals returned from both models for each voxel. Percentage
of voxels showing serial correlation by each method was tabulated.
Additionally, the Akaike Information Criteria (AIC) was computed for
each voxel. Given a set of models, the AIC determines the model that
best balances complexity with goodness of ¿t.
Results: The FXR analyses of the DCE-MRI data resulted in a
signi¿cant reduction in percentage of voxels showing serial correlation
of residuals: 42.6% +/- 12.6% and 21.5% +/- 7.7% for the FXL and
FXR, respectively (P=0.0002). In 99% of voxels, the AIC indicated that
the FXR model was superior. This translated into signi¿cant differences
in parameters extracted: 0.43 min-1 +/- 0.22 min-1 (FXR) versus for
0.25 min-1 +/- 0.10 min-1 (FXL) for Ktrans (P<0.04), and 0.33 +/- 0.08
(FXR) versus 0.12 +/- 0.05 (FXL) for ve (P<0.00001).
Discussion: The parameters Ktrans and ve are studied to both diagnose
and assess treatment response in breast cancer. The values extracted are
determined by which model is selected. We have shown here that the
FXR model is statistically superior as quanti¿ed by both the DurbinWatson statistic and the Akaike Information Criteria. An ongoing
clinical trial is examining whether the FXR is superior to the FXL in
predicting pathologic outcome in patients undergoing neoadjuvant
chemotherapy.
References: 1. Beatty et al, AJS2007:193;600-5. Yankeelov et al,
MRM2003:50;1151-69, 3. Li et al, ISMRM2007;141.
1014
Are the MRI characteristics of malignant breast lesions
different for African American women?
Jansen SA, Abe H, Shimauchi A, Karczmar GS, Olopade O, Newstead
GM. University of Chicago, Chicago, IL
Background: Disparities in breast cancer mortality and stage at diagnosis
between African American and Caucasian women has been a topic of
recent interest, with evidence to suggest earlier onset of more aggressive
cancer in African American women. This disparity has been attributed to
differences in quality of medical care and genetic background. Dynamic
contrast enhanced MRI (DCEMRI) of breast cancers is being used
increasingly due to its high sensitivity and accuracy in determining
extent of disease. DCEMRI provides both morphologic and functional
lesion characterization via contrast media uptake and washout (or
‘kinetic’) curves, which are related to tumor blood Àow. The purpose
of this study was to compare the MR presentation of malignant breast
lesions in African American and Caucasian women.
Materials and Methods: 108 patients with 122 histologically proven
malignant lesions were selected for review:51 African American
patients with 59 lesions (average age 58 yrs) and 57 Caucasian women
with 63 lesions (average age 55 yrs). The malignant lesions were
classi¿ed as ductal carcinoma in situ (DCIS), invasive ductal carcinoma
(IDC), invasive lobular carcinoma (ILC) and ‘other’. The number of
IDC lesions positive for Her2/Neu overexpression was determined.
Dynamic MR protocol: 1 pre and 5 post-contrast images using a T1weighted SPGR with 68 sec timing. Analysis of kinetic curve shape
and morphology was made by an experienced radiologist, and several
S46
quantitative parameters were derived from the kinetic curves.
Results: Overall, there were 62 IDC, 38 DCIS, 12 ILC and 10 ‘other’
malignant lesions. The predominant MR morphology was homogeneous
or heterogeneous mass-like enhancement, in a round or irregular
shape. The mean lesion size was 2.1 cm. There was no difference in
the morphology, size or kinetics of malignant lesions by race. When
considering only IDC lesions, again no signi¿cant differences in
morphology, size or kinetics by race were demonstrated. Her2/Neu
was overexpressed in 19% (6/31) of IDC lesions in African American
women, and 16% (5/31) of Caucasians.
Discussion: Despite recent evidence of racial disparities in breast cancer
stage at diagnosis, in our study, we found no difference in the lesion
size, MR morphologic or kinetic presentation of malignant lesions
between African American and Caucasian women. In addition, similar
numbers of African American and Caucasian women demonstrated
overexpression of Her2/Neu. At our institution, comparable numbers of
African American and Caucasian women present for diagnostic breast
evaluation, implying a similar level of care upon which biological
differences can be explored. Our results indicate that newly diagnosed
breast cancers in African American and Caucasian women share many
similarities. This points to future work on follow-up of the ef¿cacy of
treatment and survival in these patients.
1015
Pushing the limits: very high spatial resolution spectroscopic
MR imaging of human breast.
Medved M, Newstead GM, Abe H, Wood AM, Olopade OI, Shimauchi
A, Fischer S, Karczmar GS. University of Chicago, Chicago, IL; Philips
Medical Systems, Cleveland, OH
Background: MRI is increasingly used for breast cancer screening.
However, further improvements in specificity are needed. This
laboratory has proposed use of high spectral and spatial resolution
(HiSS) imaging of water and fat proton resonances at the spatial
resolution of conventional anatomic MR images. HiSS images offer
complete fat suppression across the entire breast and excellent image
contrast for maximum sensitivity and speci¿city for small breast lesions.
In addition, analysis of the spectral line shapes of water and fat signal
provides new sources of image contrast that may increase speci¿city.
Previously reported HiSS images were produced in 2 mm thick slices
with 1 mm in-plane resolution. Here we report HiSS images with halfmillimeter spatial resolution in 1 mm thick planes. The images show
increased anatomic detail with adequate signal-to-noise ratio.
Materials and Methods: Four women were scanned with informed
consent on a Philips Achieva 1.5T scanner, using an echo-planar
spectroscopic imaging-based sequence. The water and fat spectra in
each 0.5 x 0.5 mm voxel in 1 thick mm slices, were obtained at the
spectral resolution of approximately 5 Hz. This allowed post-processing
of spectral data through ¿tting the water and fat peaks, complete
separation of water and fat signal, and generation of water resonance
peak height images with a combination of T1 and T2 weighting. Three
to four slices were acquired in 8 minutes for each patient.
Results: Figure 1 shows a typical spectroscopic water peak height
image obtained with our technique. Water peak height images were
produced with acceptable signal-to-noise ratio, high dynamic range,
and complete separation of water and fat signal. The data may allow
high-resolution B0 mapping - possibly sensitive to calci¿cations. The
water peak height images show parenchyma clearly against a dark
background of highly-suppressed fat signal.
Discussion: These results demonstrate that HiSS imaging is feasible
with 0.5 x 0.5 mm in-plane resolution, 1 mm thick slices, and clinically
reasonable run-times. Predictable improvements in technology (e.g.
higher ¿eld strength, improved detectors) will result in even better
SNR, faster acquisition times, and/or higher spectral resolution. The
spectroscopic information can in principle be used to obtain highresolution B0 maps, and to visualize micro-calci¿cations via distortions
in the B0 ¿eld. This is a novel approach to MRI of the breast that is
likely to increase the diagnostic utility of MRI breast scans.
1016
The effect of computer-aided detection on the interpretation
of screening mammograms at Intermountain Healthcare
facilities.
Parkinson B, Belnap T, Rowley B, Blaney S, Kerry A, Pinto K, Nkoy F.
Intermountain Healthcare, Salt Lake City, UT
Background: Over the last ¿ve years, computer aided detection
(CAD) in mammography has been widely implemented throughout
the United States. CAD employs an electronic algorithm to mark
suspicious lesions on mammograms. These marks are designed to
assist radiologists in improving diagnostic accuracy. Several published
studies have assessed the effectiveness of CAD with respect to cancer
detection rate, percentage of patients called back for additional imaging
evaluation (callback rate) and percentage of patients recommended
for biopsy. These studies have evaluated the effectiveness of CAD,
but with conÀicting results. Although it is generally agreed that CAD
may ¿nd more cancers, whether or not it results in an unacceptable
callback rate is still controversial. This prospective study is designed
to determine the effect of CAD on callback and cancer detection rates
at four Intermountain Healthcare facilities.
Method: During a 12-month period (1 January 2005 to 31 December
2005) researchers at Intermountain Healthcare prospectively tracked
mammographic ¿ndings of 43,175 patients who were screened at
four breast cancer screening centers. Each mammogram was initially
interpreted without the aid of CAD, followed by an immediate reevaluation with CAD. All four facilities used the same equipment and
software; the infrastructure remaining constant throughout the study.
Each recalled case was classi¿ed into one of three categories: radiologist
and CAD both perceived ¿nding, only radiologist perceived ¿nding, or
CAD prompted radiologist to perceive ¿nding and recall patient.
Results: The recall rate in 2005 did not show a statistically signi¿cant
increase over the previous year (p<0.505, 10.85% vs 10.71%).
4,685 patients were recalled for additional imaging, resulting in a
recommendation for biopsy in 750 patients (16.0%). 701 biopsies were
actually performed and 190 cancers were diagnosed. Of the recalled
patients, 153 were found only by CAD. This resulted in a diagnosis of
seven additional cancers which would have been missed without CAD
(PPV1 = 4.58%). In other words, 22 patients were recalled by CAD
for each additional cancer detected. Overall this increased the cancer
detection rate by 3.7%.
Conclusion: The implementation of CAD at Intermountain Healthcare
resulted in the detection of seven additional cancers which would have
otherwise been missed. Given the discovery of these malignant lesions
attributed speci¿cally to the use of CAD with no signi¿cant increase in
recall rate, the use of this technology did not impose an undue burden
to the system.
1017
Telemammography in a rural community.
Lopez AM, Deasy S, Carroll M, Krupinski E, Kreykes L, Weinstein R.
University of Arizona, Tucson, AZ; Tuba City Reginal Health Care
Corporation, Tuba City, AZ
Women in the U.S. have a 1 in 7 lifetime risk for developing breast
cancer. Despite many advances in screening, mammography remains the
gold standard for detection of breast cancer. In this study, participants
included women presenting to a remote community in northern Arizona
for mammography.
One problem with rural medicine is women getting mammograms.
Many times a traveling mammographer or couriers for the ¿lms are
the only options. Due to this situation, rural women experience longer
time periods to get ¿nal mammogram results. When results become
available, it is often that the woman can’t be reached or is unable to
return to receive the results. This loss to follow-up can be devastating.
When the woman returns later, their disease can be more advanced.
In working with the rural community, a telemammography service
was established. Mammograms are performed at a ‘mobile’ clinic
and are transmitted for reads at a mammography center, over the
Arizona Telemedicine Program’s telecommunications network. The
project, which was intended to enhance timeliness of service to the
rural community, has far exceeded expectations and has had a major
impact on women’s health care in that community. By introducing an
effective turnaround time of approximately one hour, women willingly
wait for their mammography results. This enhances cancer detection
capacity by eradicating the need to track down patients who may have
moved, who may not have a phone or who do not have an address but
who now have an abnormal mammogram result. Since the conception
of this service, nearly 20,000 mammograms have been performed for
rural women. In this presentation we will discuss the clinical outcomes
of this service.
1018
Mammography screening and other preventive care among
African American and native American women with access
to health care.
Bachman SI, Shim V. Kaiser Permanente, Oakland, CA
Background: Studies show that African American and Native American
women are less likely to get screening mammograms than white women,
possibly due to lack of access or to using services only when sick. This
study looks at race differences in screening and other preventive care
in two age groups (40-49, 50-69) in an HMO population with equal
access to health care services.
Methods: We calculated two-year screening compliance rates for
188,234 women aged 52-69 and 102,652 women aged 42-51 in Kaiser
Permanente Northern California. Logistic regression models were used
to compare African Americans and Native Americans to whites: (1)
control age and tenure; (2) add utilization, primary visits and linkage to
a personal care provider (PCP); (3) add gynecology visits and linkage
only. Using administrative data, we tested group differences in routine
gynecology visits, pap smears, and breast exams and their relationship
with screening mammography.
Results: For both age groups and three models, African Americans
and Native Americans have lower compliance rates than whites. The
differences are larger in the older group. (See Table 1 for the adjusted
odds ratios). Among both age groups, both African Americans and
Native Americans have more visits and more primary care visits
than whites, but they are less likely to have a routine gynecological
exam, a pap smear, or a routine breast exam. The older women are
also less likely to have a gynecology visit or a gynecology personal
care provider. In the younger group, the minority women have more
gynecology visits than whites, but are more likely to have non-routine
visits without a routine exam. Routine gynecological care measures
show moderate relationships with mammography compliance (r ranges
from .14 to .41).
Discussion: Even with equal access to health care, African Americans
and Native Americans are less likely than whites to comply with
mammography guidelines. Although younger minority women
readily use gynecology services, they are less likely to get routine and
preventive care. Older minority women continue to use primary care
S47
services but are less likely to use gynecology services or get preventive
care. This provides some support for the theory that African American
and Native American women tend to seek health care only when in
need of treatment.
Table 1. Odds Ratios for Mammography Compliance, African Americans and Native
Americans Compared to Whites
MODEL
1
2
3
AGE 42-51
Nat Amer
.84
.75
.87
Afric Amer
.93
.86
.87
AGE 52-69
Nat Amer
.79
.72
.87
Afric Amer
.88
.86
.93
1019
Initial clinical evaluation of laser optoacoustic imaging
system for diagnostic imaging of breast cancer.
Oraevsky AA, Ermilov SA, Conjusteau A, Miller T, Gharieb RR,
Lacewell R, Mehta K, Radulescu EG, Herzog D, Thompson S, Stein A,
McCorvey M, Otto P, Khamapirad T. Fairway Medical Technologies,
Houston, TX; Seno Medical Instruments, San Antonio, TX; University
of Texas Medical Branch, Galveston, TX; University of Texas Health
Science Center, San Antonio, TX
BACKGROUND
This study was performed in order to provide preliminary clinical
feasibility testing of the Laser Optoacoustic Imaging System, a novel
imaging system that uses pulsed optical illumination of the breast in
the near-infrared spectral range (which provide high tissue contrast and
suf¿cient depth of penetration) and detection of the resulting ultrasonic
signals (which provides enhanced resolution relative to pure optical
tomography).
MATERIALS and METHODS
LOIS employs short pulses of near-infrared light to illuminate the
breast volume and generate transient pressure in blood-rich tumors
and blood vessels. These resultant acoustic signals are detected by
ultrawide-band ultrasonic transducers placed along a 180-deg concave
arc. After back-projection reconstruction, tumor location, shape and
dimensions are determined with a spatial resolution of better than 1
mm in the image plane.
RESULTS
Initial studies on 50 patients demonstrated that the optoacoustic system
can detect across varying tissue densities with maximum contrast in
younger women. Illumination at 757 nm provides contrast based mainly
on the hypoxic blood of breast carcinomas, while a wavelength of
1064 nm produces contrast dominated by enhanced water content and
normally oxygenated blood in benign ¿broadenomas. Comparison of
signal amplitudes provided tumor brightness proportional to optical
absorption. Information obtained at two different wavelengths,
one preferentially absorbed by hemoglobin (757 nm) and the other
preferentially absorbed by oxyhemoglobin and water (1064 nm) allowed
detection of breast carcinomas and their differentiation from normal
and benign tissues.
DISCUSSION
The combination of optically-induced functional contrast and
acoustically received high resolution imaging in a novel breast cancer
imaging modality demonstrated clinical feasibility and the potential
for a noninvasive diagnostics. The new modality is envisioned as an
adjuvant to X-ray mammography as an ultrasonic imaging enhanced
by the optical contrast.
1020
Sonobreast: a novel predictive model for the risk of
malignancy in solid breast nodules with echographic
expression.
Paulinelli RR, Freitas-Junior R, Lucena CEM, Moreira MAR, Moraes
VA, Ruiz AN, Bernardes-Junior JRM, Vidal CSR, Lucato MT, Costa
NGS, Teixeira DA. Federal University of Goias, Goiania, Goias, Brazil;
Santa Casa de Misericordia, Belo Horizonte, Minas Gerais, Brazil
OBJECTIVE: To create a predictive model for the risk of malignancy
in solid breast nodules, with echogra¿c expression. METHODS: This
study performed at the Federal University of Goias and at the Santa
S48
Casa de Misericordia of Belo Horizonte, included prospectively
1,403 patients with solid breast nodules. The ultrasound features were
recorded in a formulary, and compared with the de¿nitive results of the
anatomopathology or considered benign after a minimum follow up
of two years. The age of the women and the familial history of breast
cancer were also included in the model. RESULTS: 1,390 (99.1%)
nodules had a conclusive diagnosis. Among them, there were 343
(24.7%) malign tumors, and 1,047 (75.3%) benign nodules. The odds
ratio (and con¿dence interval) of breast malignancy for each variable
included in the model, as calculated by multivariate analysis, are
presented in Table 1. There were no advantage to include the presence
of internal vascularity and the presence of thickened Cooper’s ligaments
in the model. The area under the ROC curve for the model was 0.94
(0.92-0.96) (Figure 1). The predictive model was named “Sonobreast”
and it is freely available for medical purposes in the internet site:
http://www.hc.ufg.br/sonobreast/page.php. CONCLUSION: The
probability of malignancy in breast tumors can be stipulated based on
their ultrasound features, the age of the woman and the family history
of breast cancer.
Table 1. Predictive multivariate model for the risk of malignancy in solid breast nodules
based on the sonographic features, age and family history of a ¿rst-degree relative with
breast cancer (Sonobreast).
Features
B
SE
Wald p
OR
95% CI (lower, upper)
Irregular / not circumscribed 2.77 0.37 56.15 < 0.01 16.02 7.75
33.09
Heterogeneous echo texture 1.50 0.31 22.82 < 0.01 4.50 2.42
8.23
Posterior shadowing
0.87 0.34 6.63 0.01 2.38 1.23
4.62
Thick echogenic rim
0.96 0.45 4.63 0.03 2.62 1.09
6.31
Vertical orientation
0.80 0.39 4.27 0.04 2.23 1.04
4.75
Age > 40 years old
0.78 0.28 7.62 < 0.01 2.19 1.26
3.81
Positive family history
2.01 0.53 14.45 < 0.01 7.50 2.65
21.18
B: estimated coef¿cient, SE: standard error, OR: odds ratio, CI: con¿dence interval.
Constant (B = -4.71, SE = 0.37, Wald = 160.40, p<0.01, OR <0.01).
1021
High resolution positron emission mammography in breast
cancer management.
Schilling KJ. Boca Raton Community Hospital, Boca Raton, FL
Background: Whole body positron emission mammography (WBPET) has been found to be helpful in the identi¿cation of multiple
malignancies but it offers less than optimum sensitivity in breast
cancer detection and assistance in the surgical management of early
disease. Magnetic resonance imaging (MRI) is highly sensitive in the
detection of early breast cancer but has signi¿cant speci¿city issues,
often resulting in unnecessary biopsy. Positron emission mammography
(PEM) is a new high resolution metabolic imaging approach that claims
increased sensitivity and speci¿city in the evaluation of primary breast
cancer. The current pilot study was undertaken to determine the value
of PEM in comparison to conventional modalities, breast MRI and
WB-PET.
Materials and Methods: 32 patients to date have been enrolled in this
ongoing prospective IRB approved pilot study. Results from each
imaging modality were compared to each other and to the gold standard,
surgical pathology, to determine the accuracy of cancer detection.
Kinetic curves and morphology were utilized with MRI, SUV was
utilized with WB-PET while lesion to background ration was used to
assist in discriminating malignant from benign lesions with PEM.
Results: A total of 28 patients successfully completed all imaging
studies and surgery. The age range of patients was 33-85 years with a
mean of 60 years. Eight were pre-menopausal, 1 perimenopausal and
19 postmenopausal. The sensitivity in the detection of the index lesion
was 46% for WB-PET, 93% for PEM and 96% for MRI. 2 lesions were
outside the ¿eld of view for the PEM device. Lesions found in the
surgical specimen (index plus incidental) were compared to the lesions
detected with imaging. Lesion sensitivity for WB-PET was 39%, MRI
90% and PEM 92%.
Discussion: PEM provides functional information and has been found
to be superior to WB-PET in the identi¿cation of early breast cancer
and providing information useful for surgical planning. PEM appears
equivalent to MRI with regards to superior cancer detection but also
results in fewer false positive ¿ndings. Lesion to background ratio
may provide quantitative information which may be shown useful
in suggesting the severity of pathology.Continued evaluation will be
necessary to identify the eventual, most effective role of PEM in the
breast imager’s tool box.
1022
A comparison study between multidetector-row CT and
histopathological ¿ndings in terms of the extension diagnosis
of breast cancer.
Sumiyoshi K, Kani H, Nohara T, Iwamoto M, Harada T, Tanaka S,
Kimura K, Takahashi Y, Shibayama Y, Tsuji M, Kurisu Y, Tanigawa N.
Osaka Medical College, Takatsuki, Osaka, Japan
Background: With a recent widespread use of Breast-conserving
therapy (BCT), it has increasingly become important to assess the
degree of extension of breast cancer. This study was made to examine
the diagnosis of extension of breast cancer, especially for extensive
intraductal component (EIC), by multidetector-row CT (MD-CT).
Material and Methods: One-hundred and forty-eight resected lesions
of invasive breast carcinoma in which MD-CT was peformed were
subjected to this study. Seventy three cases (49.3%) were operated by
BCT. Histological preparations were made of the resected material at
interval of 5 mm, the presence of EIC was determined, and then the
results were compared to CT ¿ndings.
Results: Extending morphologies of tumors on CT were classi¿ed
into six categories, and abnormal (linear, spotty, or cord-like) stains
continuing from the main lesion were designated EIC positive. There
were 63 cases (42.6%) with histological EIC, and 85 cases (57.5%)
without histological EIC. The direction of histological EIC were,
nipple side,48.7%; opposite side of nipple,28.9%; lateral side,40.8%.
For detecting EIC by MD-CT, the sensitivity was 74.6%, the speci¿city
was 80.0%, and, and the accuracy was 77.7%. The underestimation
(detachment of more than 10mm) was noted in 18 cases and the
overestimation, in 24 cases. Sporadic EIC was apt to be underestimated.
Dif¿cult cases in evaluation were considered to be of : 1) scirrhous
carcinoma (or including scirrhous component) or lobular carcinoma; 2)
intraductal component dominant tumor (mainly DCIS); 3) mastopathy;
4) breast cancer including cystic lesion such as mucinous carcinoma;
and 5) including necrotic component such as comedo type.
Discussion: This study was to compare the accuracy of MD-CT and
MRI for evaluating EIC of 67 cases among all 148 cases. The sensitivity,
speci¿city, and accuracy in detecting EIC were 68.0%, 83.3%, and
77.6%, respectively, using MD-CT; and 72.0%, 83.3%, and 79.1%,
respectively, using MRI. There was no difference between MD-CT
and MRI in the evaluation of EIC. MD-CT is a useful modality for
preoperative examination of breast cancer, especially for assessing,
not only localized evaluation but axillary lymph node status, lung
metastasis, liver metastasis.
1023
Correlation of Ki67 expression with FDG-PET positivity in
triple negative breast cancer.
Tchou J, John T, Basu S, Rosen M, Schnall M, Alavi A. University of
Pennsylvania, Philadelphia, PA
Background: Breast cancer is a heterogeneous disease. Current targeted
therapy for breast cancer is guided by the expression of estrogen,
progesterone and Her2-neu receptors in tumors. A distinct group of
women who will bene¿t from novel targeted therapy are those with
triple negative cancer since these women do not respond to conventional
targeted therapy. Clinical trials of new agents prior to de¿nitive surgery
are perfect setting to test ef¿cacy of novel agents. We explore here
the potential use of FDG-PET imaging as a non-invasive means to
measure proliferation index of triple negative cancer by correlating
Ki67 expression with FDG-PET positivity.
Materials and Methods: Between March 2002 and July 2006, 307
women with a diagnosis of invasive breast cancer participated in
our institutional breast imaging study using a combination of digital
mammography, ultrasound, MRI, to image the affected and contralateral
breasts. Whole body FDG-PET imaging was also performed. We
excluded women who had excision biopsy of their primary cancer for
diagnosis purposes and those who had their de¿nitive surgery performed
elsewhere (n=158). Of the 149 eligible patients, 31 had triple negative
cancer (21%). We were able to perform Ki67 immunostaining on 21
of 31 triple negative cancers. FDG-PET standard uptake values (SUV)
were compared with % Ki67 nuclei stain (scale 0 – 5, 0% to > 50%).
Results: Of the 21 women with triple negative cancer, 20 had a positive
PET scan of the index cancer (95%). Ki67 nuclear stain scores were
compared to SUV of the index lesion as shown in Table. We noted that
as Ki67 score increases, the median SUV also increases although the
rise is not statistically signi¿cant.
Discussion: This is a pilot study to investigate whether the glucose
uptake FDG-PET SUVs correlate with a proliferation marker, Ki67,
in triple-negative breast cancers. Work is underway to explore the role
of FDG-PET in monitoring treatment response in the neoadjuvant
chemotherapy setting.
Ki67 nuclear stain correlation with FDG-PET Standard uptake values of
21 women with triple negative breast cancer
% Ki67 nuclear stain score
number
Median SUV
1 (0%)
2
1.7
2 (0-2%)
1
not detected
3 (11 - 25%)
0
not applicable
4 (26 - 50%)
10
3.9
5 (>50%)
8
9.0
1024
Breast optical tomography: sensitivities and speci¿cities for
the detection of cancer.
Sharma A, En¿eld L, Gibson AP, Everdell NL, Schweiger M, Arridge S,
Delpy DT, Hebden JC, Keshtgar M, Sainsbury RS, Douek M. University
College London Hospital, London, United Kingdom; University College
London, Malet Place, London, United Kingdom
Background: Mammography is the standard breast imaging modality.
It involves exposure to ionizing radiation and breast compression
which causes discomfort. Optical tomography is a functional imaging
technique that uses near-infrared (NIR) light to produce threedimensional (3D) images of the breast. We assessed the feasibility of
using optical tomography to characterise breast lumps.
Materials and Methods: Women presenting with discrete palpable
breast lumps were prospectively recruited from the breast clinic, prior
to any imaging. Ethical approval was granted and informed consent
obtained. A 32-channel time resolved imaging device, developed
at UCL, was used to scan the participants. Both variations in tissue
scatter and absorption were measured and from these, spatial maps of
blood volume and oxygenation were derived. Two assessors, blinded to
other imaging ¿ndings, were trained to interpret optical images using
scans of 8 patients with known diagnoses, con¿rmed histologically.
After training, the assessors then independently analysed scans from
subsequent patients. Scans were presented in the same con¿guration
S49
as training images. Any images that could not be obtained in the same
way were excluded. Images were graded from 1 to 5 were 1 = hardly
perceivable inhomogeneity of the scan, 2 = weak contrast scan, 3 =
contrast inferior to other homogeneities, 4 = contrast comparable to
other homogeneities and 5 = contrast of lesion dominates. For any
disagreements between assessors, scans were reviewed to reach an
agreed conclusion.
Results: A total of 80 individual breast images were obtained from 49
patients. Of the 49 patients standard imaging detected 23 breast cancers
(1 bilaterally), 12 ¿broadenomas, 6 cysts, 6 with post-operative scar
tissue and 3 patients with implants. 29 women were imaged using an
older format of the device and these images were excluded. Of the
training images, there were 4 tumours, 3 ¿broadenomas and 1 normal
image following presentation with mastalgia. Of 12 assessed images,
7 tumours, 4 ¿broadenomas and 1 example of ¿brocystic change were
presented. The assessors independently correctly assessed 9 out of the
12 images for both diagnosis and location of lesion. For the detection of
breast cancer optical tomography had a sensitivity of 100%, speci¿city
of 75% and a positive predictive value for cancer of 80%.
Discussion: Optical tomography is feasible for the characterisation of
breast lumps. Further work should focus on its potential role alongside
existing imaging modalities.
1025
Mammographic features of triple-negative versus HER2+
and ER+ breast cancers.
Yang WT, Dryden M, Broglio K, Dawood S, Valero V, Hortobagyi G,
Atchley D, Arun B. M. D. Anderson Cancer Center, Houston, TX
Background. Triple receptor negative (TRN) cancers are high grade
ER, PR, and HER2 negative cancers that represent a distinct tumor
subtype with a poor prognosis and characteristic gene expression
pro¿le (basal-like breast cancer, BLC). Tumors arising in women with
a BRCA/germline mutation share many similarities to sporadic BLC
including a TRN immunophenotype and a basal-like gene expression
pro¿le. The aim of this study was to compare mammographic breast
density, mammographic visibility, and mammographic tumor features
between cancers of different immunophenotypes.
Materials and Methods. Between January 2003 and November 2005,
204 premenopausal patients (pts) diagnosed with breast cancer from
a single institution who had mammography performed at initial
diagnosis were identi¿ed, of whom87 (43%) underwent genetic testing.
HER2- disease was de¿ned as negative expression by IHC or gene
ampli¿cation by FISH. HER2+ disease was de¿ned as 3+ on IHC
or gene ampli¿cation by FISH. Variables recorded included clinical,
histological, and mammographic features of cancers which were
strati¿ed into three groups by IHC: TRN, HER2+, and ER+.
Results. Thirty-eight (19%) pts had TRN, 67 (33%) pts had HER2+,
and 99 (49%) pts had ER+ cancers. Of the 67 pts with HER2+ cancers,
28 (42%) were also ER+. Thirteen (15%) of 87 pts who underwent
genetic testing had TRN disease. Thirteen (15%) pts showed a BRCA1/2
mutation, of whom four (31%) had TRN disease. Median age was 32,
33, and 32yrs respectively for pts with TRN, HER2+, and ER+ disease
(p=0.475). Median tumor size was 3.0, 2.2, and 2.2 cm respectively for
pts with TRN, HER2+, and ER+ disease (p=0.06). Greater than 50%
breast density was observed in 84%, 90%, and 82% respectively of the
TRN, HER2+, and ER+ cancers (p=0.39). Mammographic visibility of
the TRN, HER2+, and ER+ cancers was 86.6% (33/38), 95.5% (64/67),
and 92.9% (92/99) respectively (p=0.26). Visible cancers presented as a
mass in 86.6% (33/38), 71.6% (48/67), and 42.4% (42/99) respectively
(p < 0.00001), and as calci¿cations in 13.2% (5/38), 64.2% (43/67), and
54.4% (56/99) respectively, of the TRN, HER2+, and ER+ cancers (p <
0.00001). The 13 BRCA/germline cancers were associated with greater
than 50% breast density in 85% (11/13), were mammographically
visible in 92% (12/13), and were associated with a mass in 62% (8/13),
and calci¿cations in 31% (5/13).
Conclusion. The mammographic features of TRN breast cancers are
signi¿cantly different from HER2+ and ER+ cancers, presenting
primarily as a mass with a striking absence of calci¿cations and support
the biological concept of a distinct tumor subtype that has similarities
to tumors with a BRCA/germline mutation.
S50
1026
Effects of the steroidal aromatase inhibitor exemestane
on mammographic breast density and other end-organ
functions.
Cigler T, Fabian CF, Yaffe MJ, Johnston D, Ingle JN, Nassif E, Brunner
R, Wadden N, Pater JL, Richardson H, Tu D, Shangle Q, Goss PE.
Massachusetts General Hospital, Boston, MA; Sunnybrook Health
Sciences Centre, Toronto, ON, Canada; Kansas University Medical
Center, Kansas City, KS; Mayo Clinic, Rochester, MN; Notre Dame
Hospital, Montreal, QC, Canada; University of Nevada School of
Medicine, Reno, NV; Memorial University of Newfoundland, St. John’s,
NL, Canada; National Cancer Institute of Canada Clinical Trials
Group, Kingston, ON, Canada; (NCIC CTG) MAP.2
Background: Exemestane (EXE) is a potent aromatase inhibitor with
unique androgenicity secondary to its steroidal structure. Breast density
is a biomarker of risk that is sensitive to hormonal inÀuences: increased
by hormone replacement therapy and reduced by tamoxifen. Thus the
effects of exemestane on both mammographic density as well as on
bone and lipid metabolism were examined.
Methods: NCIC CTG MAP.2 was an international, double-blind,
placebo-controlled trial in healthy postmenopausal women without
a prior history of breast cancer and baseline mammographic density
(Boyd Grade 2-6). Women were randomized to EXE (25mg daily) or
placebo (PLAC) for 12 months and followed for a total of 24 months.
Endpoints included changes in breast density between baseline and 12
month as estimated by a computer-assisted thresholding program and
changes in plasma lipids, bone biomarkers and bone mineral density
(BMD).
Results: Ninety-eight women were randomized (49 to EXE; 49 to
PLAC). Results of breast density with attention to intra- and inter
observer variation will be presented. The percent change in the bone
resorption marker N-telopeptide was signi¿cantly higher in the EXE
arm at 12 months (29.7% EXE vs. –5.7% PLAC, p value 0.04). No
statistically signi¿cant differences in percent change in BMD (lumbar
spine and femoral neck) were observed between the two treatment arms
at either 12 or 24 months. Treatment groups differed signi¿cantly in
percent changes in total cholesterol at 6 months (-5.2% EXE vs. 0.8%
PLAC, p value 0.02), HDL at 6, and 12 months (-6.3% EXE vs. 2.0%
PLAC, p value 0.009; -6.6% EXE vs. 0.7% PLAC, p value 0.013), and
lipoprotein a at 6 and 12 months (-7.2% EXE vs. 13.3% PLAC, p value
0.006; -0.9% EXE vs. 4.2% PLAC, p value 0.034). However, changes
in total cholesterol were not apparent between treatment arms at 12 or
24 months. Changes in HDL and lipoprotein a were also not apparent
between treatment arms at 24 months. No signi¿cant differences in
percent change in LDL or triglycerides were noted at any time point.
Discussion: EXE administered for one year to healthy postmenopausal
women resulted in an increase in the bone resorption marker Ntelopeptide without signi¿cant change in BMD during and after the
treatment period. Changes in lipid parameters on this trial were mild
and reversible and of uncertain clinical signi¿cance. In light of powerful
estrogen suppression and potential androgenicity from EXE, its effects
on mammographic density are awaited with interest.
1027
InÀuence of bilateral breast magnetic resonance imaging
in treatment planning for patients with stage I/II breast
cancer.
Figueredo ND, Carruthers CL, Frazier TG. Lankenau Hospital,
Wynnewood, PA; Comprehensive Breast Center, Bryn Mawr Hospital,
Bryn Mawr, PA
Background: Traditional screening methods including physical exam,
ultrasound, and mammography may not detect the extent of disease in
newly diagnosed breast cancer patients. Prior studies have shown that
magnetic resonance imaging (MRI) changes surgical management of
breast cancer in approximately 9-30% of patients. We evaluated the
inÀuence of preoperative breast MRI in the surgical management of
patients in our community breast center.
Methods: 100 consecutively diagnosed patients with stage I/II breast
cancer treated by a single breast surgeon, in a community breast center
were evaluated. All patients had bilateral breast MRI prior to de¿nitive
surgical treatment.
Results: Prior to MRI the proposed treatment plan for these 100
patients was breast conservation. 26 of these patients (26%) had their
treatment plan altered by the MRI result. 14 of these 26 patients (53.8%)
underwent unilateral mastectomy for presumed multi-focal disease. All
14 had more extensive disease or actual multi-focal disease on ¿nal
pathology. 11 of 26 patients (42.3%) chose bilateral mastectomy based
on MRI ¿ndings. 7 of these 11 patients (63.6%) had bilateral disease
on ¿nal pathology. 1 patient of the 26 (3.84%) had bilateral unifocal
disease and chose bilateral wide segmental resection with primary
radiation treatment.
Conclusion: Bilateral breast MRI utilized as part of the staging workup
for newly diagnosed breast cancer has changed our surgical management
in 26% of cases. We conclude that breast MRI is appropriate and an
important complement to mammography and ultrasound in a signi¿cant
number of patients with presumed unifocal breast cancer.
1028
Follow-up rather than excision for benign papillary lesions
of the breast.
Copit DS, Vaidynathan S, Chaudhri Y. Albert Einstein Medical Center,
Philadelphia, PA
PURPOSE
Management of papillary lesions of the breast diagnosed at percutaneous
biopsy has been controversial. Based on several studies, at our
institution we have traditionally recommended follow up rather than
excision for these patients, assuming there are no other associated highrisk lesions. Because of the controversy that remains today, we decided
to perform a retrospective review of our data to study the safety of our
practice. We decided to include data from patients for whom we have
at least two year potential follow up.
METHOD AND MATERIALS
We performed a retrospective review of all percutaneous biopsies
performed from January 2003 through February 2005. Out of a total of
661 procedures, 28 revealed benign papillary lesions (solitary papilloma
or papillomatosis). We excluded any patients with atypia (whether or
not associated with the papillary lesion) or any other lesions that have
well-established recommendations for excision.
RESULTS
All biopsies were performed with an 11 gauge vacuum-assisted device.
A total of 23 patients had ultrasound guidance and 5 had stereotactic
guidance for their biopsy. The average length of follow up was 30.8
months (range 14-43 months). Three patients were lost to follow up. One
patient developed DCIS at her biopsy site at 1 year follow up. Seven
lesions were excised because of patient preference (n=1), surgeon’s
or pathologists’ recommendation (n=5) or radiologic-histologic
discordance (n=1). The remaining 17 have not developed cancer in
either breast.
CONCLUSION
Patients who have a percutaneous biopsy with an 11 gauge vacuumassisted device that reveal benign papillary lesions can be safely followed
with mammography rather than undergoing surgical excision.
1029
Using three-parameter empirical mathematical model
to analyze breast DCEMRI data; comparison with
conventional BI-RADS classi¿cation.
Fan X, Arkani S, Karczmar GS, Abe H, Schmidt RA, Newstead GM.
University of Chicago, Chicago, IL
Background: Dynamic contrast enhanced MRI (DCEMRI) is becoming
increasingly important for early detection of breast cancer. Optimal use
of DCEMRI data for cancer diagnosis requires objective, quantitative
analysis of rates of contrast media uptake and washout. Most DCEMRI
studies have relied on pharmacokinetic compartment modeling to
relate contrast media kinetics to tumor blood Àow. However, 3D
DCEMRI data acquired in routine clinical practice has very low time
resolution (∼60 s). Under these conditions, the accuracy of physiological
parameters obtained from compartmental models is questionable. In
addition, these models require an arterial input function, which is
dif¿cult to estimate accurately. Alternatively, empirical mathematical
equations can be used to ¿t the kinetic curves. In this study, a simple
empirical mathematical model (EMM) with only three parameters
was used to analyze 3D bilateral DCEMRI breast data. Sensitivity
and speci¿city obtained with this approach was compared to that of
the BIRADS® lexicon.
Material and Methods: 3D DCEMRI data with time resolution
of 68 s, from 34 benign and 79 malignant lesions were selected
for review. Plots of signal intensity vs. time (6 time points) were
produced from a manually selected region of interest that contained
the most rapidly enhancing contiguous pixels in a suspicious lesion.
The EMM was used to ¿t the raw data. Formulas for commonly used
diagnostic parameters,such as initial area under curve, initial slope
of enhancement, the time to peak enhancement, signal enhancement
ratio, and enhancement curvature at peak, were derived in terms of
the three EMM parameters. Finally, the sensitivity and speci¿city for
malignant lesions using these parameters were evaluated by using
receiver operating characteristic analysis, and was compared to the
kinetic curve classi¿cation according to the BI-RADS.
Results: The results demonstrate that the EMM was able to accurately
¿t all the signal enhanced kinetic curves with only 6 points. There was a
statistically signi¿cant difference between benign and malignant lesions
for several diagnostic parameters: the uptake rate, initial slope, signal
enhancement ratio, and curvature at the peak enhancement (p ≤ 0.04).
EMM analysis provided at least the diagnostic accuracy of the kinetic
classi¿ers described in the BI-RADS lexicon with the sensitivity and
speci¿city of 91% and 18%, respectively.
Discussion: Although the sensitivity and speci¿city of the EMM
approach vs. Bi-RADS were not signi¿cantly different, the EMM
offered key advantages. Unlike the BI-RADS classification, the
EMM can be used to achieve a continuous spectrum of sensitivity
and speci¿city, from which Radiologists can choose the optimal
combination, depending on other clinical factors. The EMM can be used
to standardize data from different institutions with different dynamic
protocols, so that the diagnostic parameters obtained with different
protocols can be interpreted using uniform criteria. This suggests that
the EMM may be useful for analysis of routine clinical data.
1030
A double-blind randomized controlled trial of paracetamol
as a pre-medication for mammography.
Freitas-Junior R, Nascente CM, Carvalho AA, Ximenes C, Silva MF,
Leite Filho AR, Freitas PF. Goias Federal University, Goiania, GO,
Brazil; Goiania, GO, Brazil
INTRODUCTION: Mammography represents an important method
of detection of breast cancer. However, the pain caused by this exam
is one of the principal factors why some women abandon the exam
routine, or do not follow the chronogram. The analgesic intervention
is a possible solution for minimizing pain and discomfort that are felt
during the mammography. OBJECTIVE: Verify the possibility of
diminishing pain and discomfort during the mammography procedure
trough analgesic administration. METHODOLOGY: randomized,
double-blinded, placebo controlled trial, testing paracetamol to diminish
the pain and discomfort during mammography. 300 patients that
came to the Radiology Service of HC/UFG were randomized for this
study. A questionnaire with two parts was used: the ¿rst had questions
that concerned the patient identi¿cation and factors related to the
pain during mammography; and the second asked about the scale of
discomfort (without discomfort; uncomfortable, but tolerable; extremely
uncomfortable; unbearable) and the pain (analogical linear scale) during
the mammography. Each patient received 1000 mg of paracetamol
or placebo. Afterwards each patient ¿lled out the second part of the
questionnaire. Three patients were excluded from the analysis; this
resulted in 149 in the paracetamol group, and 148 in the placebo
group. RESULTS: The two groups were homogenous concerning the
mean of the ages, weight, height and breast size. The mean of the pain
was 3.5 in the paracetamol and 2.9 in the placebo group (p=0.12).
Concerning the scale of discomfort, in the paracetamol group, 92% of
the patients said that they did not fell any discomfort or that the exam
was uncomfortable, but tolerable, meanwhile in the placebo group, this
value was 93.8% (NS). The exam was extremely uncomfortable or that
the exam was unbearable counted for 8.1% of the patients in group 1
and 6.2% of the patients in group 2 (NS). CONCLUSION: The usage
of paracetamol before the mammography did not reduce the discomfort
S51
and pain generated by the radiological exam.
1031
Why women with breast cancer do not return for
surveillance mammography.
Geller B, Skelly J, Muss H. University of Vermont, Burlington, VT;
Vermont Cancer Center, Burlington, VT
Background: Studies using health claims databases or registries have
reported between 15 – 22% of women with recently diagnosed breast
cancer (BC) did not have surveillance mammography (SM). Because
these women are at high risk for recurrence or second primary tumors
and SM is the recommended test for BC detection it is important to
understand why they do not return.
Methods: We identi¿ed women diagnosed with BC between 19982001 in the Vermont Breast Cancer Surveillance System, a member
of the NCI’s Breast Cancer Surveillance Consortium. After excluding
women with a bilateral mastectomy, stage 4 cancer, or a prior breast
cancer there were 1223 who did (controls) and 241 who did not (cases)
have SM 7-30 months after the BC diagnosis. Sampling was strati¿ed
by age groups and stage. Through telephone interviews in 2006 we
collected data on treatment and surveillance history, psychological
measures and demographics. Cases and controls were compared for
each explanatory factor.
Results: We found that 16% did not have SM during the follow up
period. After a National Death Index search and a search for current
address and telephone number, and applying matching criteria for each
sampling cell we invited 107 cases and 109 controls to be interviewed.
See Table 1 for participation rates. Of the 53 cases interviewed 49
reported having SM. We con¿rmed SM for 16 cases and converted these
to controls and 6 out of state cases were dropped from the analyses.
Thus the analyses were conducted with 31 cases and 68 controls. Of
the 4 cases reporting no SM, 3 reported having a bilateral mastectomy
and one stated she did not think she needed it. Three explanatory factors
were signi¿cantly different between cases and controls. Women who
received hormonal therapy were 2.4 times more likely to have SM
during the follow up period compared to women who did not. For
each unit increase in co-morbidity a woman’s odds of having SM was
reduce by .89. Women in the two middle income ranges had an increased
odds of having SM during the follow up period (OR=4.00 and 3.67
respectively), compared to women in the <$25,000 income range, and
although not signi¿cant, women in the highest income range were more
likely than women in the lowest range to return for SM.
Conclusion: Women using hormonal therapy and who had little or no comorbidity were more likely to have SM. Income also appeared to play a
role in not returning for SM. Database research has inherent limitations.
All but 4 of 53 cases reported SM and we were able to con¿rm 27.
Our database was missing data from out of state mammography, death
records and data on women who had moved. Although our study
showed that SM is usually obtained, it is still important for health care
providers to encourage BC survivors to participate in mammography
after treatment is completed. Supported by a grant from the Susan G.
Komen Foundation and NCI.
Table 1. Reasons for not participating
Invited
Deceased
Unable to reach or locate
Declined participation
Not inverviewed, other reason
Interviewed
Cases
107
10
26
16
2
53 (49.5%)
Controls
109
8
23
22
4
52 (46.8%)
1032
Accuracy of clinical evaluation of locally advanced breast
cancer in patients receiving neoadjuvant chemotherapy.
Prati R, Minami CA, Gornbein JA, DeBruhl N, Chung D, Chang HR.
University of California, Los Angeles, Los Angeles, CA
Background: Physical examination (PE), mammography (MG), breast
MRI, FDG-PET and pathologic evaluation are the standard assessments
of primary breast cancer. The accuracy of each of these methods has not
been well studied in patients receiving neoadjuvant chemotherapy. We
compared the accuracy of each of them in tumor and nodal assessment
in patients with T3-T4 tumors receiving neoadjuvant chemotherapy.
S52
Materials and methods: We analyzed 45 patients with T3-T4 tumors
from an ongoing trial. All patients had 4 cycles of docetaxel/carboplatin
with or without trastuzumab before surgery. Tumor assessments by PE,
MG, and MRI as well as nodal status by PE and PET were obtained
before and after chemotherapy. Final tumor and nodal staging by
pathology were also obtained. Spearman corr (r) and root mean square
error (RMSE) measured accuracy.
Results: At baseline, when compared to the tumor size measured by
PE, MRI was more accurate than MG (r=0.559, RMSE=35.4%, vs.
r=0.046, RMSE=66.1%). After 4 cycles of chemotherapy, PE tumor
assessment correlated better with pathological evaluation than MG or
MRI (r=0.656, RMSE=90% vs. r=0.126, RMSE=152% and r=0.364,
RMSE=93%, respectively). Nodal assessment after neoadjuvant
chemotherapy showed high speci¿city but low sensitivity by both
PET and PE.
Conclusion: Accurate tumor assessment of locally advanced breast
cancer (T3-T4) by PE is clinically accurate both before and after
neoadjuvant chemotherapy. Our study suggested that breast cancer size
determined by PE was more accurate when compared with imaging
to the pathology ¿ndings. Both PET and PE predicted pathologically
positive nodes but not negative nodes. Pathological nodal staging is still
the standard of care regardless of the PE and PET results.
1033
Breast speci¿c gamma imaging and managment of breast
cancer.
Stern L, Rosenberg AL, Brill KL. Methodist Hospital, Philadelphia, PA;
Jefferson Medical College, Kimmel Cancer Center, Philadelphia, PA
Intro:Scintimammography (SM), a functional breast imaging
technique, has produced high speci¿city for breast lesions of 86 - 89%
and shown to be as effective or better than breast MRI. In spite of these
promising results, SM has not been widely utilized due to its lack in
sensitivity for sub-centimeter lesions (around 55%). To address these
issues, several breast-speci¿c gamma imaging (BSGI) systems have
been introduced. The sensitivity and speci¿city for BSGI are both
upwards of 90%. Additionally, such designs allow the breast to be
imaged from several angles including those which mimic the cranialcaudal (CC) and medial-lateral-oblique (MLO) mammographic views.
MRI had also continued to develop with improving technology and
clinical experience. The ACRIN Study on breast MRI utilized both 3-D
and dynamic MRI and demonstrated a sensitivity of 88% and speci¿city
of 68%. The sensitivity and speci¿city of BSGI were analyzed and the
role and impact on management assessed.
Methods: BSGI was performed on 524 patients during the time period
from 5/1/06 through 5/1/07. We reviewed and compared the results
of ¿ndings on BSGI, MRI, mammography and ultrasound for these
patients.
Results: Indications for BSGI included: 1) Patients with recently
diagnosed breast cancer to look for multifocality and multicentricity. 2)
Patients with BRCA mutations. 3) Patients with past history of breast
cancer and possible recurrence, 3) Patients with multiple masses on
mammography and/or ultrasound, 4) Patients with unexplained pain
or palpable abnormalities, 5) Patients with extremely dense breasts,
and 6) Patients with indeterminate calci¿cations. Of the 84 patients
with BIRADS 4 or 5, 11 had a new diagnosis of cancer and 8 were
evaluated for recurrence. Mass or abnormal mammography was the
indication for 63% of patients and 13% had suspicious calci¿cations.
There were 8 patients classi¿ed as BIRADS 4 or 5 on BSGI who also
had an MRI. All 7 of the patients that had a positive BSGI and MRI had
a positive biopsy for cancer. The one patient negative on MRI was also
negative on biopsy. This would indicate a sensitivity of 87.5% and a
speci¿city of 87.5% for BIRADS 4 and 5. BSGI documented evidence
of multicentricity and contralateral disease in 16 cases. It identi¿ed
recurrent disease in 6 cases.
Conclusion: While BSGI has been directly compared to MRI only
in a few small studies, it has demonstrated comparable sensitivity but
higher speci¿city. This limited data is not suf¿cient for conclusions.
Additionally, findings on BSGI altered the subsequent surgical
management of breast cancer patients in 4% of cases due to discovery
of multicentric and contralateral disease or the presence of recurrent
disease. There are approximately 40 sites in the US performing BSGI
and around 20,000 procedures have been completed to date. The authors
of this work propose a multi-center retrospective comparative analysis
of BSGI and MRI in patients who routinely received both imaging
modalities to allow comparison of the performance of these techniques
in the detection of breast carcinoma in these patients.
1034
The missing exam in clinical breast exam.
Goodson III WH, Moore II DH. California Paci¿c Medical Center
Research Institute, San Francisco, CA; University of California, San
Francisco, CA
Background: Clinical breast exam (CBE) is necessary during diagnosis
of the 15% of breast cancers missed by mammograms (JNCI 2005;
97:1476). Inadequate application of CBE is a problem, however,
because clinicians as a group fail to make a timely diagnosis of 5
percent of breast cancers because they allow negative mammogram
results to override CBE ¿ndings (Arch Int Med 2002; 162:1343). CBE
application will not improve unless clinicians practice CBE frequently
enough to become facile with the procedure, but surveys suggest that
fewer clinicians perform routine CBE. To guide efforts to improve
CBE, we surveyed women to determine the percent that receive even
a basic CBE by asking them to compare their experience of CBE with
a minimal standard CBE.
Methods: We posted a real-time video of a minimal, 2-minute CBE
on the internet at www.2minutebreastexam.com and asked women
to compare their own experience to the CBE video. The choice of
responses was: 1) “My annual breast exam is like the exam in the
video.” 2) “My annual breast exam is not as thorough as the exam in
the video.” 3) “My doctor doesn’t do any breast exam.” We used the
internet because respondents needed proximate access to the video to
make their comparisons and, logistically, it was most feasible to make
the video accessible via the internet. We illustrated 2-minute supine
palpation suggested by Mahoney and Csima (CMA Journal 1982;
127: 729) as the minimal acceptable CBE because: a) a CBE shorter
than 2 minutes is also shorter than any longer CBE method (3); and b)
from discussion at community groups, most women receive less than
2 minutes anyway. With IRB approval, we tabulated a convenience
sample of the ¿rst 320 respondents.
Results: Only 70 (21%; 95% CI 15-26%) reported that they received a
CBE comparable to the 2-minute CBE illustrated on the site. Seventynine percent (95% CI 74-85%) received either a CBE that was not as
thorough (n=237) or no CBE (n=13). Responses were from all ten zip
code regions of the United States.
Discussion: A CBE that does not allow time to examine the breasts is
not a CBE; and, although one might debate the minimal acceptable
time for CBE, the acceptable minimum is unlikely to be less than 2
minutes. From our survey, we conclude that clinicians are abandoning an
essential clinical skill and with it the opportunity to improve diagnosis
of the 15 percent of breast cancers that are invisible to mammograms.
Based on the response to our survey, we believe that, in addition to
informing choices for cancer treatment, the internet should be used to
inform women of what they should be able to expect in breast cancer
screening, especially for their periodic clinical breast exam.
1035
Comparing performance measures in opportunistic and
organized screening mammography for early breast cancer
detection.
Hofvind S, Vacek P, Skelly J, Geller BM. The Cancer Registry of Norway,
Oslo, Norway; University of Vermont, Burlington, VT
Background: In the U.S. screening mammography is initiated by women
themselves, usually in response to a recommendation by a health care
provider. In contrast to this opportunistic screening, Norway and most
other European counties have organized screening programs in which
women are invited to attend scheduled mammography examinations at
regular intervals. In Norway women are screened every two years while
in Vermont most women are screened annually. Another difference
between Vermont’s delivery of screening mammography and Norway’s
program is the way that examinations are read with Norway routinely
using independent double reading with consensus by radiologists who
are specialists in breast imaging. The performance measures of these
two systems for delivering screening mammography have not been
previously compared.
Methods: We compared recall and detection rates, positive predictive
value, sensitivity and speci¿city in women aged 50-69 years old,
undergoing opportunistic screening mammography in Vermont
(n=45,050) and organized screening in Norway (n=194,294) during
1997-2003. The results are given for the subsequent screening
examinations.
Results: The recall rate in Vermont was more than three times higher
than in Norway (9.8% vs. 2.7%, p<0.001), while the screening detection
rate per 1,000 screens for one year follow-up was signi¿cantly lower
(3.9 vs. 5.1, p<0.001). The interval cancer rate for two year follow-up
was signi¿cantly higher in Vermont, both per 1,000 screens (1.84) and
per 1,000 women years (1.23), compared to Norway (1.73 and 0.87
respectively). Positive Predictive Values (PPV) for two-year follow-up
was 4.6% in Vermont and 19.2% for Norway for initial assessment,
19.4% and 49.4% for ¿nal assessment. The sensitivity was 77.6%
for initial assessment and 68.6% for ¿nal assessment in Vermont,
and 75.9% and 74.8% for Norway after two years of follow up. The
speci¿city was lower for Vermont compared to Norway, both for initial
and ¿nal assessment.
Conclusion: Our study suggests that screening mammography in the
organized screening program in Norway is more accurate. Lower
recall and biennial screening makes it also more ef¿cient than the
opportunistic screening in Vermont. Independent double reading with
consensus and the longer screening intervals are probably the major
reasons for the greater accuracy. Radiologists in the United States
should be encouraged to routinely use independent double reading
with consensus.
1036
Cost-effectiveness of breast cancer (BC) screening with
contrast enhanced magnetic resonance imaging (MRI)
as an adjunct to x-ray mammography (XM) in high-risk
women.
Taneja C, Edelsberg J, Weycker D, Guo A, Oster G, Weinreb J. Policy
Analysis Inc. (PAI), Brookline, MA; Bayer HealthCare Pharmaceuticals,
Wayne, NJ; Yale University School of Medicine, New Haven, CT
Background: Screening for BC with MRI plus XM is now
recommended for high-risk women; its cost-effectiveness (vs XM) is
largely unknown.
Methods: We developed a model to depict outcomes and costs of
MRI+XM vs XM screening in a cohort of 10,000 women with BRCA1/2
mutations or high lifetime risk of BC (collectively, “high risk”).
Patients were assumed to be 40 years of age, and to be screened once
at model entry. Prevalence of undetected BC (invasive and DCIS) was
assumed to be 2.3%. Sensitivity and speci¿city of MRI+XM (90.2%
and 84.1%) and XM (40.0% and 94.7%) were estimated based on
published prospective studies employing both modalities. The model
predicts the number of women correctly and incorrectly diagnosed
with each strategy, and consequences in terms of additional care
(further diagnostic evaluation, BC treatment), patient utilities, and life
expectancy. Women with BC not detected at screening were assumed
to be correctly diagnosed (often at a more advanced stage) in the next
12 months. Costs included those of initial screening, further diagnostic
work-up, and BC treatment. Cost-effectiveness was calculated as cost
per quality-adjusted life-year (QALY) gained; costs (2005US$) and
effectiveness were discounted at 3% annually.
Results: Among 230 (out of 10,000) women with undetected BC,
208 cases would be detected by MRI+XM screening and 92 by XM.
MRI+XM would yield more false-positives (37 vs 12). Cost of screening
would be $1,887 per patient for MRI+XM vs $936 for XM. MRI+XM
screening would produce an expected gain in (undiscounted) life-years
(39.50 vs 39.44). Cost per QALY gained is $27,634 for women with
BRCA mutations, and $59,639 for other high-risk women; overall, cost
per QALY gained is $53,878.
Discussion: MRI+XM screening would improve detection of BC and
thereby life expectancy in high-risk women, and is cost-effective by
current standards.
S53
1037
High incidence of brain metastases found in patients with
HER2 positive metastatic breast cancer. Should these
patients be followed by regular MR scans?
Langkjer ST, Krøldrup L, Kristiansen C, Enevoldsen K, Edal AL,
Ormstrup TE. Vejle Hospital, Vejle, Denmark
Background: A high incidence of brain metastases has been found
in studies of patients with HER2 over-expression (HER2 positive
patients). Prophylactic cerebral irradiation to this patient group has been
considered. It has been claimed that irradiation of asymptomatic brain
metastases can prevent them from becoming symptomatic. Our aim
was to study the incidence, pattern, and timing of cerebral metastases
in patients with relapse of breast cancer with HER2 over-expression in
order to evaluate weather regular MR scans should be offered to ¿nd
the brain metastases earlier when they are still asymptomatic.
Patients and Methods: Patient data from a phase II study of patients with
relapse of HER2 positive breast cancer was examined retrospectively. It
consisted of 36 patients diagnosed with disseminated breast cancer and
over-expression of HER2 status either proven by immunhistochemistry
(IHC) 3+ and or Àuorescence in situ hybridization (FISH). The patients
were treated with trastuzumab and paclitaxel either as ¿rst or second
line chemotherapy. Patients were included between November 2001
and October 2005.
Results: Approximately half a year after inclusion in the protocol the
¿rst patients developed symptomatic brain metastases. Within a few
years 18 of the 36 patients in the study were diagnosed with cerebral
metastases (50%). Especially patients with more than 2 systemic
metastatic sites seemed to be at risk. All patients with cerebral
metastases had multiple cerebral metastases and received radiotherapy
(full-dose whole brain radiotherapy, 20Gy/4 fractions). The disease
status at the time of brain metastases showed that 12 of the 18 patients
had regression or stable systemic disease.
Discussion: Our study shows that patients with HER2 over-expression
have a very high risk of developing brain metastases. Trastuzumap and
chemotherapy is effective to control the patients systemic disease but
seems to be less effective for treatment of brain metastases, because
of poor penetration of the blood-brain barrier. The median survival
time for patients with cerebral metastases is poor. Since half of HER2
over-expressing patients developed brain-metastases close surveillance
for brain metastases (clinical and/or imaging) is necessary even during
effective systemic treatment. We therefore recommend that this patient
group should be followed with regular MR scans of the brain.
1038
Concordance of contralateral breast cancer for steroid
receptor and tumour characteristics.
Absar MS, Martin C, Howe M, Zeiton A, Cramer A, Morris J, Bundred
NJ. University Hospital of South Manchester, Manchester, United
Kingdom
Contralateral breast cancers affect 5%-10% of patients. The aim of the
study was to determine whether the ¿rst cancer predicted the tumour
characteristics of the second cancer.
Materials and methods: Women who developed Bilateral breast cancer
between 1976 and 2005 were retrieved from the breast unit database.
Variables compared included mode of detection, pathological size,
histological type and grade, oestrogen receptor(ER) status, epithelial
proliferation (Ki67) and lymph node status.
Results: The mean age of diagnosis of the ¿rst cancer was 53 years.
Twenty six percent ( 66/254) of the index cases and 53% (135/254)
of the contra lateral cases were screen detected. Mammographically
detected (screen) cancer had a higher likelihood of 85% (56/66) of
having screen detected contralateral cancer (p=0.001). Symptomatic
cancers were higher grade than screen detected (p=0.005). SDCBC
tended to be smaller with 72% being <20 mm and mainly lymph node
negative (75%).whereas 50% of symptomatic cancers were > 20mm
and 47% were node positive.
Mode of detection, grade of tumour, Oestrogen receptor status
and epithelial proliferation correlated between the tumours in both
groups.
S54
Conclusion: An individuals genetic makeup determines the tumour
characteristics of both primary and contralateral breast cancer.
Mammographic follow up should be tailored to mode of presentation
and ER status of the initial primary cancer.
Tumour Concordance
Metachronous (n=197)
Concordance
Spearman correlation
Synchronous (n=76)
Concordance
Spearman correlation
Detection
mode
85%
0.001
85%
0.0001
Nodal
status
48% 52%
0.006 0.005
Size
group
53%
0.107
Oestrogen
receptor
77%
0.001
Ki67
group
72%
0.001
57% 57%
0.001 0.180
53%
0.092
95%
0.001
59%
0.001
Grade
1039
Breast cancer in the elderly: benefits of screening
mammography in the diagnosis.
Hines NL, Leibman AJ. Jacobi Medical Center, Albert Einstein College
of Medicine, Bronx, NY
Introduction: Recently, the American Cancer Society revised its
recommendations which stated that women should continue screening
mammography as long as they are in good health. As life expectancy
increases, a greater percentage of our population is becoming elderly.
At the same time, their risk for developing breast cancer increases. In
the 2006 National Vital Statistics Report by the CDC, the average life
expectancy for a female of any race at the age of 70 was reported to
be 15.9 years. Therefore, we believe that the continuation of annual
screening mammography beyond the age of 70 years will identify
clinically occult and earlier stage cancers that can be successfully
treated, and possibly prolong survival.
Materials and Methods: We retrospectively reviewed breast cancer
patients age 70 years and older presenting to our institution during
an 8 year period (1999-2007). We reviewed clinical history as well
as mammographic, pathologic and surgical data. Analysis of several
mammographic factors was performed, including screening versus
diagnostic mammography, presence of prior mammograms, length of
time since the prior mammogram as well as mammographic ¿ndings.
The type of surgery was noted. Pathology data was reviewed to
determine type and extent of tumor.
Results: 37 patients with an average age of 73.4 years (range 70 - 86
years) presented with 41 cancers. 29 of the 41 (71%) cancers were
identi¿ed on screening mammograms and 12 (29%) presented for
diagnostic mammograms. 23 (62%) patients had prior mammograms,
the average time since the prior mammogram was 1.2 years. Suspicious
calci¿cations were identi¿ed in 5 (12%), a mass was identi¿ed in
21 (51%) and a mass with calci¿cation was identi¿ed in 15 (37%).
Pathology in 11 of the 41 (27%) cancers was DCIS. In 28 (68%)
pathology demonstated in¿ltrating ductal carcinoma and in 2 (5%)
invasive lobular carcinoma. The average tumor size was 2.0 cm on
pathologic. 34 cancers were managed surgically at our institution by
either lumpectomy (n=21) or mastectomy (n=14). In the subgroup of
DCIS, 8 of 11 patients with DCIS were diagnosed based on screening
mammography ¿ndings. 7 (64%) of the DCIS patients had prior
mammograms with an average time interval of 1.5 years. Of the 11
patients with DCIS, 8 (73%) were identi¿ed on screening examinations.
Suspicious calci¿cations were identi¿ed in 3 (27%), a mass in 4 (36%)
and a mass with calci¿cation in 4 (36%).
Discussion: The population of elderly women in the US is increasing.
At the same time, the elderly have an increased rate of breast cancer.
With the enlarging group of women in this age group at increased risk,
the bene¿ts of screening mammography continue to be debated. We
reviewed the clinical history, mammography and pathology ¿ndings as
well as surgical history of 37 elderly patients. Our results suggest that
screening mammography continues to be very bene¿cial in the elderly.
Screening mammography should continue to be requested in elderly.
1040
Utility of echocardiographic screening for late-onset
cardiomyopathy in breast cancer survivors treated with
cardiotoxic chemotherapy.
Wazir S, Budd GT, Moore HCF, LeGrand S, Andresen S, Tang WH.
Cleveland Clinic, Cleveland, OH
Background: The diagnostic utility of routine surveillance
echocardiographic screening to identify late-onset cardiomyopathy
in breast cancer survivors treated with cardiotoxic chemotherapy has
not been examined.
Methods: We prospectively evaluated 157 consecutive breast
cancer survivors (>2 years in remission) who had received standard
anthracycline-based chemotherapy and who were without known
history of heart failure, ischemic heart diseases, or cardiac dysfunction.
All subjects had pre-chemotherapy documentation of preserved
LV ejection fraction. Limited echocardiography using MicroMaxx
(Sonosite Inc) were performed by a designated trained individual.
Results: In our study cohort of breast cancer survivors (mean age 57
± 10 years, 93% Caucasian, 74% received radiation therapy), none of
the subjects had impaired LV ejection fraction (all ≥50%), 2 patients
had LV dilatation (LV internal diameter >5.7cm), and 16 (10%) had
left ventricular hypertrophy, and 58 (37%) had evidence of diastolic
dysfunction by mitral inÀow patterns (E/A <1). This represented <0.5%
prevalence of screen-detected cardiomyopathy, which was even below
the expected prevalence in the general population.
Conclusion: Our data do not support routine surveillance
echocardiographic screening for late-onset cardiomyopathy in breast
cancer survivors despite prior exposure to cardiotoxic chemotherapy.
1041
Does HER-2 status inÀuence locoregional failure rates
after mastectomy in patients with pT1-3pN0 early stage
breast cancer?
Kwan W, Al-Tourah AJ, Speers C, Kennecke H, Norris B, Olivotto I. BC
Cancer Agency, Fraser Valley Centre, Surrey, BC, Canada; BC Cancer
Agency, Vancouver Centre, Vancouver, BC, Canada; BC Cancer Agency,
Vancouver Island Centre, Victoria, BC, Canada
Purpose: To determine if HER-2 positivity inÀuences locoregional
failure rates among patients with pT1-3pN0 breast cancer treated with
mastectomy and no adjuvant radiotherapy.
Methods: Nine hundred and thirty women with known HER-2 receptor
status and treated with a modi¿ed radical mastectomy without adjuvant
radiotherapy for pT1-3pN0 breast cancer diagnosed between 1986 and
1992 were analyzed for local, regional and distant relapse free survival
(LRFS, RRFS & DRFS, respectively). HER-2 positivity was de¿ned as
2+ immunohistochemistry (IHC) stain with a positive FISH, or a 3+ IHC
stain. The use of adjuvant systemic therapy (Tamoxifen, chemotherapy
or both) was documented. Trastuzumab was not available in the period
these patients were treated. Log rank statistics were used to compare
10-year Kaplan-Meier curves of LRFS, RRFS & DRFS.
Results: Median follow up was 123 months. 107 (11.5%) patients were
HER-2 positive. Equivalent proportion of patients received adjuvant
systemic therapy in the HER-2 positive vs. HER-2 negative cohorts
(32% vs 27%, respectively, p= 0.3 by Chi-Square test). 10-year LRFS
among HER-2 positive patients was 91.5% compared to 86.6% for
HER-2 negative patients (p= 0.27). 10-year RRFS for HER-2 positive
patients was 88.2% compared to 93.1% for HER-2 negative patients
(p= 0.23). 10-year DFRS among HER-2 positive patients was 62.4%
compared to 74.7% for HER-2 negative patients (p= 0.03).
Conclusions: HER-2 positivity did not signi¿cantly impact locoregional
control in pT1-3pN0 breast cancer patients treated with mastectomy.
HER-2 positivity on its own is not an indication for radiotherapy after
mastectomy.
1042
Elevated JAG1 mRNA expression, associated with the basal
phenotype, is a poor-prognosis indicator in lymph nodenegative breast cancer.
Reedijk M, Dickson BC, Pinnaduwage D, Mulligan AM, Zhang H, Bull
SB, O’Malley F, Egan SE, Andrulis IL. University Health Network,
Toronto, ON, Canada; Mount Sinai Hospital, Toronto, ON, Canada;
Hospital for Sick Children, The Toronto Medical Discovery Tower,
Toronto, ON, Canada
Background: While most women with lymph node negative (LNN)
breast cancer are cured of their disease, approximately 20% experience
a relapse. We have previously shown that expression of the JAG1 gene,
which codes for a Notch ligand, correlates with poor overall survival
in women with advanced breast cancer. We therefore undertook to
test whether expression of JAG1 is associated with reduced disease
free survival in LNN breast cancer. Methods: For analysis of JAG1
expression in LNN breast cancer we performed in situ hybridization
and immunohistochemistry on approximately 887 samples on tissue
microarrays. Results: Moderate to high JAG1 mRNA expression was
associated with reduced disease free survival (DFS) in univariate
analysis (hazard ratio of 1.58; 95% con¿dence interval, 1.04 to 2.40;
p=0.034) and correlated with large tumor size, ER and PgR negativity,
high tumor grade, and p53 antibody reactivity. JAG1 mRNA was
positively associated with expression of basal breast cancer markers,
however, in contrast to the ¿nding that basal gene expression is most
strongly associated with reduced DFS in the ¿rst 36 months of followup, JAG1 mRNA expression continued to be associated with reduced
DFS through the full follow-up period. Tumors expressing high levels
of both mRNA and protein showed reduced disease free survival as
compared to all other groups (hazard ratio of 1.73; 95% con¿dence
interval, 1.09 to 2.74; p=0.020) in univariate analysis. Conclusions:
These data reveal that JAG1 mRNA expression is associated with
poor disease free survival in LNN breast cancer over median follow-up
greater than 8 years, and con¿rm a synergistic association of elevated
JAG1 mRNA and protein with poor outcome in this disease. As JAG1
is a target of several oncogenic signaling pathways, and is a ligand for
the Notch pathway, these data provide novel insights into signaling that
may contribute to the progression of early stage breast cancer.
1043
Recurrence score by oncotype DX evaluated on the
primary breast tumor predicts the 2-year survival after
¿rst relapse.
Bianchini G, Zambetti M, Mariani P, Moliterni A, Bianchi G, Mariani
G, Fasolo A, Carcangiu ML, Valagussa P, Gianni L. Fondazione IRCCS
Istituto Nazionale dei Tumori, Milan, Italy
Background: Gene expression pro¿les of the primary breast tumors are
most often similar to those in distant metastases eventually developing
in the same patient (pt). The aim of the present study was to determine
whether the Recurrence Score (RS) assay based on 21-gene expression
also predicted prognosis after metastatic relapse.
Patients and Methods: Thirty-nine pts at ¿rst relapse after receiving the
same neoadjuvant chemotherapy for locally advanced breast cancer in a
single institution were evaluated (Gianni et al, JCO 2005). All pts with
positive estrogen receptor (ER) received adjuvant tamoxifen. Therapy
at distant relapse was not mandated, but was reasonably homogeneous.
Oncotype DX™ on paraf¿n-embedded core biopsies was performed
at diagnosis of breast cancer and it was not repeated at relapse. Two
risk groups were de¿ned using the Recurrence Score cut-off value of
25 used in the TAILORx study.
Results: All pts but one were followed for a minimum of 2 years. Of the
39 pts, 11 had a RS≤25 (28%) and 28 a RS>25 (72%). The overall 2-year
survival for the 39 pts was 48% and was signi¿cantly different in pts
with RS≤25 vs RS>25 (90% vs 32%; log-rank test P<0.01). Univariate
analysis showed that RS>25 (HR 11.2; 1.5-84 95% CI; P<0.05), short
relapse-free interval (RFI) from surgery (HR 2.79; 1.23-6.31 95% CI;
P<0.05, less than 12 vs more than 24 months), and negative ER status
(HR 2.6; 1.06-6.41 95% CI; P<0.05) had a signi¿cant association with
S55
poorer overall survival. Number of metastatic sites (3 or more) only
had a marginal association (HR 2.76; 0.99-7.66 95%CI; P=0.05) and
visceral involvement was not signi¿cant. Multivariate analysis of the
same variables showed that short RFI (HR 2.85; 1.09-7.47 95% CI;
P<.05) and RS>25 (HR 7.18; 0.9-57.7 95% CI; P=0.06) were the only
variables inÀuencing survival after relapse. The comparison of the
multivariate models with and without the RS by likelihood-ratio test
was signi¿cant (p<0.05).
Conclusion: The RS assessed on the primary breast cancer by Oncotype
DX is also associated with different trends of survival in the ¿rst 2
years after recurrence.
1044
Intracystic papillary carcinoma: a review of 917 cases.
Grabowski JE, Saltzstein SL, Sadler GR, Blair SL. UCSD, San Diego,
CA; UCSD, La Jolla, CA
Background: Intracystic papillary carcinoma (IPC) is an uncommon
breast neoplasm. There is limited data about its epidemiology and no
clear consensus regarding the optimal management of the disease. Using
a large case series, this study aimed to identify speci¿c characteristics
of patients with IPC, investigate its natural history, especially as
compared to other breast neoplasms, and determine its prognosis in an
effort to help develop evidence-based management recommendations
for clinicians.
Materials and Methods: The California Cancer Registry (CCR),
a population-based registry, was reviewed from the years 1988 to
2005. The data were analyzed with relation to patient gender, age at
presentation, tumor stage, and overall survival. Relative survival was
determined using Berkson-Gage life table analysis and was compared
to the relative survival of patients with all other types of invasive and
in-situ breast cancers. The CCR classi¿es isolated IPC as either in-situ
(CIS) or invasive, as determined by the local pathologist.
Results: A total of 917 cases of IPC were identi¿ed in the CCR. While
the majority of IPC cases occurred in women (96.5%), 3.5% of cases
occurred in men, which is signi¿cantly higher than the rate of all other
breast cancers in men (0.6%, p<.001). The median age of IPC patients
was 69.5 years old (range 27-99 years). Forty-seven percent of cases
(n=427) were CIS while 53% of cases had invasion (n=490). The vast
majority of these invasive cases were localized at the time of diagnosis
(89.6%, n=439), while 7.8% (n=39) of these cases had regional disease,
with either lymph node involvement or direct extension in adjacent
tissues. Only 2 of the cases had distant metastasis (0.4%). At 10 years,
patients with CIS and invasive disease had a similar relative cumulative
survival (96.8% and 94.4% respectively, P=0.18). The overall 10-year
relative survival from IPC, whether CIS or invasive was 95.6%, which
is similar to the 10-year relative cumulative survival of patients with
all other in-situ breast neoplasms (98.1%, p=1), but signi¿cantly better
than that of patients with all other types of invasive breast cancer
(74.6%, p<.001).
Discussion: Intracystic papillary carcinoma is a rare disease, occurring
in an older population and in a higher percentage of men than other
breast neoplasms. There is no signi¿cant difference in the long-term
survival of patients in the two histologically-derived subgroups of IPC.
The relative cumulative survival from IPC, whether CIS or invasive,
is similar to that of patients with other in-situ breast neoplasms, but
signi¿cantly better than patients with other types of invasive breast
cancer.
1045
Short term prognostic index for breast cancer: NPI or
Lpi.
Decock J, Hendrickx W, Van Belle V, Brouckaert O, Pintens S, Van
Huffel S, Paridaens R, Amant F, Leunen K, Smeets A, Berteloot P,
Van Limbergen E, Weltens C, Van den Bogaert W, Vanden Bempt I,
Drijkoningen M, Wildiers H, Vergote I, Christiaens M-R, Neven P. UZ
Leuven; ; UZ Leuven, Leuven, Belgium
Background: Lymph node involvement is the most important prognostic
factor for breast cancer survival, but is confounded by the number
of examined nodes. We investigated whether the empirical log odds
of nodal involvement (Lpi) is a better predictor of survival than the
S56
Nottingham Prognostic Indicator (NPI).
Methods: We included 2021 operable breast cancer patients treated
in UZ Leuven (2000-2006). NPI de¿nition: 0,2 x tumor size (cm) +
grade (1-3) + nodal score (1 if npos = 0; 2 if npos 3; 3 if npos > 3).
Lpi de¿nition: tumor size (cm) + 1 if grade 3 or 4 (0 otherwise) +
Log ((npos+0,5)/(nneg+0,5)), where npos and nneg are the number
of positive and negative nodes (Vinh-Hung et al, SABCS 2006 Poster
#5023). NPI and Lpi were categorized in 3 risk levels: low (NPI 3,4;
Lpi 0), intermediate (3,4 NPI 5,4; 0< Lpi 5) and high (NPI > 5,4; Lpi >
5). Disease-free survival (DFS) was analysed by Kaplan-Meier.
Results: Of 2021 patients, 188 relapsed and 37% had positive lymph
nodes. The maximum difference in DFS between the low and high; and
the low and intermediate risk group as de¿ned by Lpi is marginally
larger than between the corresponding NPI groups, respectively 34%
(Lpi) vs 32% (NPI) and 10% (Lpi) vs 9% (NPI). This slight trend could
not be found at median follow-up time (42 months), with 15% (Lpi)
vs 19% (NPI) for the low and high risk groups and 5% (Lpi) vs 10%
(NPI) for the low and moderate risk groups. Node positive patients
categorized as moderate risk by the Lpi had a worse DFS than those
with a NPI-moderate risk; a tendency which was also found for the
low risk group. Interestingly, a signi¿cant proportion of Lpi-moderate
(60%) and -low (83%) node positive patients was differentially
classi¿ed by NPI into the high and moderate risk group, respectively.
Moreover, the survival curve of these patients ¿ts perfectly with the
curves of the corresponding NPI risk groups, indicating that the Lpi in
fact misclassi¿ed them. This may explain the higher risk of recurrence
of the node positive low and moderate Lpi-de¿ned risk groups (table
1). In addition, we were not able to show that the Lpi adds signi¿cant
value to the NPI in node positive patients.
Discussion: This study does not support the hypothesis that the Lpi is
a better prognostic index than the NPI. Moreover, we did not ¿nd an
added value of the Lpi to the NPI.
Conclusions: SLN biopsy allows a more sensitive evaluation of lymph
nodes for the presence of metastatic cells. However, to date, the new
microstaging categories are not associated with signi¿cant changes
in DFS.
Short term recurrence rate for node positive cases comparing NPI with Lpi
Low % (r/n)*
Moderate % (r/n)*
High % (r/n)*
NPI
0% (0/24)
9% (27/299)
20% (83/426)
Lpi
7% (8/123)
15% (71/484)
22% (31/142)
* r/n de¿nes the number of reccurrences in a speci¿c risk group in relation to the number of
patients in this group
1046
The microstaging of sentinel lymph node biopsies is not
associated with disease-free survival in breast cancer.
Pugliese MS, Arthurs ZM, Tickman RJ, Allison KH, Beatty JD. Swedish
Cancer Institute, Seattle, WA
Introduction: In 2003, the American Joint Committee on Cancer
(AJCC) initiated the 6th edition staging criteria, including new
pN0i(+) and pN1mic categories for breast cancer. This study
examines the signi¿cance of microstaging, which to date is largely
uncharacterized.
Methods: A single institution’s prospectively collected breast cancer
registry was queried to identify patients staged with sentinel lymph
node (SLN) biopsy. SLN evaluation included serial sectioning and
immunohistochemical stains. SLN biopsies performed before January
2003 were reviewed and re-staged according to 6th edition criteria.
Results: During the study period, 954 SLN biopsies [N0i(-)=579,
N0i(+)=96, N1mic=76, N1a=157, N2a=34, N3a=12] were identi¿ed
with a mean follow-up of 41(±22) months. Compared to a 99% 5-year
DFS for pN0i(-), there was no difference in pN0i(+) or pN1mic (DFS
= 93% & 98%, respectively; P = 0.231), whereas there was a signi¿cant
difference between N1a, N2a, and N3a (DFS = 89%, 81%, & 78%,
P<0.01). Cox regression analysis identi¿ed the following variables to
negatively impact DFS: Bloom-Richardson Score (hazard ratio [HR] =
1.45; 95% CI, 1.06 to 1.99; P<0.01), pN1a (HR = 7.86; 95% CI, 2.72
to 22.67; P<0.01), pN2a (HR = 8.31; 95% CI, 2.06 to 33.51; P<0.01),
pN3a (HR = 17.88; 95% CI, 2.06 to 155; P<0.01). Both ER+ staining
(HR = 0.08; 95% CI, 0.2 to 0.40; P<0.01) and hormonal therapy (HR
= 0.21; 95% CI, 0.09 to 0.48; P<0.01) improved DFS. Age, tumor
size, multifocal disease, lymphovascular invasion, pN0(i+), pN1mic,
adjuvant therapy, and type of surgical therapy did not independently
impact DFS.
1047
Meta-analysis of gene-expression pro¿les in breast cancer:
towards a uni¿ed understanding of breast cancer sub-typing
and prognosis signatures.
Sotiriou C, Wirapati P, Kunkel S, Farmer P, Pradervand S, HaibeKains B, Desmedt C, Sengstag T, Schütz F, Goldstein DR, Delorenzi M,
Piccart M. Institute Jules Bordet, Brussels, Belgium; Université Libre
de Bruxelles, Brussels, Belgium; University of Lausanne, Lausanne,
Switzerland
Background: Breast cancer sub-typing and prognosis have been
extensively studied by gene expression pro¿ling, resulting in disparate
signatures with little overlap in their constituent genes. The biological
roles of individual genes in a signature, the equivalence of several
signatures and their relation to conventional prognostic factors are
still unclear.
Methods: Here we undertook a comprehensive meta-analysis of publicly
available gene-expression and clinical data from 18 studies totaling
2833 breast tumor samples. The concept of “co-expression modules”
(comprehensive lists of genes with highly correlated expression) was
used extensively to reveal the common thread connecting molecular
sub-typing and several prognostic signatures, as well as conventional
clinico-pathological prognostic factors.
Results: The disparity of the gene lists reported by several investigators
can be attributed to sampling variation due to small sample size relative
to the number of genes examined. Breast tumors were consistently
grouped into three main subtypes corresponding roughly to ER-
/ERBB2- (basal), ERBB2+ and ER+ (luminal) tumors. ERBB2+ tumors
showed an intermediate estrogen receptor module score which is not
obvious from the traditional ER and ERBB2 marker status combination.
Both, ER-/ERBB2- and ERBB2+ subtypes were characterized by
high proliferation, whereas the ER+ subtype appeared to be more
heterogeneous. Using our meta-analytical approach we were able to
identify 524 genes which were signi¿cantly associated with survival.
Of the 524 prognostic genes, 65% were strongly co-expressed with
proliferation, 14% with ER, 0.6% with ERBB2, 2.7% with tumor
invasion, 1.5% with immune response and 16% with none of our coexpression modules. All previously reported prognostics signatures
examined in this meta-analysis (N=9) , despite the disparity in their
gene lists, carried similar information with regard to prognostication,
with proliferation genes being the common driving force. They were
all very useful for determining the risk of recurrence in the ER+
subgroup and much less informative for ER- and ERBB2+ disease.
Combining the signatures did not improve their performances. Finally,
in multivariate analysis nodal status and tumor size still retained
independent prognostic information.
Conclusions: This meta-analysis uni¿es various results of previous
gene-expression studies in breast cancer. It reveals connections
between traditional prognostic factors, expression-based subtyping and
prognostic signatures, highlighting the important role of proliferation
in breast cancer prognosis.
1048
The presence of a ¿brotic focus and expansive growth
pattern in breast tumors is associated with gene expression
pro¿les of aggressive tumor biology.
Van den Eynden GG, Smid M, Van Laere SJ, Colpaert CG, Van Marck
EA, Dirix LY, Vermeulen PB, Foekens JA. (Lab Pathology University
of Antwerp/University Hospital Antwerp, Wilrijk; Oncology Center,
GH St.-Augustinus, Wilrijk, Belgium), Antwerp, Belgium; Erasmus
MC-Daniel den Hoed, Rotterdam, Netherlands
,QWURGXFWLRQ A ¿brotic focus (FF) is a scar-like area of exaggerated
reactive stroma formation in the centre of an invasive breast tumor. FF
is a practical, easily assessable and reproducible integrative histological
prognostic parameter in breast cancer. Furthermore, its presence
is associated with an expansive growth pattern (GP), the presence
of hypoxia and (lymph)angiogenesis. Little is known about gene
expression differences between breast tumors with and without a FF.
0DWHULDOV DQG PHWKRGV: One hundred and three patients were selected
of whom microarray data of the tumor and HE slides for histological
analysis were available. The GP (in¿ltrative, expansive or mixed) and
the presence and size of a FF (no FF, FF<1/3th or FF>1/3th tumor
diameter) were assessed. Differential gene expression between tumors
with different GPs and sizes of FF was studied using SAM, PAM, GO
and KEGG-analysis. Furthermore, the correlation of GP and FF with
other molecular breast cancer signatures and with clinico-pathological
variables and survival was investigated.
5HVXOWV The presence (p=0.002) and size (p=0.002) of an FF were
correlated with an expansive GP. The presence of a FF was associated
with the basal-like cell-of-origin subtype (Perou et al. p=0.02), a
poor prognosis 76-gene signature (Wang et al. p=0.004), an activated
woundhealing signature (Chang et al. p=0.04) and a desmoid-type
fibromatosis signature (West et al. p=0.06). The presence of an
expansive growth pattern was associated with the basal-like and
erbB2-overexpressing subtype (p=0.003), an activated woundhealing
signature (p=0.06) and the presence of an invasiveness gene signature
(Liu et al. p=0.005). Furthermore, the presence of a FF (p=0.02) and
especially of a large FF (p=0.004) was associated with shorter metastasis
free survival. Differential gene expression analysis of tumors with
different sizes of FF showed an overrepresentation of genes involved
in chemotaxis, antigen presentation and processing, humoral immune
response and response to external stimuli. Genes overrepresented in
tumors with an expansive and in¿ltrative GP belonged to amino acid
metabolism, organogenesis and Wnt signaling pathways, and to lipid
and phosphorus metabolism, respectively.
&RQFOXVLRQ The presence of a FF or expansive GP is associated with
gene expression signatures indicative of aggressive tumor behaviour.
This is in line with the association of the presence of a FF with shorter
S57
survival. Our results furthermore suggest that immune responses and
chemotaxis are different between tumors with and without a FF or
with different GPs. The Wnt-signaling pathway plays an important
role in immune reactions. Whether these differences are also involved
in the formation of a FF and their role in tumor progression remains
to be elucidated.
1049
An inÀammatory breast carcinoma signature is associated
with reduced relapse free survival in patients with noninÀammatory breast cancer.
Van Laere SJ, Van den Eynden GG, Van der Auwera I, van Dam P,
Van Marck EA, Dirix LY, Vermeulen PB. Lab Pathology University
Antwerp and Oncology Center, General Hospital Sint-Augustinus,
Wilrijk, Antwerp, Belgium
Introduction. InÀammatory Breast Carcinoma (IBC) is an aggressive
and highly metastatic form of locally advanced breast cancer,
characterized by poor patient survival. We investigated if genes,
predictive of the IBC phenotype, can be used to stratify patients with
non-InÀammatory Breast Cancer (nIBC) with respect to prognosis.
Materials and Methods. RNA was extracted from 19 IBC samples and
40 non-stage matched nIBC samples and hybridized onto Affymetrix
HGU133 Plus 2.0 chips. Using the nearest shrunken centroid
algorithm, a gene signature predictive of IBC, comprising 281 genes,
was identi¿ed. Using a centroid mediated classi¿cation algorithm,
this signature was applied onto publicly available gene expression
data from 522 nIBC samples (GSE2290, GSE3744 and GSE2034)
with survival data of 475 nIBC samples. Samples were classi¿ed as
“IBC-like” or “nIBC-like”. Relapse free survival in these groups was
compared by the Kaplan-Meier method. In addition, we classi¿ed the
same 522 nIBC breast cancer samples according to the Cell-of-Origin
Subtypes (Perou et al, Nature, 2000), the Wound Healing Response
(WHR) signature (Chang et al, Plos Biol, 2004) and the Invasiveness
Gene Signature (IGS) (Liu et al, N Engl J Med, 2007) and compared
this to the classi¿cation according to the IBC signature. Cox regression
analysis was performed to identify the most predictive signature with
respect to relapse free survival.
Results. Kaplan-Meier analysis revealed a significant difference
between nIBC breast tumours classi¿ed as “IBC-like” and “nIBC-like”
(p=0.0044) with respect to relapse free survival. Breast tumours with
an “IBC-like” phenotype demonstrate a shorter relapse free survival
interval. Classi¿cation according to the IBC signature is signi¿cantly
associated with classi¿cation according to the cell-of-origin subtypes
(p<0.0001), the WHR signature (p<0.0001) and the IGS (p<0.0001).
Breast tumours having an “IBC-like” phenotype generally belong to
the Basal-like, ErbB2-Overexpressing or Luminal B cell-of-origin
subtypes, are characterized by an activated WHR signature and express
the IGS. In addition, a signi¿cant association was found between the
IBC signature and the Nottingham Prognostic Grade (p<0.0001). Using
a conditional backward Cox regression analysis, the IBC signature was
identi¿ed as the most predictive signature with respect to relapse free
survival (Exp(B)=1.539, C.I. = 1.140 – 2.077, p=0.005).
Discussion. Our data demonstrate that nIBC breast tumours having
an “IBC-like” phenotype have a signi¿cantly reduced relapse free
survival interval. Remarkably, within this data set, our IBC signature
seems to outperform other known classi¿ers with prognostic relevance.
Nevertheless, it is important to stress that all signatures are strongly
associated, with respect to prognosis. Hence, it can be argued that each
signature reÀects a common set of phenotypic traits, associated with
1050
Plasma and serum levels of tissue inhibitor of
metalloproteinases-1 are associated with prognosis in nodenegative breast cancer – a prospective study.
Würtz SØ, Møller S, Mouridsen H, Hertel PB, Friis E, Brünner N.
University of Copenhagen, Frederiksberg, Denmark; Rigshospitalet,
Copenhagen, Denmark
The tumor tissue level of TIMP-1 has recently been suggested to be
a new prognostic marker in breast cancer. The purpose of this study
S58
was to investigate whether TIMP-1 also carries prognostic information
when measured in blood as this is a much more preferable material
compared with tumor tissue extracts. Therefore, using ELISA, TIMP1 was measured in prospectively collected pre-operative plasma and
serum samples from 519 patients with primary breast cancer and the
measurements were related to patient outcome. The median age of the
patients was 58 years (range 38-80 years) and the median follow up
time was 1043 days (range 300-1630 days). The results showed that
plasma and serum measurements correlated signi¿cantly with each
other with a Pearson correlation coef¿cient of 0.75 (p <0.0001). For
univariate survival analysis, patients were divided into four groups
according to increasing TIMP-1 levels (Q1-Q4) where Q1 was the
group with the lowest levels. Analysis of all patients showed that high
TIMP-1 plasma levels were signi¿cantly associated with a shorter
disease free survival (p = 0.0159). Sub-group analysis showed that
plasma TIMP-1 signi¿cantly predicted prognosis in the node-negative
group of patients (p = 0.0181) but not in node-positive patients.
Importantly, plasma TIMP-1 was even able to further stratify low-risk
node negative patients (p = 0.0019). High serum TIMP-1 levels were
associated with a shorter disease free survival however the association
was not statistically signi¿cant. In contrast, serum TIMP-1 signi¿cantly
predicted the prognosis in the group of node-negative (p = 0.0347) and
low-risk (p = 0.0204) patients. In multivariate survival analysis of node
negative patients including all the classical prognostic parameters,
plasma TIMP-1 remained signi¿cantly associated with prognosis
when comparing Q1 with Q2 (Hazard ratio = 5.671, p = 0.026) and
Q4 (Hazard ratio = 7.054, p = 0.012). Serum TIMP-1 only remained
signi¿cant when comparing Q1 with Q4 (Hazard ratio = 4.757, p
= 0.0200). Taken together, this study is to our knowledge the ¿rst
large prospective study suggesting that TIMP-1 carries independent
prognostic information when measured in blood, especially plasma.
This was especially true in the node-negative group of patients and
even in patients already de¿ned as low-risk patients using the currently
available prognostic parameters.
1051
1RQSURSRUWLRQDOEUHDVWFDQFHUPRUWDOLW\SDWWHUQVDFFRUGLQJ
WRH[SUHVVLRQRIWKH+(5SURWHLQ using the residual tissue
repository of the National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER) program.
Anderson WF, Luo S, Chatterjee N, Rosenberg PS, Goodman MT,
Hernandez BY, Reichman M, Dolled-Filhart MM, O’Regan RM, Perou
CM, Jatoi I, Cartun RW, Sherman ME. National Cancer Institute,
Rockville, MD; University of Hawaii, Honolulu, HI; Hartford Hospital,
Hartford, CT; Emory University, Atlanta, GA; University of North
Carolina, Chapel Hill, NC; HistoRx, New Haven, CT; National Naval
Medical Center, Bethesda, MD
%DFNJURXQG Overexpression of the HER2 protein is evident in
approximately 20% of all breast cancers. Although generally associated
with excess recurrence and death, the time-dependent prognosis
according to HER2 expression has never been fully elucidated.
0DWHULDOV: In 2001, the NCI’s Surveillance, Epidemiology, and End
Results program supplemented Tumor Registries in Hawaii, Iowa,
and Los Angeles to collect tissue blocks from pathology laboratories
within their catchment areas, linked to SEER’s main database. We
performed immunostains for HER2 (Dako polyclonal, 1:1000) using
tissue microarrays (TMAs) of incident invasive breast cancers prepared
from cases in the Hawaii Tumor Registry (HTR), diagnosed in 1995 and
followed through 2006. HER2+ was de¿ned as 3+ intensity staining in
>20-30% of tumor cells.
5HVXOWV: The TMAs contained 354 breast cancer cases, representing
51% of corresponding cases in the 1995 HTR. TMAs and HTR cases
were similar with respect to age-at-diagnosis, size, grade, histology,
stage, and estrogen receptor. HER2+ was detected in 12% of 350 cases
with evaluable tissue cores. HER2+ was associated with younger agesat-diagnosis, positive nodes (39%), and negative estrogen receptors
(68%). HER2+ actuarial survival declined rapidly for 38 months then
plateaued near 75%, with no subsequent breast cancer deaths. HER2+
hazard rates peaked near 8% per year, 2 years following diagnosis
then declined.
&RQFOXVLRQ: We assessed the time-dependent risk of breast cancer
death in patients who were diagnosed with HER2+ tumors, prior to
the availability of adjuvant trastuzumab. Trastuzumab naïve HER2+
breast cancer mortality was non-proportional, showing short-term
excess hazard and long-term event free survival.
1052
Reassigned to 3113
1053
Patterns of metastatic spread in triple negative breast
cancer.
Dent R, Trudeau M, Sun P, Narod S. Sunnybrook Health Sciences
Center, Toronto, ON, Canada; Women’s College Hospital, University
of Toronto, Toronto, ON, Canada
Background and Purpose: It is widely recognized that triple-negative
breast cancers (de¿ned as those that are estrogen receptor-negative,
progesterone receptor-negative and HER2neu-negative) have a poorer
prognosis than other subtypes of breast cancer. However, the pattern
of disease spread is not well established.
Methods: We studied a cohort of 1601 patients with breast cancer,
diagnosed between January 1987 and December 1997 at Women’s
College Hospital in Toronto. Triple-negative breast cancers were de¿ned
as those that were estrogen receptor-negative, progesterone receptornegative and HER2neu-negative. We set out to determine the temporal
distribution and pattern of metastatic spread in triple negative breast
cancers versus other breast cancers.
Results: The median follow-up time of the 1601 women was 8.1
years. 180 of 1601 patients (11.2%) had triple-negative breast cancer.
Compared to other women with breast cancer, those with triple-negative
breast cancer had an increased likelihood of distant recurrence (hazard
ratio (HR) 2.6; 95 % CI: 2.0 - 3.5, p<0.0001) and death (HR 3.2; 95 %
CI: 2.3 - 4.5; p<0.001) within ¿ve years of diagnosis. The probability
of developing visceral metastases was signi¿cantly higher among
women with triple-negative breast cancers compared to other women
with breast cancer (p< 0.0001; see ¿gure 1). However, there was no
difference in developing bone metastases between the two groups (p=
0.6). Visceral metastases occurred early in the follow-up of women
with triple-negative breast cancer with no visceral metastases occurring
after eight years of follow-up. Compared to other women with breast
cancer, those with triple-negative breast cancer were also more likely
to present with visceral metastases (vs. bone metastases) as their ¿rst
site of metastatic spread (81 vs. 50%, p = 0.0003).
Conclusions: There is a predominance towards visceral metastases in
women with triple-negative breast cancer suggesting that these tumors
possess a distinct mechanism of metastatic spread. The pathways driving
these tumors are still poorly understood; however the development of
targeted therapies could result in better outcomes for these patients.
S59
1055
Impact of hormone replacement therapy on breast cancer:
Women’s Healthy Eating and Living (WHEL) study
experience.
1054
E-cadherin levels may predeict outcome in inÀammatory
Levine PH, Ganesan C, Young HA, Portera C, Yang S, Swain SM.
The George Washington University Medical Center, Washington, DC;
National Cancer Institute, Bethesda, MD; Washington Hospital Center,
Washington, DC
Background: IBC is the most aggressive and lethal form of breast
cancer. One of the most common biomarkers implicated in IBC is
e-cadherin overexpression in the tumor cells. In our earlier study of
tumor markers in IBC (Portera et al, SABCS 2006) mean e-cadherin
expression was higher in IBC patients than controls but there was
wide individual variation. In this report we describe the relationship
of clinical parameters to e-cadherin levels.
Materials and Methods: The e-cadherin in all 48 IBC Registry patients
with pathologic con¿rmation (involvement of the dermal lymphatics)
that were part of our earlier study were analyzed by our earlier criteria
as high (>/=1.03, n=29) or low (n=19) levels. Their responsiveness
to chemotherapy was assessed based on the presence of pathological
evidence of residual tumor at mastectomy and both patient’s and the
oncologist’s assessment of the clinical response to chemotherapy. The
responses were broadly divided into excellent/good, partial, and none/
poor responses. Comparative analysis also included Her2neu, ER, PR
status, progression-free survival (PFS) and overall survival (OS), stage
at diagnosis and presence of metastasis.
Results: All patients in the low e-cadherin expression category
had either an excellent /good response to chemotherapy or a partial
response. In the high level category 3 had no response and none had an
excellent response to chemotherapy. Patients with higher levels were
more likely to present with metastatic disease (62% vs 31%) and be
Her2/neu positive (72% vs 21%, p=.0002). 17% of the patients in the
high category presented with Stage 4 disease vs. 5% in the low category.
No difference was seen regarding ER/PR receptors. Mean PFS was 842
for the high and 1424 for the low group (p=0.93, NS).but there was no
apparent difference in OS.
Discussion: The results of this study suggest that e-cadherin
overexpression is associated with increased aggressiveness of
pathologically con¿rmed IBC. It is speculated that the increased
adhesiveness of the cells facilitates the establishment of
microemboli.
Parker BA, Flatt SW, Mortimer JA, Natarajan L, Gold EB, Bardwell
WA, Jones LA, Hollenbach KA, Pierce JP. University of California, San
Diego, La Jolla, CA; University of California, Davis, Davis, CA; The
University of Texas, Houston, TX
Prior hormone replacement therapy (HRT) has been associated with
an increased incidence of breast cancer. Conflicting information
exists regarding the impact of prior HRT on subsequent breast cancer
development. We utilized data from the Women’s Healthy Eating and
Living (WHEL) Study to determine the natural history of breast cancer
in women who reported HRT prior to their diagnosis of breast cancer.
Our aim was to determine the features of breast cancer, the severity
of vasomotor symptoms, and the disease-free survival in women with
breast cancer and reported prior HRT as compared with no reported
prior HRT. The WHEL Study is a multi-institutional randomized trial
of dietary change to a diet high in vegetables and fruits in Stage IIIIA breast cancer patients within 4 years of diagnosis. Baseline data
regarding tumor characteristics, demographics, and the Thoughts and
Feelings questionnaire regarding vasomotor symptoms were analyzed.
A total of 1544 patients randomized to the non-intervention group
were included in this analysis. We used bivariate statistics to assess the
association of reported prior HRT with covariates, logistic regression to
analyze tumor histology, and a proportional hazards model for diseasefree survival. A total of 706 patients reported prior HRT including 453
who received combined estrogen and progesterone HRT for a mean of
6.8 years and 216 women with estrogen alone HRT for a mean of 9.3
years. The results of our analysis indicate that patients reporting prior
HRT as compared with no prior HRT were older (mean 57 versus 48
years), had a higher incidence of lobular cancer (10.2 % versus 6.2%),
had lower grade tumors (18.4% Grade 1 versus 13.6%), were more
likely to report hot Àashes (74.9% versus 60.6%), were more likely
to report night sweats (58.3% versus 48.0%), were more likely have
ER+PR+ tumors (63.6% versus 59.3%), and had a greater likelihood
of being disease-free at 7.3 years follow-up (84.7% versus 81.3% as
of June 1, 2006). In multivariate models, reported prior HRT weakly
predicted lobular histology of the original primary tumor (OR = 1.53,
95% CI = 0.99 – 2.36) but did not predict disease-free survival (HR
0.78, 95% CI = 0.58-1.06). However, the signi¿cant predictive effect
on disease-free survival of low tumor stage, low tumor grade and
presence of hot Àashes remained. These results add to reports suggesting
that prior HRT is associated with an increased incidence of lobular
histology at diagnosis. In our study, prognosis was similar regardless
of prior reported HRT.
1056
Survival outcomes in pregnancy-associated breast cancer.
Ali A, Wang Y, Kelly J, Falk J, Sehgal R, Vogel V. University of
Pittsburgh Medical Centre, Pittsburgh, PA; University of Pittsburgh,
Pittsburgh, PA
Introduction: Pregnancy-associated breast cancer (PABC) has been
de¿ned as breast cancer diagnosed during pregnancy or within one
year of delivery. It is currently believed that after adjusting for age
and stage, the 5-year survival rates are the same in both pregnant and
non-pregnant women. Methods: We conducted a retrospective casecontrol study among patients treated at our institution between 1990
and 2005 to compare the ¿ve-year survival outcomes for PABC with
women treated for breast cancer but not pregnant. Women were matched
for age and stage of breast cancer at diagnosis. Overall survival (OS)
and disease-free survival (DFS) were estimated by the Kaplan-Meier
method, and log rank tests were used to assess the associations between
OS, DFS and pregnancy status, HER2 status, ER/PR status and family
history. Multivariate Cox regression was used to assess the association
between OS, DFS and pregnancy status after adjusting for age, stage,
family history, ER/PR status, radiotherapy and chemotherapy. Results:
Forty women treated for PABC were compared with forty age- and
stage–matched, non-pregnant controls. The median age was 33 yrs
(range 24-42) for both PABC and non-pregnant groups. Five had stage
S60
I, 27 had stage II, 6 had stage III and 2 had stage IV disease in the PABC
group, while 5 had stage I, 27 had stage II, 7 had stage III and 1 had stage
IV disease for non-pregnant group. Twenty- three (57.5%) patients in
the PABC group had a family history of breast cancer in a ¿rst-degree
relative compared to 17 (42.5 %) in the non-pregnant group. Twentytwo (55%) patients with PABC were ER/PR receptor positive compared
with 20 (50%) for the controls. Of the 11 women with known positive
HER2/neu status, 4 belonged to the PABC group while 7 were not
pregnant. 90% of patients with PABC received chemotherapy compared
with 87.5% in the non-pregnant group. 91.5% of patients with PABC
had breast-conserving surgery and 8.5% had mastectomies compared
to 86 % and 14%, respectively, for the non-pregnant group. The median
overall survival was 4.9 years in the PABC group compared to 6 years
for the controls (p = 0.02). The median disease-free survival was 2.7
years for the PABC group compared with 5.1 years for the controls (p =
0.01). The most common site of relapse was bone for the PABC group
(27%) and local recurrence (33%) for the controls. In the univariate
analysis, OS and DFS were signi¿cantly associated with pregnancy
status, family history, ER/PR status, age and stage. After adjusting for
age and disease stage, PABC patients had higher risk of both death (p
= 0.01) and recurrence (p = 0.02) compared to non-pregnant controls.
Conclusion: Women with PABC had signi¿cantly shorter overall
survival and shorter disease-free survival compared with non-pregnant
age- and stage-matched controls.
1057
Clinicopathological and prognostic relevance of uptake
level revealed by 18F-Àuorodeoxyglucose positron emission
tomography/computed tomography fusion imaging (18FFDG PET/CT) in primary breast cancer.
Ueda S, Tsuda H, Asakawa H, Omata J, Fukatsu K. National Defense
Medical College, Tokorozawa, Saitama, Japan
385326( Integrated 18F-Àuorodeoxyglucose positron emission
tomography/computed tomography fusion imaging (18F-FDG PET/
CT) can visualize anatomical localizations of hypermetabolic cancer
lesions more accurately than 18F-FDG PET alone. In this study, the
clinicopathological and prognostic signi¿cance of 18F-FDG PET/CT
was evaluated in patients with primary breast cancer.
0(7+2'6 Clinicopathological correlation with the maximum
Standard Uptake Value in 60 min (SUV) obtained by preoperative 18FFDG PET/CT was examined in 162 patients with primary breast cancer.
The prognostic implications of the SUV were simulated by means of
the software program Adjuvant! in 146 (90%) patients with invasive
ductal carcinoma (IDC).
RESULTS: High SUV detected by 18F-FDG PET/CT was signi¿cantly
correlated with the size of the invasive component (2 cm<) (p<0.0001),
higher nuclear grade (p<0.0001), nuclear atypia (p<0.0001), mitosis
count (p<0.0001), negative hormone receptor status (p=0.001), high
c-erbB-2 expression (p=0.006), lymph node metastasis (p=0.002), and
IDC in comparision with invasive lobular carcinoma (p=0.004). The
prognostic impact of SUV in 146 IDCs was explored for six tentative
SUV thresholds: 2.0, 3.0, 3.5, 4.0, 4.5, and 5.0. Tumors with high
SUV showed poorer relapse and mortality rates than those with low
SUV, and SUV 4.0 was the most discriminable cut-off value (t=-5.99
and p<0.0001).
&21&/86,216 High uptake of 18F-FDG is predictive of aggressive
features of cancer cells and poor prognosis in patients with primary
breast cancer. 18F-FDG PET/CT could be a useful tool for pretreatment
prediction of the biological characteristics and baseline risk of breast
cancer.
1058
Prognostic differences of WHO-assessed mitotic activity
index (MAI) and mitotic impression by quick scanning
in invasive ductal breast cancer patients under 55 years
of age.
Skaland I, van Diest PJ, Janssen EAM, Gudlaugsson E, Søiland H, Baak
JPA. Stavanger University Hospital, Stavanger, Norway; University
Medical Center, Utrecht, Netherlands; University of Bergen, Bergen,
Norway; Free University, Amsterdam, Netherlands
Background: The proliferation marker mitotic activity index (MAI) is
the strongest prognostic/predictive indicator in node-negative (LN-)
breast cancer (1, 2). The World Health Organization (WHO) 2003
de¿ned procedure for determining MAI (WHO-MAI) is often replaced
by a quick-scan mitotic impression (MIMP).
Material and Methods: We evaluated the prognostic consequences of
this practice in 433 LN- invasive ductal type breast cancers with longterm follow up (median 112 months, range 12-187 months).
Results: Twenty-seven percent of the studied cases developed distant
metastases, and 25% died of disease. Agreement between WHO-MAI
(0-5=1, 6-10=2, >10=3) and MIMP (1, 2, 3) categories was 66%
(kappa=0.41), including 85% for category 1, 26% for category 2, and
52% for category 3. The WHO-MAI was a much stronger prognosticator
than the MIMP (Figure 1), and the 10-year survival rates of the same
categories (e.g., MAI and MIMP category both 2) differed greatly
(Table 1). When grade was assessed by combining WHO-MAI or MIMP
with the same values for tubular formation and nuclear atypia, grades
disagreed in 18% of the cases.
Discussion: Deviation from the formal WHO-MAI assessment
guidelines in breast cancer often results in erroneous prognosis
estimations with therapeutic consequences and may explain why the
prognostic value of proliferative activity in breast cancer is not always
con¿rmed.
References
1. Baak JP, van Diest PJ, Voorhorst FJ, et al: Prospective multicenter
validation of the independent prognostic value of the mitotic activity
index in lymph node-negative breast cancer patients younger than 55
years. J Clin Oncol 2005; 23(25):5993-6001.
2. Janssen EA, van Diest PJ, Soiland H et al. Success predictors of
adjuvant chemotherapy in node-negative breast cancer patients under
55 years. Cell Oncol. 2006;28(5-6):295-303.
Figure 1. Comparison of the signi¿cance of no probability in predicting
recurrence free survival by the MAI, the grade based on MAI, the
quick-scan derived MIMP, and the grade based on MIMP. MAI, mitotic
activity index; MIMP, mitotic impression.
S61
1060
The prognostic signi¿cance of human epidermal growth
factor receptor-2 over-expression for the development of
local recurrence after newly diagnosed breast cancer.
1059
Complementary and alternative therapies among long-term
breast cancer survivors.
Carpenter CL, Ganz PA, Bernstein L. Keck School of Medicine at
USC, Los Angeles, CA; David Geffen School of Medicine at UCLA,
Los Angeles, CA
Background: Increasing numbers of healthy adults are using
complementary and alternative medicine (CAM), in conjunction with
or instead of usual medical care. Breast cancer patients may be more or
less likely to use CAM than healthy adults. That is, breast cancer patients
may be more compliant with conventional treatment and less likely to
use CAM if they fear their cancer is worsening. On the other hand, breast
cancer patients may turn to CAM because conventional therapies are not
working. We conducted a descriptive study that examined the qualityof-life (QOL) of long-term breast cancer survivors, in relationship to
potential associations with CAM and other psychosocial, lifestyle,
behavioral and medical characteristics, to determine whether CAM
users had different patterns of association than non-CAM users.
Materials and Methods: We conducted a follow-up telephone interview
with breast cancer case patients from a population-based epidemiological
case-control study of breast cancer in young women in Los Angeles
County, California, that had survived at least 10 years. Three hundred
seventy four (374) were interviewed about surgical and reconstructive
history, disease-related and lifestyle factors, weight and exercise history.
CAM usage was measured by summarizing a list of 28 commonly used
herbal or alternative remedies. QOL was measured using the Medical
Outcomes Study Short Form 36 questionnaire (SF-36).
Results: CAM users in our study population were over-represented
(59%) in comparison to nationwide population estimates for women
using a similar CAM de¿nition (39%). Age, MET-hours of exercise
after diagnosis, extent of original disease, prevalence of smoking,
body-mass index, alcohol consumption, and fear of recurrence were
similar, on the average, for CAM users compared to non-CAM users.
Evaluating SF-36 sub-scores, CAM users had signi¿cantly lower scores
on emotional well-being (p = 0.01), and had signi¿cant emotional role
limitations (p = 0.06) compared to non-CAM users. Physical functioning
sub-scale scores did not differ.
Discussion: Moderate differences in emotional functioning among
breast cancer survivors may exist between CAM users and non-CAM
users.
Gabos Z, Thoms J, Hanson J, Ghosh S, Deschenes J, Mackey J,
Abdulkarim B. Cross Cancer Institute, Edmonton, AB, Canada;
University of Alberta, Edmonton, AB, Canada
Background: Human epidermal growth factor receptor-2 (Her-2) overexpression occurs in 20-30% of invasive breast cancer and results in
aggressive disease and high-risk of recurrence. The impact of Her-2
over-expression on the risk of local recurrence is unclear.
Objectives: In this population-based study, we have investigated the
incidence of local recurrence in newly diagnosed breast cancer patients
with Her-2 over-expression.
Methods: Newly diagnosed breast cancer patients between 01/1998
and 12/2003 with uniform Her-2 testing were identi¿ed from a cancer
registry. A total of 460 Her-2 over-expressing patients were reviewed.
A random sample of 500 patients with Her-2 negative disease was also
reviewed. Patients were excluded if there was a breast cancer diagnosed
before 01/ 1998 or other cancer. A total of 266 Her-2 positive and 338
Her-2 negative patients were included for this analysis. The groups were
strati¿ed based on surgical treatment, lumpectomy versus mastectomy.
The association between histological features and local recurrence was
evaluated with univariate and multivariate analyses.
Results: In patients treated by lumpectomy, Her-2 over-expression was
the only factor to be associated with increased risk of local recurrence,
on both univariate and multivariate analysis, hazard ratio 7.4 (95%
CI, 1.6-33.9, p=0.01). In patients treated by mastectomy it was not
associated with increased risk of local recurrence.
Conclusions: In our population-based study, Her-2/neu over-expression
is signi¿cantly associated with increased risk of local recurrence in
newly diagnosed breast cancer patients treated by lumpectomy. In
patients treated by mastectomy, Her-2 over-expression is not associated
with an increased risk of local recurrence.
1061
Do grade I breast cancers require follow-up after breast
conserving treatment?
Hamed H, Jones G, Allen D, Kontos M. Guy’s Hospital, London,
United Kingdom
INTRODUCTION
An increasing number of institutions are abandoning routine follow up
after breast conserving treatment (BCT) for early breast cancer. However
there is growing body of evidence indicating that breast cancer is not a
single disease with some types having a more “benign” course present
minor clinical problems following treatment. The discontinuation of
follow up of all breast cancer patients regardless of cancer subtypes
could potentially lead to delayed in diagnosis of recurrence especially
among the cases with the more “aggressive” tumors.
The aim of this study is to investigate the rate of the recurrences of
grade I breast cancers, which conventionally are regarded as the more
“benign” ones and to compare it to the other grades’ in an attempt to
customize follow-up strategies.
PATIENTS AND METHODS
Breast cancer patients who had Breast conserving treatment (BCT)
between the years 1990 and 1997 and followed up at Guy’s Hospital,
Breast Unit formed the basis for this study. Cases were identi¿ed from
the Patient Electronic Database. They were divided into 3 groups
based on the histological grade (I, II or III). Patients that presented
with a loco-regional relapse and contralateral disease for each group
were identi¿ed. Recurrence rates were calculated and statistically
compared. Correlation between the exact location of recurrence
(ipsilateral or contralateral breast, axilla, supraclavicular fossa or skin),
the mammographic positivity, method of detection (recurrence detected
by the patient, the doctor or the mammogram) and node positivity were
studied for each group.
RESULTS
Six hundred and ¿fty patients received BCT during the study period. Of
those 115 were grade I, 279 grade II and 256 grade III. Median follow
S62
up was 115 months (range 2-196 months). Loco-regional recurrences
were diagnosed in 3 cases (2.6%), 45 cases (16.1%) and 41 cases (16%)
in grade I, II, III respectively. The difference between grades I and II
and between grades I and III was statistically signi¿cant (p=0.000191
and 0,000221 respectively).
The location (ipsi, contra, axilla etc) of the recurrence, the
mammographic positivity, the method of detection of recurrence were
analyzed. In multivariate analysis tumor grade was an independent
risk factor.
The 3 relapses in the grade I group occurred at year 9 (2 of the 3 had
one axillary node involved in metastatic disease at the time of primary
diagnosis and treatment) and were n the breast parenchyma and were
seen on mammography.
CONCLUSION
Patients treated with BCT for grade I breast cancer present very low
risk of loco-regional recurrence or contralateral disease. Relapses were
con¿ned to breast parenchymal with no evidence of local regional
disease. The data from this study suggest that patients who presented
with grade I breast cancer and treated with BCT can be safely discharged
after completion of their treatment to The national mammographic
screening program.
1062
Prognostic factors for BRCA1/2-associated familial breast
cancer from Russian population.
Lyubchenko LN, Pospechova NI, Lushnikova AA, Portnoy SM, Bryuzgin
VV, Karpukhin AV, Garkavtseva RPh. N.Blokhin Cancer Res., Center
RAMS, Moscow, Russian Federation; Research Center for Medical
Genetics, Moscow, Russian Federation
Background: It has been demonstrated that cancer arising in carriers of
mutation in BRCA1/2 genes differs from sporadic breast cancer (BC)
of age-matched control. We have screened the patients from cancer
genetics registry of N.Blokhin Cancer Res.Center, Moscow for germline
mutations in BRCA1/2 genes to prove this observation. Materials and
Methods: DNA samples from 250 breast and/or ovarian cancer patients
with strong cancer history were studied using PCR, CSGE and direct
sequencing. Mouse mammary tumor virus (MMTV)-homologous
sequences were analyzed by lymphocyte and BC tissue DNA sample
PCR using primers for gp52- coding area of the env MMTV gene, Sagcoding area of 3’LTR and sequencing. Multivariant analysis includes 64
cases of BRCA1-linked BC. Control group consisted of 117 patients with
sporadic BC selected on the basis of age and disease stage. A mean age
was 39 years old in cancer patients group and 41 years old – in control
group. A mean menarche age was 13.3 years old in BRCA carriers and
13.7 years old in sporadic cancer patients. Results: 94(33.2%) BRCA1/2
mutations carriers have been detected. High frequency of the mutation
5382insC (76.4% of all revealed mutations) was shown. In 8 (12.2%)
BC patients with pathological BRCA genotype BC developed during
pregnancy. Histopathological characteristics of BRCA-associated BC
were the following: (1) in¿ltrated ductal carcinoma - 89.8%/87.7%;
(2) high grade – 58.2%/29.2%; (3) prominent lymphocyte in¿ltrate
– 60.2%/34.5%; (4) negative estrogen receptors – 77.6%/38.8%; (5)
complete clinical response to primary chemotherapy (anthracyclinbased treatment) followed by surgical treatment – 98.1%/38.2%,
compared with the control group (p<0.05). MMTV-related sequences
with 92-95% homology with MMTV (C3H, GR strains) were revealed
by speci¿c PCR in 38% of sporadic BC patients (n=180), in 52%
of familial BC patients (n=84) and in 57-60% BC patients during
pregnancy and lactation (n=65). MMTV- related exogenous retroviral
infection might be considered as BC risk factor, especially in familial
BC and BC during pregnancy or lactation.
1063
Restrati¿cation of the Nottingham prognostic index using
carcinoembroinic antigen cell adhesion molecule 6.
Maraqa L, Cummings M, Peter MB, Hanby AM, Shaaban AM, Horgan
K, Speirs V. St James’s University Hospital, Leeds, West Yorkshire,
United Kingdom; Leeds General In¿rmary, Leeds, West Yorkshire,
United Kingdom
Introduction: Carcinoembryonic Antigen Cell Adhesion Molecule
(CEACAM) 6 is a marker of aggressive disease in colonic, pancreatic
and other carcinomas. Its role in human breast cancer, however,
remains poorly understood. Previous work in our laboratory indicated
that CEACAM 6 was signi¿cantly up-regulated in tamoxifen-resistant
MCF-7 derivatives compared to sensitive controls. The aim of this
study was to retrospectively test its prognostic signi¿cance in a cohort
of breast cancers with long term follow up.
Methods: CEACAM 6 immunohistochemistry was performed on tissue
microarrays comprising 108 primary breast cancers which subsequently
relapsed following adjuvant endocrine therapy and 243 non-relapsed
controls. Mean age at diagnosis was 58.1 years (SD 13.9) with follow
up time of 81.5 months (range 1 – 229 months, SD 43.1). CEACAM
6 staining was scored based on the proportion of positive cells and
intensity of membranous, cytoplasmic and combined global staining.
A maximum score of 3 indicated strong staining in ≥10% of cells. After
case dichotomisation using ROC curves, CEACAM 6 was incorporated
into an outcome predictor model using Cox regression analysis.
Results: Of patients who subsequently developed a recurrence, 35/108
(33.3%) demonstrated moderate to strong membranous CEACAM
staining. This was signi¿cantly higher than the control group, 32/243
(13.2%), OR = 3.16 (95% CI 1.83 to 5.47, p < 0.0001). Although tumour
size, grade, lymph node positivity, HER-2 expression and cytoplasmic
and global CEACAM expression were signi¿cant on univariate analysis,
only the Nottingham Prognostic Index (NPI), PR and membranous
CEACAM 6 remained sigini¿cant on multivariate analysis. Using
our outcome predictor model, patients were strati¿ed into either low
or high risk groups with no intermediate categories. This performed
better than NPI alone. Moreover, it successfully restrati¿ed the NPI
intermediate risk group into higher or lower risk categories. Using this
model, 10-year Disease Free Survival was 39% for higher risk patients
versus 73% if lower risk, log rank p < 0.001.
Conclusion: Our ¿ndings strongly support the importance of CEACAM
6 as a prognostic model. Its signi¿cance lies in re-categorisation
of patients in the intermediate NPI group, potentially facilitating
chemotherapy decisions.
S63
Conclusion
Our results show that the 70-gene signature outperforms other
prognostic factors in selecting a low risk group that has a 10-year
survival of > 90%. After validation in an independent sample series
the prognostic value of the 70-gene signature in patients with 1-3
positive nodes will be prospectively validated in the MINDACT trial.
Incorporation of the 70-gene signature in clinical decision-making for
patients with 1-3 positive nodes may lead to reconsider the need of
adjuvant chemotherapy.
1065
Quantitative justi¿cation of the change from 10% to 30%
for HER-2 scoring in the ASCO-CAP guidelines: tumor
heterogeneity in breast cancer and its prognostic and
predictive implications.
1064
The Amsterdam 70-gene signature predicts outcome in
breast cancer patients with 1-3 positive axillary lymph
nodes.
Mook S, Rutgers EJT, Peterse JL, Nuyten DSA, Horlings H, van de
Vijver MJ, van ‘t Veer LJ. Netherlands Cancer Institute, Amsterdam,
Netherlands
Introduction
The axillary lymph node status is considered to be the most powerful
prognostic factor for operable breast cancer, with a direct relationship
between number of positive nodes and disease outcome. However,
approximately 30% of lymph node-positive patients will remain free of
distant metastases without adjuvant chemotherapy. Identifying patients
with lymph node-positive disease who are at low risk of recurrence
might lead to changes in guidelines for adjuvant chemotherapy. The aim
of this study was to identify a low risk group with an excellent disease
outcome in breast cancer patients with 1-3 positive lymph nodes, using
the 70-gene signature (MammaPrint®).
Methods
One-hundred-six patients with 1-3 positive lymph nodes were separately
selected from the previous described series of 295 patients (Van de
Vijver et al. NEJM 2002). Patients were diagnosed between 1984 and
1995 at the Netherlands Cancer Institute, and under the age of 53 at
diagnosis. Tumors were primary invasive breast carcinomas less than
5 cm, treated by modi¿ed radical mastectomy or breast-conserving
therapy, including dissection of the axillary lymph nodes. Eightytwo percent received adjuvant systemic treatment, consisting of
chemotherapy (59,4%), hormonal therapy (12,3%) or a combination
(10,4%). Gene expression signatures had been obtained previously;
clinical follow-up data were updated.
Results
Of the 106 patients 18 developed distant metastasis, and 88 were free
of disease at a median follow-up of 10.3 years. The median time to
distant metastasis was 2.8 years. Using the 70-gene signature 43 patients
were classi¿ed as having a good-prognosis signature, while 63 patients
were classi¿ed as having a poor-prognosis signature. At 10 years, the
probability of remaining free of distant metastases and overall survival
was 94% (SE 4%) and 97% (SE 3%) in patients with a good-prognosis
signature versus 66% (SE 7%) and 62% (SE 7%) in those with a poorprognosis signature, respectively. The estimated hazard ratio (HR) for
overall survival in the poor-prognosis signature group as compared
with the good-prognosis signature group was 7.0 (95% CI 2.1-23.3).
When adjusted for clinicopathological prognostic factors, the 70-gene
signature was the strongest predictor with an estimated HR for overall
survival of 4.2 (95% CI 1.0-17.7). Other independent prognostic factors
were angioinvasion and adjuvant systemic therapy with hazard ratios of
2.7 (95% CI 1.1-6.7) and 0.3 (95% CI 0.1-0.8) respectively.
Moeder CB, Giltnane JM, Harigopal M, Molinaro A, Robinson A,
Gelmon K, Huntsman D, Camp RL, Rimm DL. Yale University School
of Medicine, New Haven, CT; British Columbia Cancer Agency,
Vancouver, BC, Canada
Purpose:
The variability in scoring of immunohistochemistry(IHC), whether due
to true heterogeneity or artifacts in preparation, has led to decreased
reliability in companion diagnostics and the recommendation for new
standards (eg the ASCO-CAP guidelines for HER-2 testing). The basis
of this problem is the amount of tissue required to be representative of
an entire tumor. Since protein expression on tissue microarrays(TMAs)
can be rigorously measured, and one 0.6mm spot is equivalent to 2-3
high power ¿elds, we used TMAs assess levels of heterogeneity and to
determine optimal representation as a function of outcome.
Patients and Methods:
We analyzed estrogen receptor (ER), progesterone receptor (PR)
and HER-2 expression quantitatively using AQUA® on a series of
5 separate tissue microarrays made from a retrospective cohort from
Yale New Haven Hospital of nearly 700 breast cancer cases with
known outcome. We assessed heterogeneity for each of the markers
by comparing the unique array spots using linear regression analysis.
A minimum, average, and maximum score was generated for each set
that was then assessed for prognostic value. A similar analysis was
done on a 152 case retrospective trastuzumab treated cohort (metastatic
breast cancer) collected at the British Columbia Cancer Agency with
RESIST-based outcome.
Results:
Each marker shows some heterogeneity, but average r values between
0.7 and 0.8 are seen between TMA spots. Analysis for prognostic value
shows that a high maximum score (of 5 spots) is the most prognostic for
ER, while a high minimum score is most prognostic for poor outcome
for HER-2. A high minimum HER-2 score was also most predictive of
response in the trastuzumab treated cohort.
Conclusions:
These results suggest that representivity required for each biomarker
may be a function of its role in tumorigenesis. Furthermore, these results
provide scienti¿c basis for the ASCO-CAP guidelines for assessment
of HER-2 expression, but perhaps suggest that the 30% ¿gure is still
too conservative.
1066
HER2 status adds prognostic, but not tamoxifen treatment
predictive, information in hormone receptor positive
premenopausal primary breast cancer.
Rydén L, Fernö M, Stål O, Landberg G, Bendahl P-O. Clinical Science,
Lund, Lund, Sweden; Biomedicine and Surgery, Linköping, Sweden;
Laboratory Medicin, Malmö University Hospital, Malmö, Sweden
Background: Overexpression of human epidermal growth factor
(HER2) or ampli¿cation of its gene is a prognostic tumour marker in
primary breast cancer considered a predictor for tamoxifen treatment
ef¿ciency in oestrogen receptor (ER) positive disease. In the present
study we used a de¿ned cohort of breast cancer patients in order to
assess prognostic and tamoxifen treatment information yielded by
S64
HER2 status.
Methods: Premenopausal breast cancer patients with stage II tumours
(n=564) randomised to two years of adjuvant tamoxifen treatment
versus no treatment with long-term follow-up data were included.
ER and progesterone receptor (PR) status and HER2 status was
determined by immunohistochemistry using a tissue microarray.
HER2 ampli¿cation was analysed by Àuorescense in situ hybrydisation
(FISH) and tumours being ampli¿ed and/ or HER2 3+ were considered
HER2 positive.
Result: HER2 status was evaluable in 83% of the patients and 12.6%
were HER2 positive. In the control arm, HER2 positivity was a
prognostic factor in ER+ patients, HR 2.95; 95% CI 1.61-5.38, p<0.001,
but not in ER- patients, HR 0.67; 0.28-1.61, p=0.4, and a prognostic
interaction between the two markers p=0.008 was found. Two years
of adjuvant tamoxifen was bene¿cial in the ER + and HER2- cohort
(n=275), (HR 0.64; 95% CI 0.44-0.93, p=0.02), whereas no signi¿cant
effect by tamoxifen was seen in the ER+ and HER2+ cohort (n=24),
(HR 0.71; 95%CI 0.23-2.20, p=0.6). However, when the treatment
effect was explored using a multivariate interaction model including
HER2-status and treatment, there was no statistically difference in
tamoxifen treatment ef¿ciency according to HER2 status (term of
interaction, p=0.95).
Discussion: HER2 positive and hormone receptor positive breast
cancer constitutes a small subgroup of tumours with poor prognosis in
premenopausal breast cancer deserving to be identi¿ed in the clinical
setting in order to optimise adjuvant treatment options. In this study,
no tamoxifen treatment interaction was found for HER2 status in ER+
tumours. The strong prognostic interaction between HER2 and ER
should be taken into account when interpreting HER2 data in nonrandomised trials of adjuvant tamoxifen.
Figure 1. Comparison of the overall long follow-up survival associated
with MAI in patients with (a) tumours <1 cm diameter (all grades), (b)
1–2 cm, grades 1+2
1067
Prospective prognostic value of proliferation in small, lowgrade, lymph-node negative breast cancers.
Baak JPA, Van Diest PJ, Janssen EAM, Voorhorst F, and Other MMMCP
Collaborators. Stavanger University Hospital, Stavanger, Norway;
The Gade Institute, University of Bergen, Bergen, Norway; University
Medical Center, Utrecht, Netherlands; Free University Medical Center,
Amsterdam, Netherlands
Background: The proliferation factor Mitotic Activity Index (MAI) is
the strongest prognosticator in lymph-node negative invasive breast
cancer patients under age 71, and predictor of successfulness of systemic
adjuvant chemotherapy in node negative women under 55 years1,2. The
question remains, however, whether this also holds for tumors <1 cm
in diameter, in tumors ≥1 and <2 cm and grades 1+2, and tumors ≥2
and <3 cm) < 3 cm and, grades 1+2.
Materials and methods: Multicenter prospective survival analysis of the
prognostic value in a cohort of 853 long-term follow-up patients under
71 years of MAI and other prognosticators for distant recurrence-free
survival (RFS) and overall cancer-related survival (OS) of grade, MAI
The median follow-up was 116 (8-187) months.
Results: In all tumors <1 cm, all grades (n=84), and in tumors 1 to
3 cm and grades 1+2 (n=300), multivariate comparison revealed the
prognostic superiority of MAI for RFS and OS in all tumors <2cm
(Figure 1). Other features (grade, ER, diameter, age) did not enhance
its prognostic value. In tumors 2-3cm diameter, ER has additional
prognostic value but only if MAI<10.
Discussion: In patients <71 years with node negative invasive breast
cancer, the proliferation factor MAI ≥10 is the strongest prognosticator
in identifying high-risk patients in all small, grade 1+2 tumors (survival
53-57%) which should be considered for adjuvant systemic therapy,
even for tumors <1 cm in diameter.
References:
1. Baak JP, van Diest PJ, Voorhorst FJ, et al: Prospective multicenter
validation of the independent prognostic value of the mitotic activity
index in lymph node-negative breast cancer patients younger than 55
years. J Clin Oncol 2005; 23(25):5993-6001.
2. Janssen EA, van Diest PJ, Soiland H, Gudlaugson E, Nysted A,
Voorhorst FJ,
Vermorken JB, Soreide JA, Baak JP. Success predictors of adjuvant
chemotherapy in node-negative breast cancer patients under 55 years.
Cell Oncol. 2006;28(5-6):295-303.
1068
Identi¿cation of IGFBP4 as a marker of tamoxifen failure
in primary breast cancer.
Hadad SM, Robertson KE, Baker L, Bray SE, Purdie CA, Jordan L,
Vendrell JA, Cohen PA, Thompson AM. Ninewells Hospital and Medical
School, Dundee, United Kingdom; Universite Lyon, Lyon, France
Background: Insulin-like growth factor binding protein 4 (IGFBP4) is
an insulin-like growth factor (IGF) inhibitor. It is down-regulated in
tamoxifen-resistant cell lines and it may have a role in protecting cells
from over stimulation by IGFs. Using cDNA microarray, RTQ-PCR and
Immunohistochemistry (IHC) on tissue microarrays (TMA), ERα and
IGFBP4 were among the genes down-regulated and were associated
with clinical development of tamoxifen resistance. The aim of this study
was to test this hypothesis on a larger scale of patients.
Materials and Methods: IHC performed on TMAs of 117 tamoxifentreated breast cancer patients (104 ductal cancers) from a single
recruiting centre of the National Cancer Research Institute (NCRI)
Adjuvant Breast Cancer (ABC) clinical trial. Patients aged 34-76 years
(mean 51). Antibodies to ERα, IGFBP4, BCL2, c-Fos, and c-MET were
used and scored using quick-score method (scores 0-3). Patterns of
protein expression were compared with previously tested Ki67, Her2
and clinical data including minimum 5 years follow up.
Results: ERα and IGFBP4 found under-expressed in 43/115 (37.4%)
and 38/102 (37.2%) of the cases respectively. As expected, 5-year
disease-free survival was 68.9% for ER- patients compared to 91.7%
for ER+ patients (Log Rank Test; p=0.001; DF=1). Under-expression
of IGFBP4 (scores 0-1) was strongly associated with ER- tumours
(Fisher’s exact test; p=0.000) and was associated with earlier death
(Wilcoxon method; p=0.015; DF=1). We have also demonstrated a
negative correlation between IGFBP4 and Ki67 (Fisher’s exact test;
p=0.002), Her2 (Fisher’s exact test; p=0.026), axillary node status
(Fisher’s exact test; p=0.038) and histological grade (Fisher’s exact
test; p=0.002).
Conclusion: IGFBP4 under-expression is a marker of poor prognosis
and tamoxifen failure in patients receiving adjuvant tamoxifen.
1069
Genomic copy number alterations as predictive markers of
systemic recurrence in breast cancer.
Hwang K-T, Han W, Lee JW, Cho J, Ko E, Kim EK, Jung S-Y, Jeong
E-M, Kang JJ, Yang S-J, Kim S-W, Noh D-Y. Seoul National University
Boramae Hospital, Seoul, Republic of Korea; College of Medicine,
Seoul National University, Seoul, Republic of Korea; Cancer Research
Institute, College of Medicine, Seoul National University, Seoul,
Republic of Korea; Macrogen, Inc., Seoul, Republic of Korea
We tried to ¿nd novel predictive markers of systemic breast cancer
recurrence by array comparative genomic hybridization (CGH).
We performed array CGH with 4,044 human bacterial artificial
chromosome clones to assess copy number changes in 31 pairs of
clinicohistologically well matched recurred / nonrecurred fresh-frozen
breast cancer tissues. We selected those clones that hit the conditions
of frequency criteria (more than 10%), consecutive clones (more than
2 clones), chi square test (p<0.05), multiple comparison test (adjusted
p<0.05), and Kaplan-Meier test (p<0.05).
Eleven clones in gain and 3 clones in loss were selected to be the
candidate clones. The most signi¿cant chromosomal alterations were
found in the region of 5p15.33, 11q13.3, 15q26.3, 17q25.3, 18q23,
21q22.3 in gain, and 9p12, 11q24.1, 14q32.33 in loss. Especially, the
loss of 14q32.33 region was associated with good disease free survival
(p=.022) and overall survival (p=.019). We selected 4 candidate genes
in gain and 6 candidate genes in loss.
Our array CGH analysis could detect novel candidate clones and genes
for predictive markers of systemic breast cancer recurrence.
Table 1. Clinicopathological characteristics
Recurrence
Characteristics
group (31) N (%)
Age (range)
44 (32-67)
T stage
T1
4 (12.9)
T2
24 (77.4)
T3
2 (6.5)
T4
1 (3.2)
N stage
N0
9 (32.2)
N1
7 (19.4)
N2
4 (12.9)
N3
11 (35.5)
Hormonal receptor Positive
19 (61.3)
Negative
12 (38.7)
c-erbB2
Positive
16 (51.6)
Negative
15 (48.4)
S65
relapse free survival after 2 years. sHER-2/neu was measured using a
standardized ELISA (upper limit of normal 15ng/ml). As the baseline
sHER-2/neu concentrations ranged from 3.8 ng/ml to 14.0 ng/ml, results
were grouped in terciles. Data were analyzed using Kaplan-Meier and
Cox Proportional Hazards survival analysis.
Results: Material was available from 80 patients in leuprorelin arm and
53 patients in CMF arm. 65 of 133 patients had relapsed during the
follow-up time of up 7 years after treatment. The median RFS was 62.9
mo. The RFS time depended on the concentrations of sHER-2/neu at
baseline: RFS was signi¿cantly shorter in patients of the third tercile
with sHER-2/neu levels >8.8 ng/ml than in patients of the ¿rst tercile
with levels <7.2 ng/ml (p=0.0232). Five years after initial therapy, we
found that 73% of patients in the ¿rst tercile group of baseline sHER2/neu had no relapse. In the second tercile, 63.3% of patients were
relapse-free, while in the third tercile only 47.2% of patients had not
suffered a relapse.
Conclusions: Increased sHER-2/neu concentrations at the beginning of
adjuvant therapy in the TABLE-Study have a prognostic importance
for RFS. This observation was evaluated irrespective of the HER-2/neu
tissue status and could be of clinically importance for adjuvant therapy
with the monoclonal anti-HER-2/neu antibody trastuzumab or other
anti-HER-2/neu targeted therapies.
Non-recurrence
group (31) N (%)
46 (31-65)
4 (12.9)
23 (74.2)
3 (9.6)
1 (3.2)
9 (32.2)
7 (19.4)
4 (12.9)
11 (35.5)
19 (61.3)
12 (38.7)
16 (51.6)
15 (48.4)
Table 2. Candidate clones and chromosomal alteration regions
Clone
Cytoband
X2 test
FDR*
DFS†
5262
5p15.33
0.011
0.003
0.0108
2312
5p15.33
0.022
0.006
0.0256
124
11q13.3
0.034
0.007
0.0141
2776
15q26.3
0.009
0.010
0.0300
2547
17q25.3
0.034
0.012
0.0402
5883
18q23
0.003
0.015
0.0101
5877
18q23
0.013
0.022
0.0178
5516
18q23
0.005
0.022
0.0091
641
21q22.3
0.006
0.032
0.0159
2806
21q22.3
0.005
0.034
0.0156
5856
21q22.3
0.020
0.043
0.0325
1000
11q24.1
0.010
0.011
0.020
710
14q32.33
0.021
0.024
0.022
4688
9p12
0.023
0.026
0.039
*False Discovery Rate; †Disease Free Survival
1070
Prognostic value of the shed antigen of HER-2/neu in
premenopausal breast cancer patients in the TABLEstudy.
Lueftner DI, Pechlivanis K, Geppert R, Possinger K. Charite Campus
Mitte, Berlin, Germany
Background: Increased serum HER-2/neu (sHER-2/neu) concentrations
at the beginning of adjuvant breast cancer therapy have been shown to
be of prognostic importance. Using the sera from the Takeda® Adjuvant
Breast Cancer Study with Leuprorelin (TABLE), we tested for the
prognostic value of sHER-2/neu.
Material and Methods: A total of 133 premenopausal, node-positive,
hormone-receptor positive patients received either 11.25 mg of
leuprorelin s.c. every 3 months over 2 years or CMF chemotherapy for
6 cycles. Blood samples were collected at baseline and at 3, 6, 12, 18,
24 and 30 mo. The primary endpoint of the study was to determine the
1071
Down regulation of ()(03 is associated with unfavourable
prognosis in sporadic breast cancer patients.
Ramser J, Harbeck N, Sadr-Nabavi A, Naehrig J, Busch R, KiechleBahat M, Meindl A. Tech. University, Munich, Germany
Background: EFEMP1 belongs to the ¿bulin gene family, a newly
characterized family of extracellular matrix proteins that are localized
at basement membranes, stroma and ECM ¿bres. Recently, EFEMP1
was described to be an angiogenesis antagonist and to act as a suppressor
of formation and progression of human malignancies.
Materials and Methods: Immunohistochemistry on tissue microarrays of
203 clinically well characterized primary breast carcinomas, was used
to assess the potential clinical relevance of reduced EFEMP1 protein
expression regarding patient outcome. Cox regression for multivariate
survival modelling as well as univariate analyses were performed.
Next to immune reactivity score for EFEMP1 expression, tumor grade,
hormone receptor-, lymph node- and Her-2 status, tumor size, and type
of adjuvant systemic therapy were included into analysis.
Results: Analysis of the total cohort (n=203: 17 N0, 186 N+) revealed
no signi¿cant impact of EFEMP1 expression on patient outcome.
However, in the 186 node-positive cases, multivariate regression
analysis revealed that next to tumor size and grade, EFEMP1 expression
remained in the survival model as a relevant factor inÀuencing disease
free and overall survival at borderline signi¿cance (DFS: p=0.14; OS:
p=0.077). We further investigated the relevance of EFEMP1 expression
in subgroups with homogeneous adjuvant systemic therapy. Signi¿cant
correlations of low EFEMP1 expression with poor DFS (p=0.037)
and OS (p=0.032) were only seen in those node-positive patients with
adjuvant anthracycline-containing chemotherapy (n=31) but not in
those treated by either CMF (n=49) (DFS: p=0.605; OS: p=0.934) or
S66
adjuvant endocrine therapy (tamoxifen) alone (n=106) (DFS: p=0.735;
OS: p=0.275). Median DFS in anthracycline-treated patients was > 10
years if tumors showed high EFEMP1 expression, compared to only
3.1 years with low EFEMP1 expression. Similarly, median OS was >
10 years when tumors had high EFEMP1 expression in contrast to 4.5
years associated with low EFEMP1 expression.
Discussion: In a substantial cohort of 203 primary breast cancer cases
we found that next to tumor size and grade, low EFEMP1 expression
was associated with poor patient outcome in node-positive patients.
Univariate analysis displayed signi¿cant correlations only in nodepositive patients with anthracycline-containing chemotherapy. In
our retrospective cohort, patients with anthracycline-containing
chemotherapy were also those patients with a clinically perceived
high risk of relapse. Thus, at present we cannot distinguish a potential
predictive impact of EFEMP1 expression with regard to response to
anthracycline chemotherapy from a merely prognostic impact with
regard to survival of high risk breast cancer patients. However, keeping
the biological role of EFEMP1 in mind, it is not unreasonable to assume
that its anti-angiogenic properties may enhance an anti-angiogenic
chemotherapy effect of anthracyclines.
1072
Cell cycle proteins add independent prognostic information
to Nottingham Prognostic Index (NPI).
Loddo M, Kingsbury S, Sainsbury R. University College London,
United Kingdom
INTRODUCTION: Mitogenic growth signaling leads to passage
through the restriction point, initiation of DNA replication and
ultimately cell division. Proteins critical for progression through the
G1-S and G2-M transitions include the DNA replication licensing
factors (RLFs) which render chromosomal replication origins competent
for DNA synthesis and mitotic kinases which orchestrate passage
through mitosis. Both RLFs and mitotic kinases have been highlighted
as targets for therapeutic intervention, with mitotic kinase inhibitors
already in phase I/II trials. The aim of this study was to investigate
the prognostic value of these cell cycle proteins in the management of
MATERIALS AND METHODS: 182 cases of primary breast cancer
were sectioned and immunohistochemically stained for ER, PR, HER2,
the proliferation marker Ki67, and a selected set of RLFs and mitotic
kinases. Antibodies were either commercially obtained or raised in
house. Follow up data for all patients was available for recurrence (632
years; 3.8 per subject) and survival (684 years; 4.1 per subject) and the
NPI was calculated (0.2x size + grade + nodes).
RESULTS: NPI was signi¿cantly related to both recurrence (HR
[95% CI]: 1.79 [1.46 to 2.20]; P<0.001) and survival (HR: 2.18 [1.63
to 2.93]; P<0.001) in this series. There was a signi¿cant association
between the studied biomarkers and grade and NPI, but not between the
markers and DNA ploidy, nodal status or size. HER2 and ploidy were
not correlated, although increased staining of HER2 was associated
with increasing NPI scores (P=0.014). Importantly, several of the
biomarkers individually added additional information to NPI score
(up to an additional HR of 3.31 [1.57 to 6.97]; P=0.002), allowing
wide separation of the NPI survival curves. Inclusion of one signi¿cant
biomarker is enough to add to the prognostic value of NPI; no further
markers are necessary in adding further prognostic capability.
DISCUSSION: The G1-S and G2-M transitions of the cell cycle act
as relay stations for growth regulatory signaling pathways. NPI is one
prognostic tool in common use but is relatively crude. A variety of
additional parameters to render it more sensitive have been proposed,
but few have stood the test of time. Several of the studied cell cycle
biomarkers are strongly associated with recurrence and remain
statistically signi¿cant after adjusting for NPI, so that they are predictive
independent of NPI. This type of biomarker analysis could also be used
as a predictive test for mitotic kinase inhibitors and may help decide
which patients would bene¿t most from this new treatment option.
1073
The prognostic signi¿cance of androgen receptor expression
in breast cancer.
Peter M, Maraqa L, Horgan K, Speirs V, Shaaban A. University of
Leeds, Leeds, W Yorks, United Kingdom; Leeds General In¿rmary,
Leeds, W Yorks, United Kingdom
Androgens have been hypothesised to inÀuence risk of breast cancer
but the precise role of the androgen receptor (AR) as a prognostic factor
in breast cancer is still unclear. The aim of this study was to determine
the prognostic signi¿cance of AR in a large cohort of breast carcinomas
with long term follow up.
Four hundred and eight cases of invasive breast cancer were
incorporated into tissue microarrays (TMAs) retrospectively selected
from 1993-1997. Mean age at diagnosis was 58.4 (± 14.5) with an
average follow-up period of 91.9 months (± 42.21). Two hundred
and sixty patients had Tamoxifen therapy and 60 patients relapsed
after endocrine treatment. TMA sections were stained with a speci¿c
monoclonal antibody for AR and scored as continuous variables and
using the Allred score. Results were then correlated with patient and
histopathological variables including overall survival (OS), disease free
survival (DFS), relapse on Tamoxifen, Nottingham Prognostic Index
(NPI), estrogen receptor α (ERα) and progesterone receptor (PR).
Nuclear expression of AR signi¿cantly correlated with age, grade,
recurrence, distant metastasis, death, ERα and PR. AR expression,
calculated using the Allred Score or as a continuous variable
respectively correlated with better OS (p=0.0098, p=0.04), DFS
(p=0.0096, p=0.0028) using cut off values of 3(Allred) and 10% positive
cells (continuous). In the cohort of patients on Tamoxifen therapy, AR
expression was additionally associated with a reduced risk of recurrence
after endocrine therapy (Allred: p=0.0021, continuous: p=0.0017).
This study suggests that AR expression may have a role in stratifying
patients for treatment alongside the conventional prognostic variables
of NPI, node positivity, ERα and PR. Measurement of AR in clinical
practice could also be used to predict the likelihood of recurrence whilst
on adjuvant endocrine therapy.
1074
Comparative analysis of uPA/PAI-1 in core biopsies versus
surgical breast cancer samples.
Vetter M, Lantzsch T, Abraha-Späth RS, Olenik C, Thomssen C, Dittmer
J. Martin-Luther University, Halle/Saale, Germany; St. Elisabeth &
St. Barbara Hospital, Halle/Saale, Germany; University Hospital
Eppendorf, Hamburg, Germany; American Diagnostica GmbH,
Pfungstadt, Germany
Background: It has been estimated that 70% of the patients with breast
cancer without axillary node involvement would survive 10 years after
surgery without additional systemic adjuvant therapy. Nevertheless, all
of these patients usually get chemotherapy. To avoid this unnecessary
therapy, additional biological markers can be assessed. The invasion
protein uPA (urokinase-type plasminogen activator) and its inhibitor
PAI-1 are well established markers for this purpose. Originally, 300
mg of surgically removed tissue was used to determine the level of
these proteins by ELISA. Nowadays, patients are often core needle
biopsied which may remove much of the tumor tissue leaving little for
uPA/PAI-1 measurement. In addition, these presurgical manipulations
may change gene expression pattern in the remaining tissue. Hence,
we explored the possibility to use core biopsies as a alternative source
for uPA/PAI-1 measurement.
Design: Fresh frozen material of 2-3 core needle biopsies and the
corresponding surgically removed tumor material were collected,
snap frozen on liquid nitrogen and analyzed for the uPA/PAI-1 status
by ELISA. Only those areas in the remaining tumor were selected that
were not close to the side of a core needle insertion. In three different
sets, each with tumors from 30 patients, uPA/PAI-1 values in core
biopsies were compared to values in remaining tumor. In the ¿rst set,
core biopsies were taken ex vivo, in the second set, core biopsies were
taken in vivo, but not examined by pathologist for tumor content and
in a third set in vivo core biopsies were examined by a pathologist
and only parts of the biopsies that were proven to contain tumor cells
were used.
Results and Conclusion: In all sets of experiments, uPA and PAI1 levels in core biopsies signi¿cantly correlated with those in the
corresponding surgical samples. The calculated negative predictive
values for uPA were as followed: 1.00 for set 1; 0.84 for set 2 and 0.85
for set 3. The appropriate npv for PAI-1 are 0.83, 0.74 und 0.77. Hence,
core biopsies can be suggested as an alternative source to measure
uPA/PAI-1 levels.
1075
Risk of dementia in older breast cancer survivors:
a population-based cohort study of the effect of
chemotherapy.
Baxter NN, Durham SB, Phillips K-A, Virnig EA, Virnig BA. University
of Toronto, Toronto, ON, Canada; University of Minnesota, Minneapolis,
MN; Peter MacCallum Cancer Centre, Melbourne, Australia
Background: An association between adjuvant chemotherapy for breast
cancer and cognitive impairment in young women has been found in
some studies; however these studies included few older women and the
effect of chemotherapy on development of dementia in older survivors
has not been evaluated.
Methods: We conducted a retrospective cohort study using Surveillance,
Epidemiology, and End Results cancer registry data linked to Medicare
claims data to determine if there is a signi¿cant association between
adjuvant chemotherapy and development of dementia in women over
age 66 with breast cancer in the United States who did not have a
previous dementia diagnosis. Women age 66 to 80 diagnosed with
non-metastatic invasive breast cancer from 1991 through 1999 were
included. We determined whether patients had undergone chemotherapy
within 6 months of diagnosis using standard ICD-9 and CPT codes.
We evaluated the effect of chemotherapy on the diagnosis of dementia,
adjusting for potential confounders using a proportional hazards model.
We strati¿ed our analysis for age at diagnosis (66-70, 71-75, 76-80)
Results: 18931 women met our study selection criteria, 2823 were
exposed to chemotherapy, 16108 were not. Women in the exposed
group were younger than in the unexposed group (mean = 70 vs.
73 years) (p<0.001) justifying a strati¿ed analysis. Mean follow-up
time for the entire cohort was 62.4 months. Dementia developed in
4.9% (936) women - 2.7% of exposed women (n=76) and 5.3% of
unexposed women (n=860). Within the ¿rst 5 years of our study period,
the cumulative incidence of dementia was as follows: of women age
66-70, 2.1% in the exposed group vs. 1.6% in the unexposed group;
of women age 71-75, 2.6% vs. 4.4%; and of women age 76-80, 6.8%
vs. 9.3% (Figure). In our proportional hazards model, after controlling
for other factors, we did not ¿nd a signi¿cant association between
receipt of chemotherapy and development of dementia. In fact, while
not statistically signi¿cant, all models suggest that women receiving
chemotherapy were less likely to develop dementia. Only an elevated
comorbidity index was consistently associated with development of
dementia across age strata.
Conclusions: Receipt of chemotherapy in older women with breast
cancer is not associated with an increased risk of diagnosis of
dementia over time; however in this age group, women who undergo
chemotherapy may be at lower baseline risk of cognitive impairment.
S67
1076
Final results of the AGO breast cancer study group
MAMMA-3 trial: ¿rst-line capecitabine + paclitaxel vs
epirubicin + paclitaxel for high-risk metastatic breast
cancer.
Lück H-J, du Bois A, Schrader I, Huober J, Heilmann V, Fasching
PA, Stähle A, Jackisch C, Marth C, Richter B, von Minckwitz
G. HSK, Klinik für Gynäkologie und Gynäkologische Onkolgie,
Wiesbaden, Germany; Henriettenstiftung, Frauenklinik, Hannover,
Germany; Universitäts-Frauenklinik Tübingen, Tübingen, Germany;
Universitäts-Frauenklinik and Poliklinik Ulm, Ulm, Germany;
Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Germany; St.
Vincentius-Krankenhäuser, Frauenklinik, Karlsruhe, Germany; Klinik
für Gynäkologie und Geburtshilfe Klinikum Offenbach, Offenbach,
Germany; Universitätsklinik für Frauenheilkunde Innsbruck, Innsbruck,
Austria; Elbland-Kliniken Meiβen-Radebeul, Standort Radebeul,
Frauenklinik, Radebeul, Germany; Zentrum Frauenheilkunde und
Geburtshilfe, Frankfurt, Germany
Background: Anthracycline/taxane combinations are now standard
adjuvant chemotherapy for early breast cancer, and are highly effective
for high-risk metastatic breast cancer (MBC). Addition of capecitabine
(X) to docetaxel signi¿cantly improves overall survival (OS) in MBC.
Phase II studies of X + paclitaxel (XP) show high ef¿cacy and good
tolerability. Therefore we performed a randomized, phase III trial of
XP vs epirubicin + paclitaxel (EP).
Methods: The primary objective was to demonstrate non-inferior
progression-free survival (PFS) with XP vs EP. Secondary endpoints
were OS, response rate (RR; RECIST), safety (NCI CTC v2.0) and
QoL (EORTC C30 and BR23). Female MBC patients (pts) aged 18-75
years with no prior chemotherapy for MBC were randomized to six
21-day cycles of either XP (X 1,000 mg/m2 bid, d1-14; P 175 mg/m2
d1) or EP (E 60 mg/m2; P 175 mg/m2, both on d1).
Results: Accrual of 340 pts (170 per arm) completed in April 2005.
Median age was 55 years (XP) and 56 years (EP). Most patients were
anthracycline-naive (81% and 80%, respectively). Visceral metastases
were present in 56% and 47%, respectively. In both arms, a median of
6 cycles were delivered. Median doses delivered per cycle were: P 175
mg/m2 (both arms), E 60 mg/m2, X 926 mg/m2 bid. After 9.9 months’
median follow-up, PFS and OS were not signi¿cantly different (Table).
The most frequent grade 3/4 toxicities were neutropenia (XP: 38% of
pts; EP: 52%) and leukopenia (XP: 12%; EP: 41%). Grade 3 hand-foot
syndrome occurred in 12% of XP pts (absent with EP) and grade 3/4
diarrhea in 5% vs <1%, respectively. Rates of grade 3/4 cardiotoxicity
were 1% with XP vs 2% with EP.
Conclusions: The primary endpoint, to show that XP is non-inferior
to EP, was met. XP is well tolerated compared with other nonanthracycline-containing combination regimens, and is a valid and
active ¿rst-line treatment option for patients with high-risk MBC. Final
ef¿cacy results (due July 2007) and QoL data will be presented.
Median PFS, months (95% CI)
Median OS, months (95% CI)
Overall RR
Complete response
Partial response
Stable disease
XP
12.0
(10.2-13.9)
25.6
(20.1-28.0)
52%
7%
45%
35%
EP
11.1
(7.7-14.4)
24.0
(18.0-30.1)
51%
8%
43%
37%
S68
1077
Combined trastuzumab (HER)/docetaxel (TAX) versus
sequential trastuzumab followed by docetaxel at progression
as ¿rst line chemotherapy for Her2-positive metastatic
breast cancer: preliminary results (multicenter BOOGstudy; 2002-02).
Hamberg P, Bontenbal M, Vernhout RM, Bos MM, Braun HJ, Erdkamp
F, Stouthard JML, van Deijk GA, Schmitz PIM, Seynaeve C, Klijn JGM.
Erasmus University Medical Center, Daniel den Hoed Cancer Center,
Rotterdam, Netherlands; Reinier de Graaf Hospital, Delft, Netherlands;
Vlietland Hospital, Vlaardingen, Netherlands; Maasland Hospital,
Sittard, Netherlands; Haga Hospital, Den Haag, Netherlands; Medical
Center Rijnmond-Zuid, Rotterdam, Netherlands; Erasmus University
Medical Center, Rotterdam, Netherlands
Background
Trastuzumab (HER) in combination with chemotherapy (CT) is superior
over CT alone in Her2 positive metastatic breast cancer (MBC). At this
moment, it is not yet clear what the outcome is of sequential treatment
with HER followed by CT. The HERTAX study is a randomized
multicenter phase II study designed to determine progression free
survival (PFS) of the combination of HER and docetaxel (TAX) (arm
A) versus sequential therapy of HER followed by TAX at progression
(arm B).
Methods
Patients with HER2-positive MBC, eligible for ¿rst line CT, were
randomized in a 1:1 fashion. Adjuvant non-taxane containing CT
was allowed, previous HER therapy not. Treatment A consisted of:
weekly HER (2 mg/kg, after a loading dose of 4 mg/kg), combined
with TAX 100 mg/m2 every three weeks until progression. Patients in
arm B were treated with HER monotherapy at the same schedule, and
upon progression with TAX (100mg/m2, q 3 weeks). Current analysis
is performed on the time from date of ¿rst administration until date of
¿rst progression, by using the log-rank test.
Results
A total of 98 patients were randomized, ef¿cacy data are currently
available on 89 patients. Patient characteristics are: median age 51
years (range 32-74 years), prior adjuvant CT administered in 58%,
and adjuvant endocrine treatment in 30% without major differences
between treatment arms. The median PFS signi¿cantly differed between
the combination regimen and monotherapy HER, being 9.1 months
and 4.0 months, respectively (p = 0.004). Data regarding the complete
sequential treatment are in the process of analysis.
Two deaths occurred during study treatment both in arm A, caused by
pneumonia and neutropenic fever/diarrhea. In arm A, 25 serious adverse
events (SAE’s) occurred (including the two deaths), mainly consisting
of neutropenic fever (n=14) and fever/infection without neutropenia
(n=7). 4 SAE’s were noticed in arm B, being allergic reactions (n=2),
pulmonary embolism (n=1) and syncope (n=1). No statistical difference
in cardiac toxicity (measured by a LVEF decline below 50%) was
observed between the treatment arms (13% and 7% in arm A and B,
respectively; p=0.34).
Conclusion
Combination therapy with HER/TAX results in a signi¿cantly longer
PFS as compared to HER monotherapy, at the cost of more severe
toxicity. Whether the shorter PFS during monotherapy HER will extend
beyond the PFS on combined HER/TAX after complete sequential
therapy (accompanied by less toxicity) is being analyzed. These data
will be available at the meeting.
1078
Phase III study of gemcitabine plus docetaxel versus
capecitabine plus docetaxel for anthracycline-pretreated
metastatic breast cancer patients: survival results.
Chan S, Romieu G, Huober J, Tubiana-Hulin M, Schneeweiss A, Lluch
A, Llombart A, du Bois A, Carrasco E, Thareau Vaury A, Fumoleau
P. Nottingham City Hospital, Nottingham, United Kingdom; CRLC
Val d’Aurelle, Montpellier Cedex 5, France; University of Tuebingen,
Tuebingen, Germany; Centre Rene Huguenin, Saint Cloud, France;
University of Heidelberg, Heidelberg, Germany; Hospital Clinico
de Valencia, Valencia, Spain; Hospital Arnau de Villanova, Lerida,
Spain; Dr. Horst-Schmidt-Klinik, Wiesbaden, Germany; Eli Lilly Spain,
Madrid, Spain; Eli Lilly France, Suresnes Cedex, France; Centre
Georges-Francois Leclerc, Dijon, France
Background:
Patients (Pts) pre-treated with anthracyclines frequently receive
combination chemotherapy with a taxane and an antimetabolite like
gemcitabine or capecitabine in metastatic setting. This phase III study
directly compared gemcitabine plus docetaxel (GD) combination
with capecitabine plus docetaxel (CD), in pts with metastatic breast
cancer (MBC). Primary objective was progression-free survival
(PFS), and secondary objectives included overall response rate (ORR),
time to treatment failure (TtTF), overall survival (OS), and toxicity
assessments. In a previous analysis GD demonstrated similar ef¿cacy
to CD but with a better non-hematological toxicity pro¿le [Chan et al,
ASCO-2005]. This report presents the ¿nal OS analysis
Pts with histologically/cytologically con¿rmed MBC who had received
anthracycline-based regimen either in neoadjuvant, adjuvant, or ¿rstline metastatic setting, were randomized to GD (G=1000 mg/m2 d1,8;
D=75 mg/m2 d1) or CD (C=2500 mg/m2 d1-14; D=75 mg/m2 d1) q21
days.
Results:
Characteristics of the 305 included patients (GD=153; CD= 152)
were previously reported. A median of 6 cycles was delivered on both
arms. CTC grade 3/4 hematologic toxicity was similar in both arms,
except for grade 3/4 thrombocytopenia GD=11%; CD=3%; p=0.014).
Nonhematologic toxicities were low in both arms, but signi¿cantly
different grade 3/4 toxicities were more pronounced in CD arm; diarrhea
(GD=8%; CD=18%; p=0.0088), mucositis (GD=4%; CD=15%;
p=0.0008), and hand-foot syndrome (GD=0%; CD=26%; p<0.0001).
13% of pts stopped therapy due to adverse event on GD vs 30% on CD.
Best overall response rates in both arms were 32% (p=0.93). Median
PFS (with 1% of patients censored in GD and 7% in CD) was 8.05
months (95% CI 6.60-8.71) on GD arm, and 7.98 (95% CI 6.93-8.77)
on CD arm (log-rank p=0.121). Of notice when interpreting this data,
11% in GD arm vs 26% in CD arm received additional chemotherapy
before progression. With a median follow-up of 19.2 months, and 23%
of patients censored, the median overall survival was 19.29 months
(95% CI 15.57-23.59) on GD arm, and 21. 45 (95% CI 17.12-24.94)
on CD arm (log-rank p=0.983).
Conclusion: These data suggest that the two regimens are also
comparable in OS; however a more favorable toxicity pro¿le on GD
arm may be a determining factor in selecting a better treatment option.
Exploratory sub-group ef¿cacy analysis results will be presented at
the meeting.
1079
Analysis of chemotherapy-induced amenorrhea by three
different chemotherapy regimens in premenopausal women
with early breast cancer.
Han HS, Lee KS, Kim SY, Ro J. National Cancer Center, Goyang-si,
Korea
Background: Although the incidence or implication of chemotherapyinduced amenorrhea (CIA) have been studied more recently, the data on
CIA are inadequate with newer regimens. The objective of this analysis
was to evaluate CIA in premenopausal women with early breast cancer
on three different preoperative or adjuvant chemotherapy regimens.
Methods: We conducted a retrospective cohort study on a phase III
trial at the National Cancer Center, Korea involving node positive
S69
breast cancer patients who were randomized to receive preoperative
doxorubicin⁄cyclophosphamide (AC) versus docetaxel/capecitabine
(TX), then postoperatively crossed over to the other therapy (n = 96).
For the comparison, we reviewed the medical records of premenopausal
early breast cancer patients receiving adjuvant AC followed by
paclitaxel (T) (n = 26) or 5-Àuorouracil/doxorubicin/cyclophosphamide
(FAC) (n = 96).
Results: Between 3/2002 and 7/2005, total 218 patients who took one
of above three regimens were analyzed for the data. There were 115
patients ≥ 40 years and 103 patients <40 years with a median age of 41
years (range, 21 to 49) and a median follow-up of 40 months (range, 8
to 60). The distribution of age, body mass index, use of tamoxifen were
well balanced in each chemotherapy regimen. CIA rates were 97%, 96%
and 91% by AC/TX, AC followed by T and FAC, respectively at the 6th
month (p=0.169) and 94%, 89% and 81% by AC/TX, AC followed by T
and FAC, respectively at the 12th month (p=0.035), which decreased to
70%, 65% and 72% by AC/TX, AC followed by T and FAC, respectively
by the 24th month (p=0.789). More than 60% of patients were still
amenorrheic at the end of 3 years. Age (p<0.0001), tamoxifen (p=0.011)
and chemotherapy regimen (p=0.007) were signi¿cant factors for CIA
by multivariate analysis after the initial ¿rst year. Age and tamoxifen
remained signi¿cant variables for CIA after 2 years.
Discussion: The type of chemotherapeutic regimen is a signi¿cant factor
affecting CIA rates by the end of ¿rst year, which however, becomes
insigni¿cant after the second year. More than half of patients continue
to be amenorrheic even after 3-4 years by these chemotherapeutic
regimens. The persistent signi¿cant predictors of CIA are age and
tamoxifen. Supported by NCC Grant 0610240-2.
1080
A descriptive study of pharmacokinetic alterations of
epirubicin as a function of body size.
Madarnas Y, Clemons M, Walker S, McLean H, Nakatsu K, Sawka
C. Queen’s University; ; University of Toronto; Cancer Centre of
Southeastern Ontario; Toronto-Sunnybrook Regional Cancer Centre;
Princess Margaret Hospital
Background: Obesity (Ob) prevalent among women with breast cancer
(BC) and is known to adversely affect BC outcomes. We postulate that
Ob contributes to suboptimal chemotherapy (CT) dosing as a result of
associated physiologic changes affecting the pharmacokinetics (PK)
and pharmacodynamics (PD) of antineoplastic drugs. Alterations in
the disposition of many drugs in Ob have been described, but few
publications speci¿cally address PK alterations of antineoplastic
agents in the setting of Ob. Methods: This is a descriptive PK study
in women with BC spanning a broad range of body size who received
BSA-dosed epirubicin (E)-based CT at two institutions. A total of 56
women were enrolled providing 8 samples each (pre/post infusion, at
1, 2, 4, 24, 48 and 72 hrs post E infusion). Serum concentrations of
E were determined and for each patient and standard PK parameters
were derived. Body mass index (BMI) and body surface area (BSA)
were derived from recorded height and weight. The relationship
between the different pharmacokinetic parameters and body size was
then examined. Results: Median BMI was 25.15kg/m2 and median
BSA was 1.72m2. We observed substantial interpatient variability in E
concentration at each timepoint. Most women had no measurable E by
24hrs post infusion, and all but one by 48hrs. Observed E half life (t1/2)
was signi¿cantly shorter than that reported in the literature, suggesting
extremely rapid drug elimination. Volume of distribution (Vd) could
not be accurately estimated, but was very large. Body size displayed a
signi¿cant positive linear correlation with area under the concentration
vs time curve (AUC), which was attenuated when E concentration at
1hr was omitted. Graphic relationship of AUC with BMI and BSA is
displayed below. Further analyses with other modeling techniques
are underway to better understand our data and will be presented.
Conclusion: In this group of women, E PK parameters displayed
signi¿cant interpatient variability despite E being dosed on the basis of
BSA; observed t1/2 and Vd differed signi¿cantly from what is reported in
the literature; and AUC increased with increasing body size.
1081
A multicenter, randomized, double-blind, parallelgroup phase II study of ge¿tinib (IRESSA) or placebo
in combination with docetaxel, as ¿rst-line treatment in
Tubiana-Hulin M, Spielmann M, Dieras V, Fumoleau P, Delaloge S,
Mefti F, Girre V. Centre Rene Huguenin, Saint Cloud, France; Institut
Gustave Roussy, Villejuif, France; Institut Curie, Paris, France; Centre
G.F. Leclerc, Dijon, France
Background: This double-blind, placebo-controlled, parallel-group,
Phase II study (1839IL/0148) evaluated docetaxel alone or combined
with ge¿tinib (IRESSA) in patients with untreated metastatic breast
cancer.
Methods: Women (18-70 years) eligible for ¿rst-line chemotherapy
were randomized 2:1 to receive continuous ge¿tinib 250 mg or placebo
orally once daily, plus docetaxel 100 mg/m2 iv every 21 days for up to 8
cycles. Maintenance ge¿tinib/placebo therapy was allowed, concurrent
with hormonal therapy if indicated. Treatment was continued until
disease progression, unacceptable toxicity or withdrawal of consent.
Primary endpoint was objective response rate (ORR, RECIST criteria).
Secondary endpoints were time to progression (TTP), response
duration, overall survival (OS), time-to-treatment failure (TTF), and
pharmacokinetic evaluations. Adverse events (AEs) were assessed by
CTC version 3.0.
Results: 76 patients (median age 56 years [30-70]; PS 0-2; prior
adjuvant anthracycline n=75) received combination therapy (n=50) or
docetaxel monotherapy (n=26). At median time on trial of 172.5 days,
ORR was 46.0% (95% CI 31.8, 60.7) and 53.8% (95% CI 33.4, 73.4),
median TTP was 215 (95% CI 129, 263) and 328 (95% CI 238, 363)
days, response duration was 188 (95% CI 147, 364) and 213 (95% CI
185, 297) days, and TTF was 129 (95% CI 84-188) and 238 (95% CI
180-270) days, for combination and monotherapy, respectively. Median
OS was not reached for combination therapy. Addition of ge¿tinib
to docetaxel had no effect on steady state exposure of docetaxel. No
statistically signi¿cant difference was observed in ge¿tinib responders
in correlation with hormonal status. Grade 3/4 AEs were reported
by 88.0% of combination and 96.2% of monotherapy patients. The
incidence of the following AEs tended to be higher in the combination
arm than in the monotherapy arm: febrile neutropenia (42.0% and
26.9%), diarrhea (66.0% and 38.5%), nausea (54.0% and 34.6%),
S70
vomiting (26.0% and 19.2%), stomatitis (24.0% and 11.5%), rash
(32.0% and 15.4%) and anorexia (18.0% and 3.8%).
Conclusions: In this parallel-group study in metastatic breast cancer,
there appeared to be no bene¿t of adding ge¿tinib to docetaxel.
IRESSA is a trademark of the AstraZeneca group of companies.
1082
VinÀunine in combination with trastuzumab: an active
combination in the treatment of HER2 positive metastatic
breast cancer.
Paridaens R, Wildiers H, Dalenc F, Rixe O, Roche H, Cadic V, Delgado
F-M. UZ Gasthuisberg, Leuven, Belgium; Institut Claudius Regaud,
Toulouse, France; Hopital Pitie-Salpetriere, Paris, France; Institut de
Recherche Pierre Fabre, Boulogne-Billancourt, France
Background
VinÀunine (VFL, JAVLOR®) is a microtubule inhibitor of the vinca
alkaloid class with high activity in several tumour types especially
in second line treatment of metastatic breast cancer (MBC). Overexpression of HER2 is observed in 20-25% of all breast cancers and is
associated with a poor prognosis. Anti-HER2 therapy with trastuzumab
(T) signi¿cantly increases survival in HER2 positive MBC. Both
compounds have single agent activity in MBC, therefore a combination
regimen study was warranted.
Methods
This phase I was designed to determine the recommended dose (RD) of
VFL in combination with T for treatment of ¿rst or second line MBC
patients (pts). Subsequently safety pro¿le (NCI CTC version 2.0) of the
combination together with its antitumour activity were explored.
Results
Thirty pts, median age 55 [33-74] years, WHO performance status
0/1: 18/12 pts, respectively were given VFL 280 mg/m² (9 pts) or
320 mg/m² (21 pts) day 1 every 3 weeks (w) in combination with T
(loading dose 4 mg/kg and subsequently 2 mg/kg/w). Six pts were
chemonaive and ¿ve pts received this combination in second line for
advanced metastatic disease. In the ¿rst step of the study 6 pts were
given VFL 280 mg/m² and none of them experienced dose-limiting
toxicity. The RD was then established at the second VFL dose explored
of 320 mg/m² in the following six pts. Nine pts were given 280 mg/m²
while 21 received 320 mg/m². In both groups, the median number of
VFL administrations per pt was 8. All pts were evaluable for safety.
Grades (G) 3 and 4 haematological toxicities were with VFL 280 and
320 mg/m², respectively: anaemia 0 and 1 pt; neutropenia 4/18 pts,
febrile neutropenia 0/1 pt. Among the 9 pts treated at 280 mg/m², for
a total of 83 cycles, one single G 3 non-haematological adverse event
(AE), sensory neuropathy, was recorded in one pt. Among the 21 pts
who received 320 mg/m², for a total of 204 cycles, G 3 AE (no G 4
recorded) were: constipation, fatigue, myalgia in 5 pts; infection with
neutropenia, abdominal pain in 2 pts; arthralgia, hyponatraemia, ileus
in 1 pt. No signi¿cant cardiac events were observed (based on MUGA
scans done on a regular basis).
An external radiologist reviewed all ¿les and response rates were 66.7%
[95% con¿dence interval (CI): 29.9-92.5] and 76.2% [95% CI: 52.891.8] in pts receiving VFL at 280 mg/m² and 320 mg/m² respectively.
As of today, median progression free survival and duration of response
are not mature.
Conclusions
In MBC, the combination of vinÀunine/trastuzumab resulted in a very
encouraging response rate with an acceptable safety pro¿le. Updated
results of this ongoing trial will be presented at the meeting. A phase III
study comparing VFL + T versus paclitaxel + T has been initiated.
1083
A phase III study on the ef¿cacy and safety of docetaxel,
every three weeks or as a weekly regimen in patients with
Willemse PH, Munck L, Creemers GJ, Graaf H, Smit W, Erjavec Z,
Stouthard JM, Deijk G, Bochove A, Vader W, Westermann AM. UMC,
Groningen, Groningen, Netherlands; Comprehensive Cancer Centre
North-Netherlands, Groningen, Groningen, Netherlands; Catharina
Ziekenhuis, Eindhoven, Brabant, Netherlands; MCL Zuid, Leeuwarden,
Friesland, Netherlands; Medisch Spectrum Twente, Enschede,
Overijssel, Netherlands; Delfzigt Ziekenhuis, Delfzijl, Groningen,
Netherlands; MCR-Zuid, Rotterdam, Zuid-Holland, Netherlands;
HAGA Ziekenhuis-Rode Kruis, Den Haag, Zuid-Holland, Netherlands;
ZaansMC, Zaandam, Noord-Holland, Netherlands; Sano¿-Aventis,
Gouda, Zuid-Holland, Netherlands; AMC, Amsterdam, Noord-Holland,
Netherlands
Introduction. The standard schedule of docetaxel is effective but
weekly administration of docetaxel might have a favourable safety
pro¿le. This randomised phase III study compared two schedules of
docetaxel for anthracycline-resistant metastatic breast cancer (MBC)
for safety pro¿le, ef¿cacy and quality of life.
Methods 162 patients with MBC previously treated with anthracyclins
were randomised to receive either docetaxel 36 mg/m2 weekly for 6
weeks followed by 2 weeks rest (arm A; 3 cycles) or docetaxel 100
mg/m2 every three weeks (arm B 6 cycles). Primary end point: safety
pro¿le. Secondary end points: time to progression (TTP), response rate
(RR), overall survival (OS) and Quality of Life (QoL)
Results. 81/79 patients received treatment: 81 in arm A and 79 in arm
B. In this analysis median follow-up was 15 months. 72/70 patients
were evaluable for safety and QoL, whereas 51/63 patients for response.
More grade 3/4 hematological toxicities were reported for arm B
versus A: 3 % vs. 5% cycles with neutropenia, and 1 vs. 11 admissions
for febrile neutropenia (FN p<.05). Grade 3/4 non- hematological
toxicities were different in cycles of arm A vs. arm B: 2% vs. 5% for
gastro-intestinal toxicities, 15% vs 10% for fatigue, 8% vs. 0% for Àuid
retention (p<.05), 1% vs. 4% for peripheral sensory neuropathy, 0% vs.
5% for stomatits and 12% vs. 2% for skin- and/or nailtoxicity (p<.05).
Treatment was discontinued due to toxicity in 26 (27%) vs. 12 (13%)
patients and completed in 15% vs. 36% of patients treated in arm A
and B respectively (p<.05). QoL scores were not different for patients
in arm A and B at treatment start or after 12 or 24 weeks. There were
no differences between arm A and B in RR, with PD in 63% vs 51%
and median TTP 21.2 vs 21.9 wks. Clinical bene¿t was apparent in
37% vs. 49% of patients while the median duration of 32 and 30 wks
for patients in arm A and B resp.
Conclusion: Although more pts had PD on Arm A, the ef¿cacy of
both docetaxel regimens was comparable in terms of clinical bene¿t,
TTP and OS. Against expectations there was more fatigue, skin + nail
toxicity and Àuid retention in Arm A, but more FN in arm B. Patients
in either arm had comparable QoL scores.
1084
Benchmarking quality oncology care in the community
setting.
Schwartzberg LS, Tauer K, Blakely J, Johnson R, Reed J, Somer B,
Wheeler B, Walker MS, Stepanski EJ, Fortner BV. The West Clinic,
Memphis, TN; Accelerated Community Oncology Research Network,
Memphis, TN
Background: The cancer death rate has been falling since 1991 in part
due to wider access to quality care. Continuing this trend will require
provision of state-of-the-art treatment regimens, and the establishment
of benchmarks of quality cancer care. This preliminary report presents
¿ndings from a pilot project for benchmarking standards of oncology
care among patients (pts) being treated in the community setting.
Method: Retrospective review of electronic or paper medical records
assessed demographic characteristics, and quality indicators selected
for concordance with previous research. These included general
indicators, and guideline-speci¿c use of supportive care, treatment and
surveillance. Eligible pts had stage I – IIIC breast cancer (BrCa), had
≥ one cycle of chemotherapy between July 2004 and 2005, and had ≥
12 weeks of documented follow-up after ¿rst treatment visit.
Results: The sample comprised 102 BrCa pts treated by 10 medical
oncologists across four practice sites. The sample was 54% Caucasian,
35% African American, and 11% other ethnicity. The mean age was
54.6 (range: 34 - 81), and 67% had private insurance. The Table shows
the percentage compliance with key quality indicators.
Quality indicator
General
--Pathology report present in chart
--Stage of disease documented in chart
Treatment Speci¿c
--First-line chemotherapy regimen identi¿ed
--Chemotherapy education provided before treatment
--Anti-emetics used with chemotherapy
--Pain assessed at each visit
--Nausea and vomiting assessed at each visit
--Fatigue assessed at each visit
--Documentation of hospitalization
--Guideline-speci¿c use of chemotherapy induced anemia treatment
Breast Cancer Speci¿c
--Taxane-based therapy for node+ disease
--Yearly mammogram after treatment
--Hormone therapy for hormone receptor positive tumors
--Radiation therapy post surgery for T3-T4 or N2-N3 disease
Mean Compliance
Compliance
99.0%
95.1%
100.0%
92.2%
100.0%
86.8%
91.2%
86.3%
100.0%
83.3%
95.8%
74.5%
98.2%
94.4%
92.6%
Compliance across 14 areas of care averaged 92.6%, and was < 80%
for only one survey item—documentation of yearly mammogram
following treatment. There were no signi¿cant differences in the rate of
compliance across pt age, ethnicity, or insurance status. Documentation
of follow-up mammogram varied by treatment location (p = .004).
Assessment of pain and fatigue, and chemotherapy education tended
to vary by treatment location (p < .10).
Conclusions: Establishing meaningful benchmarks of quality care
is feasible in the community oncology setting. Preliminary evidence
suggests compliance is intrinsically high. Benchmarks should encompass
disease site-speci¿c aspects of cancer care, as well as patient-oriented
processes related to education and symptom assessment. Ongoing
research will include documentation of the administrative burden
associated with routine assessment of the quality of care, and inter-rater
reliability for these measures.
1085
Age and prognosis – how did adjuvant therapies inÀuence
the real prognosis?
Morishita M, Thomas G, Leonard R. South West Wales Cancer Institute,
Swansea, United Kingdom; Velindre Hospital, Cardiff, United Kingdom;
Imperial College School of Medicine, London, United Kingdom
Background: Adjuvant chemotherapies for breast cancer have been
regarded as major contributor to improve the prognosis. This effect was
examined by comparing different age groups. Material and methods:
We reviewed 918 breast cancer patients operated during 1996-2000
and followed their outcome against prognosis as determined by the
Nottingham prognostic index (NPI). Categorization of NPI score,
expected good prognosis (G=NPI ≤3.4), moderate prognosis (M=NPI
3.41-5.4), poor prognosis (P=NPI >5.4). Age groups are divided as 3544 years old (yo) (n=93), 45-54yo (n=277), 55-64yo (n=251), 65-74yo
(n=196) and over 75yo (n=101), prognostic groups were distributed as
G 31%, M 50%, P 19% in 35-44yo group, G 36%, M 49%, P 15% in
45-54yo group, G 51%, M 30%, P 19% in 55-64yo group, G 38%, M
46%, P 16% in 65-74yo group and G 32%,M 48%, P 20% in over 75yo
group. Results: Median follow up time was 5.5 years. Most of patients
had received adjuvant hormonal therapy in all age groups (94.6-96.4%)
regardless ER status. Neo-adjuvant and/or adjuvant chemotherapy was
used in 81% in 35-44yo group, 66% in 45-54yo group, 34% in 55-64yo
group, 16% in 65-74yo group and 1% in over 75yo group patients
(regimens consisted of CMF(84%), Anthracycline based (11%) and
others (5%). Percentages of death from breast cancer were similarly
seen in each age group, 22%, 17%, 16%, 20% and 21%. Most of
those cases (>60%) were seen in poor prognostic groups (NPI>5.4) in
older age groups (>55yo) while 15% in younger age group (35-44yo).
Discussion: Neo-/adjuvant chemotherapies were used in most of cases
in younger age group (>80% in 35-44yo patients), this may contributed
to lower mortality (17%) in high risk group (NPI>5.4) in those young
patients, however, 33% of patients in moderate risk group (NPI 3.415.4) died. Many cases, 66% in 45-54yo and 34% in 55-64yo groups
received neo-/adjuvant chemotherapy, the actual mortality was not
signi¿cantly different with those of older groups (> 65yo), majority of
those did not have adjuvant chemotherapy (only 16% in 65-74yo and
1% in over 75yo group). However, elderly patients among high risk
group (NPI>5.4) may have had bene¿t from adjuvant chemotherapy.
S71
The lack of overall differences in survival between the different age
groups may be due to a segregation of better biology in the older age
groups (eg. Grade 3 tumor rate was 46% in 35-44yo, 35% in 45-54yo,
27% in 55-64yo, 28% in 65-74yo and 26% in over 75yo group). Further
study is necessary to improve prognosis.
Number of patients (%) and mortality [%] in different age groups
NPI
35-44yo
45-54yo
55-64yo
65-74yo
3.4
29 (31) [7]
99 (36) [0]
129 (51) [2] 74 (38) [1]
3.41-5.4 46 (50) [33] 135 (49) [18]
75 (30) [13] 90 (46) [18]
>5.4
18 (19) [17] 43 (16) [56]
48 (19) [56] 32 (16) [69]
>75yo
32 (32) [1]
48 (48) [15]
21 (20) [62]
1086
Dexamethasone, metoclopropamide and omperazole
combination is simple, safe and effective for delayed nausea
and vomiting control in adjuvant chemotheray for early
breast cancer.
Sanchetee SC. Sanchetee Hospital and Cancer Insitute, Jodhpur,
Rajasthan, India
BACKGROUND: Delayed nausea and vomitting in chemotherapy
are the most frequently of side effect. Our study aimed to determine
the effectiveness of Dexa+omeprazol versus Dexa+omeprazol+met
oclopramide in the prophylaxis of dealyed emesis after emetogenic
chemotheray.
METHODS: Patients after treated with FAC regimen-adjuvant
chemotherapy for early stage breast cancer, receive dexamethasone
4mg oral, twice time daily and omeprazol 20mg oral, twice time daily,
all for ¿ve days (Daxo) or dexamethoasone 4mg oral, twice time daily,
omeprazol 20mg oral, twice time daily and metoclopramide 20mg oral,
thrice time daily, all for ¿ve days (DexoPrim). Patient diary with nausea
and vomiting module and toxicity criteria were used to monitor and
evaluate patient outcomes.
RESULTS: From Jan 2004 to Dec 2005, 122 (mean=45,7years)
outpatients were randomized with 60 Dexo and 62 DexoPrim con¿rmed
eligible. Patient characteristics were similar between the two groups.
No drug related serious adverse evetns were reported. During ¿rst cycle
fo chemotherapy, DexoPrim was complete protection against vomiting
better Dexo(78vs.52%;p=0.05). For the entire study period, there was
better DexoPrim (69vs, 48%;p=0.02), lower average nausea score (0.02
vs. 0.39, p=0.04) and no cases must entry hospital for recuing anti eetic.
Global QoL declined in both groups during chemotherapy but DexoPrim
was less than Dexo (p=0.03). Appetite was the same in both groups.
There were no signi¿cant differences in toxicity.
CONCLUSION: The use of combination DexoPrim oral daily for ¿ve
day after chemotherapy is simple, cheap cost, safe, and effective in
preventing vomiting, reducing nausea and preserving QoL.
1087
N0332 phase II trial of weekly irinotecan and docetaxel in
refractory metastatic breast cancer: a North Central Cancer
Treatment Group trial.
Tan WW, Hillman D, Salim M, Northfelt DW, Anderseon DM, Stella
PJ, Niedringhaus R, Bernath AM, Gamini SS, Frances P, Perez PA.
Mayo Clinic, Jacksonville, FL; Mayo Clinic, Rochester, MN; Allan
Blair Cancer Center, Saskatchewan, Canada; Mayo Clinic Scottsdale,
Scottsdale, AZ; Abbott Northwestern Hospital, Minneapolis, MN;
Michigan Cancer Research Consortium, Ann Arbor, MI; Duluth CCOP,
Duluth, MN; Geisinger Clinic & Medical Center, Danville, PA; Missouri
Valley Cancer Consortium, Omaha, NE
Background: Capecitabine is approved to treat patients with refractory
metastatic breast cancer (MBC) after anthracycline and taxane treatment,
with response rates of 20-25% and median survival of less than a year.
There is a need to test other approaches to improve tumor response
and potentially survival in this population. Weekly irinotecan had been
found to lead to a response rate of 23% in a similar patient population
treated in a previous NCCTG trial (Perez EA,et al. JCO 2004). Several
studies in other tumor types have documented the ef¿cacy of irinotecan
and docetaxel in the clinical setting ( breast, lung, esophageal, gastric)
with partial non-cross resistance and tolerability. Patients & Methods:
A single stage phase II study with an interim analysis of irinotecan
and docetaxel was conducted with these objectives: tumor response,
toxicity, time to progression and overall survival. Regimen: docetaxel
S72
25 mg/m2 and irinotecan 70 mg/m2 days 1 and 8 of each of 3- week
cycle. Results: 70 patients were enrolled from May 2004-October 2006;
64 patients were evaluable. Number of prior metastatic regimens:0 in
14 patients, 1 in 34 patients and 2 in 16 patients.A median of 4 cycles
were administered. Overall 16 patients (25%) (95% CI:15-31%) had a
tumor response ( 1 CR and 15 PR. Additionally, four patients had stable
disease for greater than 6 months, for a clinical bene¿t rate of 31%.
Median duration of tumor response was 5.6 months (95% CI:2.8-16.4
months). Median follow up of 10.6 months range (1.7-30.4 months).
Median progression-free survival was 5.1 months (95% CI:3.1-7.2
months). The 6 months overall survival was 84% (95% CI:76-94%)
and 6-month progression free survival was 44% (95% CI: 33-59%).
The median dose level administered was 25 mg/m2 for docetaxel and
70 mg/m2 for irinotecan for cycles 1-9. The range of cycles given was
0-22.The most common severe (grade 3/4) adverse events were fatigue
14 (22%), neutropenia 13 (20%), diarrhea 9 (14%), dyspnea 6(9%) and
nausea 6 (9%). 61% (39/64) of patients experienced a grade 3+ adverse
event (AE) and 17% experienced a grade 4+ AE.Conclusion: Weekly
irinotecan and docetaxel combination is active in heavily pretreated
MBC. The combination under study showed fairly similar ¿ndings
to historical data of other chemotherapy regimens, and is an option to
consider for patient treatment.
1088
Reduced incidence of febrile neutropenia and related
complications in elderly breast cancer patients receiving
chemotherapy with peg¿lgrastim primary prophylaxis
versus current practice neutropenia management – results
from an integrated analysis.
Aapro M, Schwenkglenks M, Lyman G, Lopez Pousa A, Easton V,
Skacel T, Bacon P, Von Minckwitz G. Clinique de Genolier, Genolier,
Switzerland; University of Basel, Basel, Switzerland; University of
Rochester, Rochester; Hospital Sant Pau, Barcelona, Spain; Amgen
Ltd, Cambridge, United Kingdom; Amgen (Europe) GmbH, Zug,
Switzerland; University of Frankfurt, Frankfurt, Germany
Background Recent EORTC/ASCO guidelines recommend
granulocyte colony stimulating factor (G-CSF) primary prophylaxis
(PP) for cancer patients at overall ≥20% risk of febrile neutropenia (FN)
during chemotherapy (CT). Patient-related FN risk factors (particularly
age ≥65 years) should be considered as well as the mean risk from a
given CT regimen. In this subgroup analysis from the NeuCuP project,
the incidence of FN and related complications is compared for elderly
breast cancer patients receiving CT supported by PP peg¿lgrastim or
any G-CSF according to current practice (CP).
Methods Studies involving breast cancer CT regimens with moderate
(15–20%)/high (≥20%) FN risk were identi¿ed by literature review.
For this integrated analysis, individual patient data were available from
8 clinical trials and 3 observational studies (conducted 1998–2005)
involving these regimens and PP peg¿lgrastim (6 mg dose, all cycles)
or CP neutropenia management (no G-CSF or peg¿lgrastim/daily GCSF in any cycle). The primary outcome measure was the incidence
of FN over all cycles. Descriptive data are reported for the subgroup
of patients aged ≥65 years.
Results 254/2282 patients were aged ≥65 years and included in this
analysis. Patients’ mean age (±SD, years) was 69±4 for PP vs 68±3 for
CP; 37% vs 31% had Stage IV disease, 95% vs 79% were ECOG 0–1
(1% vs 15% missing) and 32% vs 30% had prior chemo/radiotherapy.
Docetaxel was the most common regimen (41% vs 47%), followed by
TAC (24% vs 27%), and ADoc (28% vs 7%). In cycle 1, 73% of CP
patients received no G-CSF, 13% received peg¿lgrastim only, and 14%
received various G-CSF regimens. FN, FN-related hospitalization and
CT delivery parameters are shown (table).
Conclusions In elderly breast cancer patients receiving CT with
moderate/high FN risk, PP peg¿lgrastim was associated with a lower
overall incidence of FN vs CP neutropenia management (including
cycle 1, when most FN occurs). PP peg¿lgrastim also resulted in fewer
dose delays and dose reductions. Peg¿lgrastim provided effective
PP in elderly patients, who are particularly vulnerable to FN and its
complications.
FN
FN-related hospitalization
Dose delay >3 days
Dose reduction 15%
All cycles
% patients (95% CI)
PP (n=150)
CP (n=104)
6 (2, 10)
24 (16, 32)
5 (2, 9)
15 (8, 22)
14 (8, 20)
21 (13, 29)
15 (9, 20)
29 (20, 38)
Cycle 1
% patients (95% CI)
PP (n=150) CP (n=104)
3 (0, 6)
15 (8, 22)
4 (1, 7)
13 (6, 19)
N/A
N/A
N/A
N/A
1089
Pegfilgrastim promotes neutrophil recovery in elderly
breast cancer patients following anthracycline-containing
chemotherapy.
Brugger W, Bacon P, Lawrinson S, Romieu G. Schwarzwald-Baar
Clinic, University of Freiburg, Villingen-Schwenningen, Germany;
Amgen (Europe) GmbH, Zug, Switzerland; Amgen Ltd, Uxbridge,
United Kingdom; CRLC Val d’Aurelle, Montpellier, France
Background: Myelosuppressive chemotherapy (CT) is associated
with risk of febrile neutropenia (FN), particularly in elderly patients.
FN frequently leads to CT dose delays and dose reductions that may
compromise treatment outcome, while FN itself has an inhospital
mortality rate up to 10%. Prophylactic granulocyte colony stimulating
factors (G-CSFs) aid neutrophil recovery following CT, reducing
duration of neutropenia and risk of FN, and facilitating delivery of
subsequent CT cycles. In a phase II study of neutropenic events in
elderly patients receiving pegfilgrastim as primary or secondary
prophylaxis (PP or SP) after Àurouracil/epirubicin/cyclophosphamide
(FEC) CT (Romieu et al. Crit Rev Onc Haem 2007), the pro¿le of
neutrophil recovery in cycle 1 was assessed.
Methods: Elderly patients ≥65 years with stage II–III breast cancer
were included in the study and treated with up to 6 cycles of adjuvant
F 500 mg/m2 / E 100 mg/m2 / C 500 mg/m2 (FEC100). Patients were
prospectively randomized to receive open-label peg¿lgrastim PP (6 mg
sc) on Day 2 after CT from cycle 1, or peg¿lgrastim SP (on Day 2 of
all cycles subsequent to a neutropenic event). In this analysis, the mean
absolute neutrophil count (ANC) pro¿le in cycle 1 (during which no
SP patient received peg¿lgrastim) was reviewed.
Results: Sixty patients were randomized to PP (n=31) or SP (n=29)
peg¿lgrastim. The mean (±SD, years) age in the PP group was 67.5±3.6
vs 69.0±3.2 in the SP group; 71% vs 62% had ductal breast carcinoma,
68% vs 83% were ER positive and 68% vs 72% had ≥4 positive lymph
nodes. The mean ANC at baseline was 4.3±1.0 vs 4.0±1.2 x109/L,
respectively. The ANC pro¿le in cycle 1 for patients (n=59) receiving
prophylactic peg¿lgrastim or no growth factor support is shown. Mean
ANC was ≥1.0 x 109/L from Day 9 in patients receiving peg¿lgrastim
compared with Day 18 in those receiving no growth factor. All cycles
were delivered at planned dose and schedule in 26/30 (87%) of PP
patients compared with 20/29 (69%) of the SP group.
Conclusions: In cycle 1, pegfilgrastim promoted ANC recovery
compared with no growth factor support in elderly patients. On average,
the depth and duration of ANC nadir was reduced in patients receiving
peg¿lgrastim compared with those receiving no growth factor, therefore
reducing the period of risk for FN and complications due to grade
3/4 neutropenia. PP may therefore reduce CT dose delays and dose
reductions in subsequent cycles compared with SP.
1090
Pre-treatment differential white blood cell counts can be
used to identify patients who are at increased risk of severe
myelosuppression following adjuvant chemotherapy.
Jenkins P, Benstead K, Owen R, Elyan S, Ingledew I, Bristol J,
Chan C, Freeman S. Cheltenham General Hospital, Cheltenham,
Gloucestershire, United Kingdom; University of Birmingham,
Birmingham, Edgbaston, United Kingdom
Introduction
Maintaining the dose intensity of adjuvant breast cancer chemotherapy
is important to maximise the results of treatment. The identi¿cation of
factors that predict for severe myelosuppression would enable clinicians
to better target growth factor support. We have previously demonstrated
that obesity does not predispose to excess haematological toxicity (EJC
43 544). Here we report our observations on the predictive value of
pre-treatment full blood count parameters.
Methods
360 patients (pts) receiving 6 cycles of adjuvant FEC chemotherapy
were studied. The regimen employed comprised 5-Àuorouracil 600mg/
m2, epirubicin 60mg/m2 and cyclophosphamide 600mg/m2, cycled at
3 weekly intervals. Chemotherapy was delayed for one week if the
neutrophil count on the date of treatment was <1.5x109/l. Following 2
delays, or an episode of neutropaenic sepsis, a 20% dose reduction was
made. Chemotherapy dose intensity (DI) was considered suboptimal of
it fell below 85% of that planned (DI<85). 55 pts in whom the schedule
was modi¿ed due to non-haematological toxicity were excluded from
the analysis. Haematological growth factors were not employed in the
period of this audit. Parameters from the pre-treatment full blood count
were analysed for there ability to predict for a DI<85.
Results
In total 108 (35%) pts had a schedule modi¿cation due to haematological
toxicity. 26 (9%) pts had an episode of neutropaenic sepsis and 88 (29%)
had one or more treatment delays. The mean dose intensity was 93.8%.
64 pts (21%) received a DI<85%. On univariate analysis (t-test) only
the absolute neutrophil count (ANC), the absolute lymphocyte count
(ALC) and the total white cell count (WCC) were associated with the
DI<85 (p<0.005). On multivariate analysis (logistic regression) ALC
and WCC remained signi¿cant (p<0.01). Using the median values of
ANC (4.1x109/l) and ALC (2x109/l) we developed a simple model
which categorised pts into four risk groups with a 8%, 18%, 25% and
36% chance of receiving suboptimal DI (see ¿gure).
Conclusions
Differential white blood cell counts can be used to de¿ne groups at
increased risk of receiving suboptimal DI. This will aid clinicians in
targeting cytokine growth factors and prophylactic antibiotics to the
groups that most need it. We are currently developing a validation
sample.
S73
1091
Quality of life in the Intergroup Exemestane Study (IES) 5
years post-randomisation.
Fallow¿eld LJ, Langridge CI, Kilburn LS, Jones SE, Snowdon CF, Bliss
JM, Coombes C. Brighton & Sussex Medical School, Falmer, United
Kingdom; Institute of Cancer Research, Sutton, United Kingdom; US
Oncology Research, TX; Imperial College London, United Kingdom;
on behalf of the IES Group
Background: IES has shown switching to exemestane (E) following 2-3
years of tamoxifen (T) improves disease outcome in hormone sensitive
postmenopausal breast cancer patients compared to 5 years of T alone1;
and without detriment to QoL up to 24m post-randomisation2. Few
adjuvant hormonal trials have reported long-term QoL. Here we report
QoL through to 60m including post treatment follow-up.
Methods: 582 women entered the QoL substudy, with FACT-B-ES
questionnaires at baseline (BL) 3, 6, 9, 12, 18, 24, 30, 36, 48 and 60m.
Primary endpoint was trial outcome index (TOI), a summation of the
physical, functional and breast cancer concerns subscales. Secondary
outcomes were overall endocrine symptom (ES) scores plus severity
of individual symptoms. Most patients ¿nished trial treatment by
30-36m.
Results: Questionnaire completion was good with 84.4% available for
analysis. Overall QoL did not differ signi¿cantly between groups; both
showed a gradual improvement over time. There were no signi¿cant
differences between groups for ES; both groups reported a lessening of
symptoms over time and post treatment. Severe vasomotor complaints,
especially hot Àushes and night sweats, remained problematic for
both groups on treatment. Reports of severe vaginal discharge were
signi¿cantly higher (p<0.01) with T at 6, 9, 12, 18 and 24m. Libido
never recovered to BL levels for either group, even post treatment. At
60m 32.5% (22.6%-43.7%) reported a considerable loss of libido in
both groups.
Discussion: Mature IES data suggest that the benefits of E are
accompanied by good overall QoL. Further research is needed to
ameliorate the sexual and gynecological symptoms associated with
hormonal treatment.
1. Coombes RC et al. Lancet 2007; 369: 55970
2. Fallow¿eld LJ et al. JCO 2006; 24; 6: 910-916.
N
TOI 24m
60m
ES
24m
60m
E
T
E
T
E
T
E
T
224
212
102
103
225
213
101
107
Change from BL within
groups (mean (95%CI))
-0.46 (-1.65, 0.73)
0.52 (-0.62, 1.66)
-0.46 (-2.39, 1.47)
0.11 (-1.85, 2.06)
1.91 (0.96, 2.86)
1.49 (0.56, 2.42)
3.11 (1.44, 4.78)
3.36 (1.98, 4.74)
p=
0.45
0.37
0.64
0.91
<0.001
0.002
<0.001
<0.001
Change between
p=
groups (mean (95%CI))
-0.98 (-2.62, 0.67)
0.24
-0.57 (-3.30, 2.16)
0.68
0.42 (-0.91, 1.74)
0.54
-0.25 (-2.40, 1.89)
0.82
1092
Prospective multi-center study of the impact of the 21-gene
recurrence score assay on patient satisfaction, anxiety and
decisional conÀict for adjuvant breast cancer treatment
selection.
Mumby PB, Lo SS, Norton J, Smerage J, Joseph K, Chew HK, Hayes
D, Albain KS. Loyola University Medical Center, Maywood, IL;
University of Michigan, Ann Arbor, MI; Edward Hospital, Naperville,
IL; University of California, Sacramento, CA
Background: Use of the Oncotype DX Recurrence Score assay (RS) in
a prospective, multi-institutional study resulted in a change in medical
oncologist (MO) adjuvant treatment recommendation in 31.5% (n=28)
of cases; the most common change was from chemo/hormonal therapy
(CHT) to hormone therapy (HT) (Lo et al., ASCO 2007). This new
report analyzes the patient (pt) portion of the study, with objectives to
determine the impact of the RS on pt’s treatment decision-making and
anxiety level before and after the test.
Material and Methods: Patients at 1 community and 3 academic
centers completed 3 questionnaires pre- and post-RS: 1) the Patient
Treatment Decision Making Questionnaire; 2) the Decisional ConÀict
Scale (DCS); and 3) the State-Trait Anxiety Inventory. Frequency
distributions, means and standard deviations were used to summarize
data. Paired samples t-tests assessed anxiety, satisfaction, and decisional
conÀict pre- and post-RS.
S74
Results: Accrual goal was met with 89 evaluable pts. 95% (n=81) of
pts were glad they took the test, and 83% (n=89) reported the assay
inÀuenced their treatment choice. 26.8% (n=24) of pts had a change
in treatment plan post-RS, with 10.1% (n=9) changing from pre-test
CHT to post-test HT. Results from the DCS indicate reduced conÀict
over treatment decision post-RS (p <.0001), greater pt satisfaction, and
increased con¿dence with choice of adjuvant therapy (p <.0001). State
anxiety was also reduced post-RS (p. = 001).
Discussion: Results of the RS changed both MO’s and pt’s decisions
regarding adjuvant therapy. Use of the assay resulted in less
chemotherapy use, decreased pt anxiety and increased pt con¿dence
regarding adjuvant treatment decisions.
1093
Predictors of weight gain in patients with early stage breast
cancer.
Mills JB, Gui J, Mulrooney TJ, Schwartz GN. Dartmouth-Hitchcock
Medical Center, Lebanon, NH; Dartmouth Medical School, Hanover,
NH
Background: Weight gain after the diagnosis of breast cancer occurs
frequently in women who receive adjuvant chemotherapy, and it can
be a distressing and hazardous burden for breast cancer survivors. Prior
series have found up to a 5 kg median weight gain associated with
chemotherapy, but it is not known what effect newer adjuvant therapies
containing taxanes or aromatase inhibitors may have on weight gain.
Material and Methods: A retrospective cohort of 90 women who were
diagnosed with Stage I-II breast cancer between July 2001 and June 2004
and treated with adjuvant therapy had weight and BMI, chemotherapy
and endocrine therapy treatment, age, baseline menopausal status
and change in menopausal status, the use of antidepressants, thyroid
function, hemoglobin, and fatigue assessed at baseline, and at 6, 12,
and 24 mo after diagnosis. Correlates of weight gain were identi¿ed by
univariate analysis, and joint associations were identi¿ed by combining
predictors in a multiple regression model.
Results: The median age at diagnosis was 55 and 25% of the subjects
were <50 at diagnosis. The median BMI was 26.2 at baseline, 36%
had a BMI <25, and 26% had a BMI>30. 50% of patients received
chemotherapy and 32% received a taxane-based regimen. 74% were
given tamoxifen and 12% received an AI. 20% were treated with an
SSRI. The median weight gain was 0.8 kg at 24 mo. Median weight
gain at 24 mo was 2 kg in premenopausal women and 0.4 kg in
postmenopausal women. Baseline weight, age at diagnosis, menopausal
status, anemia, a change in menopausal status, the use of an SSRI,
baseline TSH, fatigue score, chemotherapy, and endocrine therapy were
not signi¿cantly associated on univariate or multivariate regression
with weight gain at any time point. Only a lower baseline BMI was
predictive of subsequent weight gain (p<0.05).
Discussion: Our experience ¿nds no association of weight gain with
breast cancer therapy, including the newer systemic regimens. The
only predictor for weight gain following diagnosis of early stage breast
cancer was a lower BMI at baseline. Women who are not overweight at
baseline are at risk for weight gain following a breast cancer diagnosis
and could be targeted with interventions to prevent weight gain, such as
exercise to reduce therapy-related changes in body composition.
1094
Memory loss after adjuvant chemotherapy for breast
cancer: a preliminary analysis of mediating variables
utilizing cross-sectional correlations and multilevel
longitudinal analysis.
Beadle G, Rolfe M, Vearncombe K, Andrew B, Mengersen K, Wright
M. Queensland Institute of Medical Research, Brisbane, Queensland,
Australia; Southern Cross University, Lismore, New South Wales,
Australia; University of Queensland, Brisbane, Queensland, Australia;
Queensland University of Technology, Brisbane, Queensland,
Australia
BACKGROUND
Cognitive impairment is a well recognized complication of adjuvant
chemotherapy but further research is required to identify factors that
mediate cognitive change in breast cancer survivors.
METHODS
This study investigated cognitive change in verbal memory in 119
women aged less than 70 years before, at completion of, and 6 months
after adjuvant chemotherapy. Verbal memory was assessed with the
auditory verbal learning test trials 1-5 (AVLT1-5) and executive
processing of immediate and delayed recall with the AVLT7 and the
AVLT8 respectively. Cross-sectional correlations were performed with
time invariant variables of age, years of education and general cognitive
ability utilizing the national adult reading test (NART). Correlations
with time varying variables included quality of life measures (HADS,
FACT-B and FACT-F) and changing hormonal phenotype (cessation
of hormone replacement therapy after diagnosis of breast cancer and
changing menstrual function after chemotherapy). Unconditional
random intercept quadratic regression models were ¿tted to AVLT1-5,
AVLT7 and AVLT8, with temporal and subject level variances estimated
by restricted maximum likelihood.
RESULTS
In this exploratory analysis, age, NART and years of education were
signi¿cantly correlated with AVLT1-5, AVLT7 and AVLT8 at all time
points (all p values <0.05). Quality of life correlates were inconsistent
at most time points but statistically signi¿cant when all time points
were combined (HADS depression <0.05 and FACT fatigue <0.05
for AVLT8; FACT-B <0.05 for AVLT1-5, and <0.01 for AVLT7 and
AVLT8). Age, NART and years of education were signi¿cant predictors
of these changes (p <0.01). In particular, a high NART predicted a
less steep decline of memory over time. There was no evidence of
a statistically signi¿cant association between AVLT and self-report
measures of quality of life or changing hormonal phenotype after
adjustment for age and NART.
CONCLUSION
A signi¿cant decline of the AVLT occurred during and after treatment
with adjuvant chemotherapy. Age, NART and years of education were
strongly associated with AVLT at all time points but not quality of life
or changing hormonal phenotype. Further investigation of memory
and executive functioning is currently underway in a larger sample of
patients followed over a longer time. Multilevel longitudinal analysis
is a promising tool for investigating longitudinal data that contain
multiple changing covariates.
1095
Research on optimal recovery practices in breast cancer:
the RESTORE trial.
Kimmick GG, McCoy TP, Milhalko SL, Ribisl PM, Anderson RT. Wake
Forest University School of Medicine, Winston-Salem, NC; Wake Forest
University, Winston-Salem, NC; Duke University Medical Center,
Durham, NC
Background: Post-treatment behavioral interventions, designed to
prevent disability and improve quality of life in breast cancer survivors,
are needed. Emotional distress, fatigue and psychosocial issues may be
signi¿cant and persist over time. The RESTORE study is a randomized,
controlled, clinical trial designed to test and compare the effectiveness
of a moderate, tailored exercise program on improving quality of life
(FACT-B)and physical function (six-minute walk) of women treated
for stage I to III breast cancer at 18-months post-enrollment, versus
usual care.
Objectives: Women, with stage I-III breast cancer treated at one of
two large medical centers, were recruited within 6-12 weeks of surgery
and randomized to treatment or control. Those in the treatment group
began a center-based exercise and a lymphedema education program
2 to 3 days per week gradually shifting to the home. Controls received
patient education. Study participants were assessed at 3-month intervals
through 18-months. Distributions over time were examined using box
plots and smoothed curves. Repeated measures analysis of covariance
was used to model the total meters walked over time and FACT-B
scores. Models were adjusted for baseline measurement, baseline
affected arm volume, number of nodes removed during surgery, age
at randomization, # of self-reported symptoms, baseline SF-12 mental
and physical components scores, visit and treatment group. Signi¿cance
was considered to be a 2-sided p-value < 0.05.
Results: There were 105 women in the study, 82 of whom completed
all 18 months of the study. Mean age (range) was 53.6 (32-82) years;
88% were Caucasian; 45% were employed full-time; 44% and 27% were
overweight and obese. At baseline 46% had breast conserving surgery;
79% had axillary node dissection; 59% received chemotherapy and 64%
received radiation. Patients in the treatment group had increased total
meters walked compared to controls: adjusted means (SE) were 606.5
(10.7) and 577.1 (6.8) respectively (p=0.025). There was no difference
in the adjusted means for FACT-B scores: 117.2 (2.0) for the treatment
group and 114.7 (1.5) for the control group (p=0.33).
Conclusions: With this early exercise intervention after breast cancer
diagnosis, signi¿cant improvement was achieved in physical ¿tness
over time with no decline in health-related quality of life, as measured
by FACT-B.
1096
Breaking bad news: experiences receiving breast cancer
diagnosis in a specialty breast center versus community
practice.
Smith RL, Crawford BJ, Petersen LR, Johnson RE, Mandrekar J, Cha
S, Rhodes DJ, Hartmann LC. Mayo Clinic, Rochester, MN
Context: Recommendations for “breaking bad news” and disclosure
of cancer diagnosis have been promoted for many years. In view of
the rise in specialty breast centers and less invasive biopsy techniques,
current experiences of women receiving breast cancer (BC) diagnosis
are not well characterized.
Methods: A total of 177 subjects responded to a questionnaire regarding
the experience receiving BC diagnosis: 121 women (68%) received BC
diagnosis then were referred to a specialty breast center (community,
CP) and 56 (32%) received BC diagnosis within the specialty center
(SC).
Speci¿c items included recent stress levels; context factors (i.e. location,
duration, privacy), clinician behaviors (i.e. providing educational
materials, using touch to comfort, approach to discussing diagnosis)
and patient-clinician relationship. Satisfaction was also rated on a 5
point scale.
Results: Patients were enrolled 1 to 54 days following BC diagnosis.
Mean age of SC patients was higher (63 vs. 56 yrs, p=0.005). Context
factors differed between groups, with mode of delivery shown in
Table 1.
In decreasing frequency, CP patients received diagnosis from
generalists, surgeons, radiologists, nurses, NP/PAs, gynecologists,
specialists, family members and secretaries. CP patients described
relationship with person who disclosed diagnosis as excellent (21%),
good (25%), satisfactory (26%), inadequate (7%), poor (5%) and did
not know well enough (15%). Almost all SC patients received diagnosis
from a breast specialist. Selected differences in clinician behavior and
content are shown in Table 2.
BC stage did not differ between CP and SC patients. Patient satisfaction
was favorable, but differed between groups, (CP 3.50 vs SC 4.60, p
<.0001).
Conclusions: Patient experiences receiving BC diagnosis are variable
and may be associated with patient satisfaction. Differences in the
experience provide an opportunity to identify factors with potential to
inÀuence satisfaction with medical care and psychological outcomes.
Table 1: Mode of Delivery
Community
(N=121)
71 (59%)
48 (40%)
1 (1%)
Specialty Center
(N=56)
19 (34%)
35 (63%)
0 (0%)
Table 2: Clinician Behavior and Content
Community
Clinician Behaviors + Content
(N=121)
Information found helpful
58 (48%)
Educational materials provided
23 (21%)
Opportunity to ask questions
89 (74%)
Touch used to comfort
27 (22%)
Specialty Center
(N=56)
42 (75%)
34 (67%)
53 (96%)
27 (51%)
Mode of Delivery
Telephone
Face to Face
Letter
Signi¿cance
p = 0.0003
p = 0.006
p = 1.00
Signi¿cance
p = 0.010
p < 0.0001
p = 0.0001
p = 0.0003
1097
Appraisals, coping and distress among couples dealing with
breast cancer.
Hernandez AM, Bigatti SM. Indiana University Purdue University
Indianapolis, Indianapolis, IN
This study aimed to investigate the cognitive appraisals, coping styles
and levels of distress of couples dealing with breast cancer. Cognitive
S75
appraisals are evaluations individuals make of stressful situations in
order to categorize them as benign/irrelevant, challenge, threat, or
harm. These cognitive appraisals predict coping mechanisms, which in
turn impact levels of distress. Studying couples, or dyads, is important
because the coping style of one individual in the dyad is associated
with outcomes in the other. One adaptive form of coping is emotional
approach coping, which consists of emotional processing and emotional
expression. Breast cancer patients currently undergoing chemotherapy
treatment (n = 22) and their spouses (n = 22) were recruited from a
breast cancer clinic. Both the patient and spouse completed surveys at
home and returned them by mail. Stanton’s Emotional Approach Coping
Scale, Kessler’s Cognitive Appraisal of Health Scale, and the Pro¿le
of Mood States (POMS) were included in the questionnaire packages.
Most of the patients had stage IV breast cancer (68.2%). The average
age for patients was 53.55 (SD = 11.571) and for husbands was 54.49
(SD = 11.784). Participants were married an average of 27.28 years
(13.99). Most reported a yearly income above $70,000. Husbands scored
higher in the anxiety subscale of the POMS and were more likely to
appraise the cancer as a threat than the patients themselves. We grouped
couples into those who matched on appraisals and those who did not
and examined the groups’ level of distress and coping. We found no
differences by group for husbands on either variable, or for wives on
the POMS. However, wives who did not match on appraisals with their
husbands engaged in more emotional approach coping F(1,20)= 6.474,
p=.019), and more speci¿cally emotional expression F(1,20) = 4.969,
p = .037) and emotional processing coping F (1,20) = 6.089, p = .023).
These ¿ndings suggest that patients who have a different view of the
cancer than their partners may need to engage in more coping efforts
than those who have the same view. Possibly agreement, regardless
of the appraisal agreed upon, relieves the patient from reappraising.
On the other hand disagreement may require both processing and
expression to determine whether the appraisal is in fact correct or should
be reconsidered. Because appraisals change throughout the cancer
experience, it may be that one impetus for reappraisals is disagreement
with a spouse and subsequent emotional work.
1098
The psychosocial issues for women diagnosed with breast
cancer who have a concurrent pregnancy or want the option
of a subsequent pregnancy.
Ives A, Longman G, Saunders C, White K. The University of Western
Australia, Perth, WA, Australia; University of Sydney, Sydney, NSW,
Australia
Objectives: To identify psychosocial issues for women diagnosed
with breast cancer when pregnant or who become pregnant after their
diagnosis and develop strategies to assist others who go through this
experience in the future.
Methods: Women were randomly invited to participate in this study
via the Western Australian Department of Health. Interviewees were
from one of three groups of women less than 45 years of age when
diagnosed with breast cancer; either with gestational breast cancer,
or who subsequently conceived or with breast cancer unrelated to
pregnancy.
Semi-structured interviews were recorded and transcribed verbatim.
During the interviews, the researcher sought to identify any
psychological and social issues related to the decisions made by
women diagnosed with breast cancer and relating to their concurrent or
subsequent pregnancy. Areas of interest included: coping mechanisms
used; formal and informal support structures; breast cancer treatment
and outcome issues; fertility and contraception issues; pregnancy events;
dealing with illness and a young child. The data was analysed by four
researchers using thematic analysis consistent with this explorative
qualitative research design.
Results: Motherhood was identi¿ed as of key importance to these
women. For example, protecting their young children or an unborn
child – for some of them this was foregoing treatment but for others
it was terminating their pregnancy to ensure they could have the
necessary cancer treatment to spend time with their other children.
Three unmet needs were highlighted: isolation, lack of support and lack
of information. The feelings of isolation came from believing that they
were the only person who had ever been through such an experience;
S76
a feeling that was not dispelled by their health professionals. These
women needed to make dif¿cult decisions about their breast cancer
management and/or pregnancy and they felt that that they were being
judged and not supported in the decisions. There was also a lack of
information on available breast cancer and pregnancy management
options for these women and treating clinicians did not appear to have
access to the small but relevant knowledge base available.
Conclusions: The study highlighted the high priority women place on
doing the best or the right thing by their child or children. Every woman
behaved differently based on her life experiences but simple steps such
as a telephone support network and unbiased support could reduce the
stresses of such life changing events. There is also a growing need for
better evidence based information to be readily available to this group
of women and their treating clinicians.
1099
Prevalence of cognitive complaints is not higher in
postmenopausal breast cancer patients before adjuvant
hormonal therapy compared to healthy controls.
Schilder CM, van Dam F, Boogerd WS, Seynaeve C, van de Velde
CJ, Nortier HW, Linn SC, Schagen SB. Netherlands Cancer Institute,
Amsterdam; Erasmus Medical Center, Rotterdam; University Medical
Center, Leiden, Netherlands
Background
Breast cancer (BC) patients (pts) treated with adjuvant therapy often
report cognitive changes such as memory or concentration problems. Up
till now, it is insuf¿ciently investigated whether cognitive complaints
are already present after BC surgery and before subsequent adjuvant
treatment. The aim of this study was to assess the prevalence of
cognitive complaints before adjuvant Hormonal Therapy (HT) in
postmenopausal BC pts. In addition, relationships with time since
diagnosis and surgery, and symptoms of anxiety/depression and
fatigue were studied. This information will provide more insight into
the association between cognitive complaints, speci¿c treatments and
disease- and treatment related factors.
Methods
Occurrence of cognitive complaints was studied in 1) BC pts not
quali¿ed to receive chemotherapy (n=205, mean age 68.9 yrs; range 5084) participating in the TEAM-trial, a randomized study investigating
tamoxifen and exemestane as adjuvant HT, and 2) a control group of
healthy female friends/relatives of the TEAM pts (n=124, mean age
66.5 yrs; range 49-87). Participants were interviewed about memory,
concentration, thinking and language problems, after surgery (mean
nr. of days since surgery 42, range 9-140) but before adjuvant HT.
15% of the pts underwent radiotherapy at the moment of the interview.
Anxiety/depression was measured with the Hopkins Symptom Check
List (HSCL), fatigue with the Multidimensional Fatigue Scale (MFI;
scales general and physical fatigue). Group differences were analyzed
with χ 2-tests, correlations with Spearman correlation coef¿cients.
Results
BC pts did not report a higher frequency of memory, thinking and
language problems than controls. A lower frequency of concentration
problems even was observed in BC pts versus controls (6% versus 13%,
p=.04). The occurrence of cognitive complaints did not correlate with
age or IQ. Time since diagnosis and surgery, and current radiotherapy
(y/n) were not related to presence of cognitive problems. In both groups,
a signi¿cant higher proportion of persons that scored in the ‘possibly
depressive case’-range (HSCL ≥ 1.55; BC pts 23%; controls 14%,
p=.045) reported concentration problems compared to nondepressed
persons (BC pts: 15% versus 3%, p=.007; controls: 41% versus 9%, p=
.002). For memory, thinking and language complaints no relationships
with anxiety/depression were found. General and physical fatigue were
not related to cognitive complaints.
Conclusion
Shortly after BC surgery and before adjuvant HT, the prevalence of
cognitive complaints is not higher in postmenopausal BC pts than in
a healthy age-matched population. In both pts and controls, higher
anxiety/depression scores were associated with a higher frequency of
concentration complaints, but not with memory, thinking and language
complaints. Neither general and physical fatigue, nor treatment related
factors were associated with cognitive complaints.
1100
Unexpected effects of reassurance in women with low-risk
breast cancer.
Griggs JJ, Corbin K, Weiss M, Shields CG. University of Michigan, Ann
Arbor, MI; University of Rochester School of Medicine and Dentistry,
Rochester, NY; breastcancer.org, Narberth, PA
Objective: Patients with low-risk breast cancer are often told they
have a “good cancer.” The purpose of this study was to investigate
the impact of this form of reassurance on distress and concerns about
recurrence in women with ductal carcinoma in situ (DCIS) and early
stage invasive breast cancer. Methods: We conducted an anonymous
survey on the website of breastcancer.org, a non-pro¿t organization.
The survey inquired about disease and treatment characteristics and
contained the Positive and Negative Affect Scale (PANAS) and the
Concerns about Recurrence Scale (Vickberg, Ann Behav Med 2003).
Participants were also asked if they had been told by any of their medical
providers that they had a “good cancer” or “favorable cancer” Analyses
were performed to investigate the impact that being told one has or had
a “good cancer” and feelings of reassurance, isolation, distress, guilt,
and concerns about recurrence. Results: A total of 646 participants
with localized or regional breast cancer (n = 323) or DCIS (n = 323)
breast cancer completed the survey. Being told that she had had a “good
cancer” was reported by 62% of women with DCIS and 32% of women
with invasive disease. Among those told they had a good cancer, 59%
reported that being told this led to their feeling moderately-to-extremely
“reassured.” A high percentage of respondents (29%) reported feeling
minimally reassured by this phrase. Many respondents also reported
moderate-to-severe negative responses to being told that they had a
good or favorable cancer—feeling moderately-to-extremely “isolated”
(21%), “distressed” (40%), “scared” (45%), or “guilty” (20%). In
addition, among women with DCIS, the good cancer message was
associated with greater level of concern about recurrence, controlling
for age, time since diagnosis, surgical treatment, and mental health (p
< .005) Conclusions: Although telling patients they have a “good” or
“favorable” cancer leads to feelings of being reassured in many women,
such terms may also contribute to distress, feelings of isolation, and
guilt among many patients who otherwise might enjoy a good prognosis
quality of life. Providing reassurance is a complex process. Further
research into effective ways of communicating reassurance is warranted
in order to minimize distress and enhance quality of life.
1101
Breast reconstruction in a university-based public
hospital.
Levine SM, Vaksman A, Hiotis K, Levine JP. New York University
Medical Center, New York, NY
Breast reconstruction rates continue to rise in large part due to
patients and communities becoming more knowledgeable about postmastectomy options. Overall satisfaction with breast reconstruction
is traditionally high only adding to the popularity of the choice. Prior
research has demonstrated that race, age, and socioeconomic status,
are important determinants in whether a patient undergoes breast
reconstruction; speci¿cally, indigent women have only an 8% rate of
breast reconstruction compared with a national average of 42 %. Our
study retrospectively examined the breast reconstruction choices made
by patients at a large public hospital in New York City where resources
for reconstruction are fully available, within a multidisciplinary
clinic environment. Between January 2001 and December 2006, 179
patients underwent mastectomy, and 73 (41 %) elected reconstruction.
Patients in age ranges 20-39 and 40-59, were both signi¿cantly more
likely to undergo reconstruction than patients greater than 60 years
of age. Disease stage was not signi¿cantly related to rates of breast
reconstruction. Reconstruction rates by race and ethnicity were analyzed
and demonstrated a signi¿cantly lower rate of breast reconstruction in
Asian women (32 %) compared with Hispanic women (47 %), despite
the same access to available services. Our data demonstrate breast
reconstruction rates signi¿cantly higher than prior studies for women
in this public hospital demographic, while at the same time maintaining
other trends with regard to breast reconstruction. These data suggest that
indigent patients are more likely to have breast reconstruction when their
care is delivered at a university based public hospital where consistent
patient education is practiced, in a multidisciplinary fashion.
1102
Anti-tumor activity of motesanib diphosphate alone and
in combination with docetaxel or tamoxifen in xenograft
models of human breast carcinoma.
Coxon A, Bush T, Belmontes B, Saffran D, Ona V, Rex K, Caenepeel
S, Hughes P, Kaufman S, Radinsky R, Kendall R, Price J, Polverino
A. Amgen Inc, Thousand Oaks, CA; UT MD Anderson Cancer Center,
Houston, TX
Background: Angiogenesis is necessary for tumor growth and vascular
endothelial cell growth factor (VEGF) and its receptors play a pivotal
role in the neovascularization process. Motesanib diphosphate (AMG
706) is a highly selective, oral agent that is being evaluated for its
ability to inhibit angiogenesis and lymphangiogenesis by targeting
vascular endothelial growth factor receptors 1, 2, and 3 (VEGFR1-3).
It is also under investigation for its potential direct anti-tumor activity
by targeting platelet-derived growth factor receptor (PDGFR), and
stem cell factor receptor (c-kit) signaling. In this study, we examined
the effects of motesanib diphosphate in preclinical models of human
breast carcinoma, both as a single agent and in combination with
docetaxel or tamoxifen.
Materials and Methods: The ability of motesanib diphosphate to
inhibit the growth of MDA-MB-231 (mesenchymal), MCF-7 (luminal),
Cal-51 (basal) and GILM2 (basal) breast carcinoma cells cultured in
vitro was determined using the ATPlite cell viability assay. To determine
in vivo ef¿cacy, nude mice bearing established (∼100-200 mm3) MCF-7,
MDA-MB-231, Cal-51 or GILM2 xenografts were treated orally with
motesanib diphosphate BID at 7.5, 25 and 75 mg/kg. For combination
experiments, docetaxel and tamoxifen were administered IP at 20 mg/kg
once weekly and 30 mg/kg ¿ve times per week, respectively. At the end
of treatment, tumors were collected for blood vessel area (anti-CD31
staining) and viable tumor area (hematoxylin) assessment.
Results: Motesanib diphosphate had no effect on the in vitro growth of
any of the breast cancer cell lines. In contrast, treatment with motesanib
diphosphate in vivo resulted in a dose-dependent inhibition of tumor
growth in all four breast cancer models. Signi¿cant inhibition (p
<0.05) was observed with all three doses of motesanib in the Cal-51
and GILM2 basal models. In the MCF-7 model, signi¿cant inhibition
(p <0.0005) was achieved at the 25 and 75 mg/kg doses, whereas only
the 75 mg/kg dose was signi¿cant (p <0.0001) in the MDA-MB-231
model. Histological analysis of the MDA-MB-231, Cal51 and MCF-7
tumors revealed a signi¿cant decrease in viable tumor fraction and a
reduction in blood vessel area after motesanib treatment. In combination
studies, treatment with motesanib diphosphate in the MDA-MB-231
and MCF-7 models signi¿cantly enhanced the anti-tumor activity of
docetaxel and tamoxifen respectively (p <0.05). Together, these data
suggest that motesanib diphosphate inhibited tumor growth via an
inhibition of angiogenesis, and that this was enhanced when combined
with standard chemotherapy.
Conclusion: The preclinical anti-tumor activity of motesanib
diphosphate in multiple models of breast carcinoma supports the
development of this anti-angiogenic agent in the broad management
of breast cancers, in combination with other current breast cancer
therapies.
1103
Non-invasive LQYLYR subcellular multicolor imaging of the
tumor microenvironment and drug response in real time.
Yang M, Jiang P, Al-Zaid M, Hoffman RM. AntiCancer, Inc., San Diego,
CA; University of California, San Diego, San Diego, CA
Background: In order to non-invasively image cancer-cell—stromalcell interaction in the tumor micro-environment and drug response
at the cellular level in live animals in real time, we developed a new
imageable three-color animal model.
Materials and Methods: The model consists of GFP-expressing mice
transplanted with dual-color breast cancer cells labeled with GFP in
the nucleus and RFP in the cytoplasm. The Olympus IV100 Laser
Scanning Microscope, with ultra-narrow microscope objectives (“stick
S77
objectives”), is used for three-color whole-body imaging of the twocolor cancer cells interacting with the GFP-expressing stromal cells. In
this model, drug response of both cancer and stromal cells in the intact
live animal is also imaged in real time.
Results: Various in vivo phenomena of tumor-host interaction and
cellular dynamics were imaged including mitotic and apoptotic tumor
cells, stromal cells interacting with the tumor cells, tumor vasculature,
and tumor blood Àow. This new model system enables the ¿rst cellular
and subcellular images of unperturbed tumors in the live intact animal
at the subcellular level.
Discussion: New visible real-time targets for novel anticancer agents
are provided in this model including the color-coded interacting cancer
and stromal cells, tumor vasculature, and blood Àow. This imageable
model should lead to many new insights of in vivo cancer cell biology
and to novel drug discovery.
1104
Anti-angiogenic potential of coenzyme Q10, riboÀavin and
niacin in breast cancer patients undergoing tamoxifen
therapy.
Panchanatham S. DR. A.L.M.P-G.I.B.M.S., University of Madras,
Tarmani Campus, Chennai, Tamilnadu, India
Background: To evaluate the anti-angiogenesis effect of CoenzymeQ10,
riboÀavin and niacin (CoRN) in breast cancer patients undergoing
tamoxifen therapy. Efficacy of the combinatorial (CT) drug was
correlated with serum angiogenic marker levels.
Methods: Eighty four women with breast cancer undergoing tamoxifen
therapy were treated with 100 mg CoenzymeQ10, 10 mg RiboÀavin
and 30 mg Niacin for 90 days. Blood samples were collected at the
start of the study, at 45 days and 90 days of the treatment regimen.
Circulating markers such as Vascular endothelial growth factor (VEGF),
Matrix metalloproteinase (MMP) - 2, MMP-9, Tissue Inhibitor of
metalloproteinase (TIMP) - 1, TIMP-2, Interleukin (IL) -1β, IL-6, IL-8,
Tumour necrosis factor (TNF) -α, Extracellular domain (ECD) Her2/neu, c-myc, Epidermal growth factor (EGFR), VCAM-1, E-selectin,
Tumour growth factor (TGF) –β, Angiogenin, Carcinoembryonic
antigen (CEA) and Carbohydrate antigen (CA) 15-3 were evaluated
to determine the anti-angiogenic of this CT drug.
Results and Discussion: We found a statistically signi¿cant correlation
between CoRN supplementation and reduction in angiogenesis markers.
There was a reduction in the levels of serum IL-1β, IL-6, IL-8, TNF-α,
MMP-2, MMP-9, Angiogenin, E-selectin, VCAM-1 EGFR, TGF-β
and VEGF levels, which are stimulators of angiogenesis as well as
factors for cancer cell proliferation and growth. There was a signi¿cant
reduction in tumour marker levels of CEA, CA15-3, ECD Her-2/neu
and c-myc. In conclusion, this study suggests that supplementation of
CoRN to tamoxifen therapy may provide good treatment prognosis by
reducing the risk of cancer recurrence and metastases by decreasing the
levels of angiogenic and tumour markers and importantly, the relation
between dietary supplementation and cancer treatment may also have
therapeutic implications in the future.
1105
Molecular imaging in the mouse model of breast cancer
based on optical illumination and ultrasonic detection.
Oraevsky AA, Ermilov SA, Eghtedari MA, Conjusteau A, Miller T,
Radulescu EG, Herzog D, Gharieb RR, Lacewell R, Thompson S, Mehta
K, Stein A, Motamedi M. Fairway Medical Technologies, Houston, TX;
Seno Medical Instruments, Houston, TX; University of Texas Medical
Branch, Galveston, TX
BACKGROUND
A three-dimensional laser optoacoustic imaging system was developed,
which combines the advantages of optical spectroscopy and high
resolution ultrasonic detection to produce high contrast maps of optical
absorbance in tissues. The images were based on spatial distribution of
desoxyhemoglobin and oxyhemoglobin, which are the main endogenous
tissue chromophores in the red and near-infrared spectral ranges.
Visualization of these chromophores provides structural information on
tissue vasculature and functional information on blood concentration
and oxygen saturation.
S78
MATERIALS and METHODS
The system was tested in a nude mouse model of breast cancer
and produced deep tissue images with sub-millimeter resolution.
Optoacoustic imaging using two or more illumination wavelengths
permits a quantitative assessment of the angiogenesis-related
microvasculature, and thereby, an evaluation of the tumor stage and
its metastatic potential.
The optoacoustic system was also used to generate molecular images of
the malignancy-related receptors induced by the xenografts of BT474
mammary adenocarcinoma cells in nude mice. The acquisition of the
latter images was facilitated by the use of an optoacoustic contrast
agent that utilizes gold nanorods conjugated to monoclonal antibody
raised against HER2/neu antigens. These nanorods possess a very
strong optical absorption peak that can be tuned in the near-infrared
by changing their aspect ratio. The effective conversion of the optical
energy into heat by the gold nanorods followed by the thermal expansion
of the surrounding water makes these nanoparticles an effective
optoacoustic contrast agent.
RESULTS
Three-dimensional images of mouse circulation as well as breast tumors
grown from xenografts of BT474 cells were obtained. Administration
of the gold nanorod bioconjugates to mice resulted in an enhanced
contrast of breast tumors relative the background of normal tissues in
the nude mouse model.
DISCUSSION
In the presence of advanced tumor angiogenesis, the developed system
can provide functional information on blood concentration and its
oxygen saturation in the tumor microvasculature. In the absence
of a suf¿cient endogenous contrast in certain types of tumors, the
combination of the nanoparticulate contrast agent and the optoacoustic
imaging has the potential to become a useful imaging modality for
preclinical research in murine models of cancer.
1106
Variation of circulating angiogenic factor level and its
potential value during chemotherapy in patients with
Tang J, Zhao J, Qin J, Pan L, Xu Z. Jiangsu Tumor Hospital, Nanjing,
Jiangsu, China; Nanjing University of Traditional Chinese Medicine,
Nanjing, Jiangsu, China
Background: Systemic chemotherapy is crucial for advanced or
metastatic breast cancer. However, that is not well understood whether
angiogenic factors from tumor and/or other tissue cells are inÀuenced
by chemotherapy and whether the changes of their circulating levels
add useful information to conventional tumor markers in monitoring
breast cancer. This study aimed to investigate the changes in circulating
vascular endothelial growth factor (VEGF) and endostatin (ES) levels
during chemotherapy and to discuss their correlations with conventional
tumor markers, therapeutic response and survival.
Materials and Methods: 120 series serum samples form 40 patients
with metastatic breast cancer were collected before chemotherapy (B0),
at the end of 1 cycle (B1) and 5-6 cycle chemotherapy (B2). Serum
VEGF or ES level was measured by ELISA, and serum CA153 or CEA
level was determined by electrochemiluminescence immunoassay.
The positive predictive values (PPV) of each marker and of marker
combinations for different types of clinical response were calculated.
Results: (1)The median levels of 496.6 (range, 62.5-1106.7), 524.8
(range, 69.0-1463.5) and 306.5 (range, 62.5-1004) pg/ml serum VEGF
with the positive rates of 57.5%, 52.5% and 35.0% in B0, B1 and B2
samples were obtained, respectively. There was statistically signi¿cant
difference between B1 and B0 (P=0.047) and between B2 and B0 or B1
(P<0.001). (2)ES medians in B0, B1 and B2 samples were 95.5 (range,
48.0-164.7), 110.5 (range, 52.0-179.9) and 113.3 (range, 62-208.0)
ng/ml, respectively. Although there was an upward trend from B0 to
B2, but no statistical difference was observed between different groups
(P>0.05). (3)The changes in serum VEGF levels after 5 or 6 cycles
of chemotherapy correlated with clinical response. VEGF level in 27
patients with partial response (PR) and stable disease (SD) showed a
signi¿cant decrease (287.4 vs 501.2pg/ml; P<0.001), neither but in 13
patients with progressive disease (PD; 568.9 vs 493.9pg/ml;P=0.312).
VEGF showed the highest PPV for SD (61.9%), and CA153 showed
the highest PPV for both PR (42.9%) and PD (70.0%). Moreover, a
combination of CA153 and VEGF could signi¿cantly increase the
PPV for PD to 100% and the PPV for PR+SD to 81.3%. (4)Before
treatment, serum VEGF levels correlated with increasing clinical stages
and visceral involvement. After treatment, three of the 4 patients with
both persistently high VEGF and CEA levels died of carcinoma within
2-year follow-up, which showed a worse outcome than that with VEGF
or CEA elevated alone (75% vs 44.4% or 60%).
Conclusion: Systemic chemotherapy for breast cancer results in a
signi¿cant decrease of serum VEGF level, but has only minor effect
on ES without statistical signi¿cance. The change in VEGF level may
provide additional information to that obtained from CA153 or CEA in
estimating the clinical response and predicting the prognosis.
1107
Association of genetic polymorphisms of VEGF and
VEGFR-2 with outcome in E2100.
Schneider B, Wang M, Radovich M, Sledge G, Badve S, Thor A,
Flockhart D, Hancock B, Davidson N, Miller K. Indiana University
School of Medicine, Indianapolis, IN; Harvard, Boston, MA; University
of Colorado Health Sciences Center, Denver, CO; Johns Hopkins Sidney
Kimmel Cancer Center, Baltimore, MD
Background: E2100 was a phase III, Intergroup trial that demonstrated
an improvement in progression free survival (PFS) and response
rate (RR) when adding bevacizumab to paclitaxel for women
with previously untreated metastatic breast cancer. There was also
signi¿cantly more hypertension in women who received bevacizumab.
To date no biomarkers have been identi¿ed to predict outcome with
use of an anti-angiogenic agent. Genetic variability has the potential
to predict differences in incidence of malignancy, prognosis, and
altered metabolism of certain drugs. Several polymorphisms within
the angiogenesis pathway have demonstrated capacity to discriminate
biologic phenotypes for processes that rely on angiogenesis. The
Vascular Endothelial Growth Factor (VEGF) -1498C allele has
previously been associated with increased promoter activity and an
increased risk of breast cancer.
Methods: DNA was extracted from tumor blocks of 363 patients from
E2100. Approximately 50% were from the control arm (paclitaxel)
and 50% from the experimental arm (paclitaxel + bevacizumab).
Genotyping was performed on VEGF (-2578C/A, -1498C/T, -1154 G/A,
-634G/C, & 936C/T) and VEGF-Receptor 2 (VEGFR-2) (889G/A &
1416A/T) genes. Testing for correlations between each polymorphism
with ef¿cacy (PFS and RR) and toxicity (grade 3/4 hypertension)
was performed. Cox’s proportional hazards method and Fisher’s
exact test were used to assess association. P-values were two sided.
Testing for associations of polymorphisms with overall survival and
expression (immunohistochemical assessment of VEGF and VEGFR2) is planned.
Results: The -1498C and -634G alleles were associated with grade
3/4 hypertension in the experimental arm. Percentage of grade 3/4
hypertension for women who received bevacizumab by -1498 C/T
genotype was: CC=33% (n=24), CT=27% (n=63), TT=10% (n=48)
(p=0.03). Percentage in the -634G/C genotype was: GG=26% (n=51),
GC=27% (n=64), CC=0% (n=19); (p=0.02). -1498 C/T and -634
G/C are in linkage disequilibrium. Signi¿cantly higher response rates
were seen for patients with the VEGFR-2 889A allele: AA=100%
(n=2), GA=57% (n=30), GG=37% (n=121) (p=0.02). No difference,
however, was observed for PFS for this allele. A trend for inferior
PFS for patients with VEGF 936TT genotype was observed (TT v.s
CC+CT; HR=2.30(95% CI=0.93, 5.68), p=0.07) but there were only
¿ve patients with this genotype.
Conclusion: Our data support an association between increased risk of
grade 3/4 hypertension with the VEGF -1498C and the -634G alleles.
Findings of an inferior PFS for those with the VEFG 936TT genotype
are provocative but there were too few numbers to draw de¿nitive
conclusions. These results should be re-evaluated in an independent
data set.
1108
A novel assay to assess the antiangiogenic potential of
cytotoxic drugs in human breast cancer.
Lyons, III JM, Anthony CT, Woltering EA. Louisiana State University
Health Science Center, New Orleans, LA
Background: Trends in breast cancer management advocate
individualizing therapy. Investigators often use tumors’ cellular
proliferation or growth factor expression as a measure of drug ef¿cacy;
however, there are no human, tumor-based assays available which
evaluate a drug’s antiangiogenic potential. To develop such an assay, we
hypothesized that fresh, surgically-harvested, human, malignant breast
tumors would develop an angiogenic response in a ¿brin-thrombin
clot, sprouting neovessels in a time-dependent fashion. We further
speculated that treatment of tumors with standard antineoplastic drugs
would inhibit the percent of tumor explants that developed invasion of
neovessels into the ¿brin-thrombin clot.
Materials and Methods: Fragments of freshly harvested human breast
tumors were embedded in ¿brin-thrombin clots and treated with ¿ve
cytotoxic agents commonly used in breast cancer: Adriamycin, Taxol,
5-FU, Methotrexate, and Vincristine (n=30 explants per treatment
group). Tumor fragments were tested with a single dose of each reagent
at or above its clinically achievable in vivo concentration. These
experiments were repeated using four separate breast cancer specimens.
The angiogenic response was visually assessed noting the angiogenic
invasion into the clot (% I) and the extent of angiogenic growth (AI)
using a previously validated scale. These data were then combined to
give a mean overall angiogenic effect for each treatment group.
Results: All four breast cancer specimens tested developed an
angiogenic response sprouting neovessels in vitro in a time-dependent
fashion (r = .81, p =.0008). Taxol statistically inhibited angiogenesis in
all 4 tissues with a decrease in the mean angiogenic initiation, neovessel
growth, and overall effect that were 76%, 66%, and 94% of control
values, respectively. Vincristine also inhibited the overall angiogenic
effect in all 4 tumors (mean decrease compared to control = 90%).
Methotrexate increased mean angiogenic initiation, neovessel growth,
and overall effect by 8%, 8%, and 14%, respectively. These results
were not statistically signi¿cant. 5-FU inhibited angiogenesis in 3 of 4
breast cancers (mean decrease in overall effect compared to control =
78%), while Adriamycin inhibited angiogenesis in 2 of 4 tissues (mean
decrease in overall effect compared to control = 60%).
Discussion: Freshly harvested breast cancer specimens develop an
angiogenic response in our assay system, and they respond to treatment
with antineoplastic /antiangiogenic drugs. The antiangiogenic potential
of commonly used breast cancer drugs varied among individual human
breast malignancies. Data obtained from this model is unique and could
potentially be used to further enhance the ef¿cacy of cytoxic regimens
and further individualize patient therapy.
1109
Comparing serum levels of vascular endothelial growth
factor in premenopausic women with breast cancer
according to menstrual cycle phase.
Rios Zaragoza S, Martinez Chequer J, Mainero Ratchelous F. Hospital
“Luis Castelazo Ayala” IMSS, Mexico, DF, Mexico
Background. Breast cancer (BC) is a serious and increasing health
problem in Mexico. There are no available assays that compare serum
levels of vascular endothelial growth factor (VEGF) in premenopausic
women with BC undergoing surgical treatment. Hypoxia and steroid
hormones (specially progesterone) among other factors, stimulate
angiogenesis. This can be measured by determining serum levels of
VEGF. Premenopausic women have hormonal level variations by
effect of the ovulation process throughout their menstrual cycle (MC).
Hence we considered the next question: what’s the effect of menstrual
cycle phases on angiogenesis in breast cancer patients? Our objective
was to evaluate serum concentrations of VEGF in premenopausic
women with BC according to the phase of their MC. Material and
methods. Two groups of patients were considered. The ¿rst group
was for premenopausic women with BC in the proliferative phase
(PP) of their MC prior to the surgery date. The second group was for
those in the secretory phase (SP). They were ¿rst divided by means of
their last menstrual period date (LMP) obtained by direct questioning
S79
and afterwards hormonal levels for each patient were compared with
the LMP in order to con¿rm that each patient belonged to the correct
group. Blood samples were drawn from all patients and processed
the day before and the day after the surgery. Luteinizing hormone,
follicle-stimulating hormone, estrogen, progesterone and VEGF serum
levels were measured to these samples via quimioluminiscence and
ELISA (using Quantikine© human VEGF immunoassay). Results
were compared between both groups. Once the statistical analysis was
completed it resulted as follows. Results. After comparing hormonal
status and LMP for each patient, both groups of study were established:
the PP group (n=24) and the SP group (n=42) Mean age was 40.6 years.
The mean concentration of VEGF for patients in PP was of 239,16
pg/ml (SD 107,05 pg/ml) whereas for the group of patients in SP was
of 600,72 pg/ml (SD 297,06 pg/ml) the variance analysis revealed
that VEGF concentrations were signi¿cantly higher for the group of
patients in secretory phase that in those of the group in proliferative
phase (p = 0.001) A subgroup variance analysis of histological type,
number of axillary lymph nodes and clinical stage showed similar
results. Conclusions & discussion. With these results, a precedent is
set concerning the impact of hormonal status in premenopausic patients
with BC as an angiogenesis-stimulating inÀuence particularly during
the SP of the MC. This study continues in order to gather additional
information on the inÀuence of surgical timing; surgical and hormonal
impact of these results combined and follow-up along with survival
rates in these patients.
1110
Nuclear FoxO3a expression is associated with lymph node
negative, ER+ invasive ductal carcinomas.
Turashvili G, Fridman E, Romanska H, Lam E, Skarda J, Murray
P, Kolar Z, Lalani E-N. Institute of Pathology, University Olomouc,
Palacky, Czech Republic; Tel Aviv University, Chaim Sheba Medical
Center and Sackler School of Medicine, Tel Aviv, Israel; Division
of Cancer Studies, University of Birmingham, Birmingham, United
Kingdom; Imperial College, London, United Kingdom
INTRODUCTION. The FoxO (Forkhead bOX-containing protein, O
subfamily) family of transcription factors have been implicated in a
number of processes including tumour suppression, promoting apoptotic
cell death and protecting cells from DNA damage and oxidative stress.
The activity of FoxOs is primarily controlled via the phosphoinositide3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) pathway. Recent
evidence suggests that deregulation of FoxOs may occur in a variety
of tumors including breast cancers.
AIM: The aims of our study were to: a. assess the pattern of protein
expression of FoxO3a; and b. determine if there was any association
between pattern of FoxO3a expression with grade, stage, oestrogen
(ER), progesterone (ER) and c-erbB2 receptor expression, in invasive
ductal breast carcinomas (IDCs).
MATERIAL AND METHODS. We constructed a tissue microarray
from 80 IDCs. TMA sections were stained using standard
immunohistochemical methods and expression analysis of FoxO3a,
ER, PR and c-erbB-2 was undertaken utilizing commercially available
monoclonal and polyclonal antibodies.
RESULTS. 78.8% (63/80) of the IDCs expressed FoxO3a. Two
predominant subcellular localisation patterns of FoxO3a were observed:
a. Cytoplasmic in 24/63 (38%) samples and b. nuclear-cytoplasmic in
39/63 (62%) samples The majority of cases with nuclear-cytoplasmic
pattern 87% (34/39) were lymph node negative. The converse (only
37.5%, 9/24) was observed in cases with the cytoplasmic expression
only. c-erb2 was ampli¿ed in 50% of the cases in which cytoplasmic
FoxO3a expression was seen but in none of the cases with nuclearcytoplasmic expression. The pattern of FoxO3a expression was
associated with ER+ status but not histological grade or PR status.
CONCLUSION. The in vivo FoxO3a pattern of expression appears to
relate to its function and biological behaviour of IDC. The functional
link with c-erbB2 ampli¿cation remains to be elucidated.
S80
1111
Labeling pattern of breast cancer stem phenotype in invasive
breast carcinomas: an immunohistochemical analysis.
Shaye AN, Sahin AA, Huo L, Woodward WA. UT M.D. Anderson Cancer
Center, Houston, TX
Background: The epithelial component of breast parenchyma is thought
to arise from a stem cell which is capable of pluripotent differentiation
and self-renewal. Breast carcinomas are thought to originate from these
stem cells or their immediate progeny. The identi¿cation of these stem
cells and their further characterization have important implications for
the understanding of carcinogenesis and may suggest new approaches
for the treatment and prevention of breast cancer. Results of Àow
cytometric studies suggest that breast cancer stem cells are characterized
by a CD44+/CD24- phenotype. The purpose of this study was to
evaluate the distribution of CD44+/CD24- phenotype cells in invasive
breast carcinoma and adjacent non-neoplastic breast parenchyma using
immunohistochemistry (IHC).
Materials and Methods: Serial sections from archival paraf¿n-embedded
tissue blocks from 33 invasive primary breast carcinomas were
analyzed using IHC for CD44 (Novocastra; Boston, MA) and CD24
(Neomarkers; Freemont, CA). Positive tumor cell staining was de¿ned
as circumferential membrane labeling for CD44 and as cytoplasmic
labeling for CD24. The number of tumor cells expressing CD44 and
CD24 was assessed by light microscopy and grouped into the following
categories for both invasive carcinoma and carcinoma in-situ: <5%,
5-50% and >50% labeling.
Results: Both invasive and in situ carcinomas showed varying
expression and distribution patterns of CD44 and CD24 labeling.
Labeling percentages for both markers in invasive and in situ carcinoma
components are shown in Table 1.
Benign stromal cells and myoepithelial cells also stained positively
for CD44 in >80% of cases where it was present in the tissue section.
CD24 positivity was identi¿ed in a similar proportion of cases, and
was con¿ned to luminal cells.
Discussion: In the majority of the invasive carcinomas, <50% of
cells showed immunohistochemical labeling for CD44; whereas,
CD24 labeling was more diffuse. There was no consistent pattern of
distribution of CD44 positive cells in invasive carcinoma. Similarly,
the staining pattern of invasive and in-situ carcinoma components were
not always concordant. There was no pronounced difference in labeling
of invasive or in-situ carcinoma for CD24. The higher proportion of
positive labeling tumor cells for CD44 using immunohistochemistry
compared to previously reported Àow cytometric studies suggests that
immunohistochemistry may lack speci¿city in the identi¿cation of
breast cancer stem cells. Further studies are required in order to evaluate
the utility of immunohistochemistry in the identi¿cation of tumor cells
which express the breast cancer stem cell phenotype, CD44+/CD24-.
Additional markers need to be investigated.
Labeling Percentages
Invasive Carcinoma (n=33)
<5%
5-50%
>50%
CD 44
13
13
7
CD 24
9
10
14
In-situ Carcinoma (n=13)
<5%
5-50%
>50%
4
2
7
2
2
9
1112
Differential proteomic pro¿les observed in FFPE breast
tissue specimens of several pathologic states.
Izbicka E, Streeper R, West FB, Yeh I-T. CTRC, San Antonio, TX;
UTHSCSA, San Antonio, TX
Background: Proteomic analysis of tissue specimens allows for the
characterization of protein expression pro¿les that reÀect the altered
physiologic state of cells present in pathology tissue specimens.
The differences observed may serve to guide the identi¿cation of
pathognomonic protein expression patterns that will facilitate the
early detection of pathologic transformations with high speci¿city and
sensitivity. Formalin ¿xed paraf¿n embedding is the storage method
of choice for diagnostic specimens in pathology departments. We
undertook this study determine the identities of differentially expressed
protein species in FFPE specimens from various pathological states
of breast tissue
Materials and Methods: We examined FFPE archival breast tissue
specimens including normal (n = 23), ¿broadenomas (n = 21), node
negative (n = 25) and node positive (n = 22) breast cancers. Ten micron
sections were microdissected, de-paraf¿nized and digested with trypsin.
Digests were then analyzed by liquid chromatography electrospray
ionization mass spectrometry (LC-ESIMSMS) Differential analysis
of the resulting mass spectral data allowed for the identi¿cation of
differentially expressed mass/time signals which were then subjected
to both on line and off line mass spectrometry-mass spectrometry
(MSMS) analysis for the determination of peptide sequence. The data
were analyzed and putative protein identi¿cations were made using the
Mascot protein mass spectral database search software. Clinical data
including histological subtype, estrogen and progesterone receptor
status, HER2 status, p53 and Ki-67 status were also evaluated in the
breast cancer specimens.
Results: MS analyses of FFPE tissue digests allowed the identi¿cation
of a number of proteins and classes of proteins that are differentially
expressed in the examined pathologic states relative to the levels
observed in the analyses of normal tissue samples. We have observed
that a number of proteins are either over or under expressed in the
examined specimens. Notable is the relative dearth of peptide signals
observed in the breast cancer specimens, both node negative and node
positive. Identi¿ed classes include types of intra-cellular structural
proteins, proteins involved in energy metabolism, transcriptional
regulation and intra and inter cellular signaling pathway related
species.
Discussion: These results of our examination of the proteomic pro¿les
of FFPE breast tissues show a number of signi¿cant differences between
normal and tumor tissues. The physiological implications of the observed
differences suggest a number of lines of inquiry for future studies. The
results are to a degree confounded by factors including variability in
tryptic digestion ef¿ciency due to gross structural differences, differing
degrees of formalin mediated crosslinking within the specimens or basic
proteomic changes characteristic of malignant tissues.
1113
Insulin-like growth factor I activates gene transcription
programs strongly associated with ER – breast cancer and
Creighton CJ, Casa A, Lazard ZW, Tsimelzon A, Hilsenbeck SG, Lee
AV. Baylor College of Medicine, Houston, TX
Background: Substantial evidence implicates insulin-like growth factor
I (IGF-I) signaling in the development and progression of breast cancer.
To identify transcriptional targets of IGF action, we performed gene
expression pro¿ling (>22,000 RNA transcripts) of IGF-I-stimulated
MCF-7 cells, a well characterized breast cancer cell line highly
responsive to IGFs.
Materials and Methods: We de¿ned an IGF-I gene signature pattern of
hundreds of genes either up- or down-regulated at both 3 and 24 hrs
in vitro. After removing genes considered generic to cell proliferation,
the signature was examined in various public pro¿le datasets of human
breast tumors, as well as in pro¿le datasets of experimental models for
various oncogenic signaling pathways.
Results: Genes with early and sustained regulation by IGF-I were highly
enriched for transcriptional targets of the estrogen, Ras, and PI3K/Akt/
mTOR pathways. The IGF-I signature appeared activated in most ERhuman breast tumors and in a substantial subset (∼25%) of ER+ breast
tumors. Patients with tumors showing activation of the IGF-I signature
tended to have a shorter time to disease recurrence (including patients
not receiving adjuvant therapy), both when considering all patients and
the subset of ER+ patients.
Discussion: We found evidence for cross-talk and common
transcriptional endpoints between the IGF-I and estrogen systems. Our
results support the idea that the IGF-I pathway is one mechanism by
which breast tumors may acquire hormone independence and a more
aggressive phenotype.
Multivariate Cox analysis of tumor characteristics and IGF gene signature in relation to the
likelihood of distant recurrence.
van de Vijver dataset Wang dataset
Miller dataset
Variable
P-value 95% CI HR P-value 95% CI HR P-value 95% CI HR
Age
0.37
0.43-1.38
--0.38
0.36-1.50
Tumor size
0.05
1.00-2.38
--0.004
1.38-5.78
Grade
0.26
0.86-1.72
--0.76
0.54-1.58
LN
0.19
0.50-1.15
--<0.001 1.66-5.54
ER status
0.31
0.61-4.47
0.62
0.60-2.34
0.32
0.57-5.46
ER mRNA
0.78
0.68-1.65
0.04
1.01-1.89
0.24
0.83-2.01
PR mRNA
0.02
0.58-0.96
<0.001 0.56-0.87
0.54
0.64-1.27
HER2 mRNA 0.21
0.93-1.35
0.69
0.79-1.17
0.08
0.97-1.65
IGF signature <0.001 1.36-2.53
0.004
1.12-1.82
0.006
1.17-2.79
Age, size, LN, and ER-status were binary variables (0 for age<50y and 1 for age>=50, 0
for dia<=2cm and 1 for dia>2cm, 0 for LN- and 1 for LN+, and 0 for ER- and 1 for ER+,
respectively). Grade was binned as 1, 2, and 3, for low, medium, and high, respectively.
ER mRNA, PR mRNA, HER2 mRNA, and the IGF gene signature coef¿cient were each
transformed to SD from the mean.
1114
HER-1 overexpression is found only in oestrogen receptor
negative breast cancer and is rarely associated with +(5
gene ampli¿cation.
Pintens S, Vanden Bempt I, Drijkoningen M, Van Belle V, Brouckaert
O, Christiaens M-R, Neven P, De Wolf-Peeters C. UZ Leuven, Leuven,
Belgium; ESAT, Leuven, Belgium
Background and Aims: Recently, it has been hypothesized that HER-1
overexpression plays a role in triple ER-/PR-/HER-2- negative breast
carcinomas. As HER-1 might be a target for therapy, we investigated
the HER-1 status in triple negative compared to grade-matched nontriple negative breast carcinomas.
Materials and methods: In total, 57 high-grade breast carcinomas
were studied: 25 triple negative cases and 32 grade-matched controls
with variable ER/PR/HER-2 phenotypes. For all cases, formalin-¿xed
paraf¿n-embedded material was available. HER-1 expression was
examined by immunohistochemistry (IHC) using the standardized
PharmDx kit (Dakocytomation). Cases with membrane staining in
more than 10% of invasive tumour cells were regarded as showing
HER-1 overexpression. HER-1 gene copy number was determined by
Fluorescence in situ Hybridisation (FISH) using a probe for HER-1 and
a control probe for chromosome 7, on which HER-1 is located (Vysis).
A mean ratio of HER-1 gene to chromosome 7 copy number greater
than 2 was considered to be HER-1 gene ampli¿cation.
Results: Overall, HER-1 overexpression was found in 20 out of 57
(35.1%) high-grade breast carcinomas, all of them being ER negative.
Out of the 25 triple negative cases, 13 showed HER-1 overexpression
(52.0%). HER-1 gene ampli¿cation was found in 5 cases (8,8 %) and
was always associated with HER-1 overexpression. Of note, HER-1
gene ampli¿cation was a generalized event, as it was found in more than
90% of the tumours cells in all 5 cases. By contrast, HER-1 expression
was more variable throughout the tumour. Still, 3 out of 5 HER-1
ampli¿ed cases also showed generalized HER-1 overexpression.
Interpretation and Conclusion: HER-1 overexpression was restricted
to ER-negative breast carcinomas, half of which were triple negative.
HER-1 overexpression was accompanied by HER-1 gene ampli¿cation
in only a minority of the cases. Therefore, HER-1 gene ampli¿cation
is unlikely to be a driving mechanism for HER-1 overexpression.
Nevertheless, it might delineate a particular subgroup of ER-negative
breast carcinomas that might benefit from therapy with HER-1
inhibitors.
1115
Effectiveness of RAD001 (everolimus) in combination with
endocrine therapy varies with cell phenotype.
Farmer I, Pancholi S, Thornhill A, Evans DB, Lane HA, Dowsett M,
Martin L-A. Institute of Cancer Research, London, United Kingdom;
Novartis Institute for BioMedical Research-Basel, Basel, Switzerland
Background: Cross-talk between Receptor Tyrosine Kinase (RTK) and
ER signal transduction pathways appears to contribute to endocrineresistance leading to elevations in phosphorylated ERK1/2 and AKT.
Based on this evidence, one strategy to improve the ef¿cacy of current
endocrine agents as well as delaying the onset of resistance is to target
the ER and pertinent signal transduction pathways concomitantly. An
S81
obvious choice is mTOR (a down-stream member of the PI kinase
family), which regulates cell cycle progression, by enhancing translation
initiation and/or the stability of cell cycle regulatory proteins such
as D-type cyclins. In the following study we investigated the use of
RAD001 (everolimus), a speci¿c inhibitor of mTOR in combination
with tamoxifen or letrozole on a panel of human breast cancer cell lines
modelling endocrine-sensitive and -resistant disease.
Materials and Methods: Human breast cancer cell lines with varying
expression levels of ER and HER2 [MCF7 (ER+HER2-), BT474
(ER+, HER2++) and SKBR3 (ER-, HER2++)] were engineered to
express aromatase. The effect of RAD001 ± tamoxifen or letrozole was
assessed in proliferation and ER alpha-mediated transcription assays.
Immunoblotting was used to monitor the effect of RAD001 on mTOR
signalling and cell cycle. Xenograft studies with MCF7-AROM1
cells and BT474-AROM3 were carried out to compare RAD001 in
Results: Treatment of the target cell lines with increasing concentrations
of RAD001 resulted in a concentration-dependent decrease in
proliferation regardless of the cells ER/HER2 status. A concomitant
reduction in phosphorylated p70 S6 kinase and S6 coupled with
an increase in phosphorylated AKT was also noted. RAD001 in
combination with either tamoxifen or letrozole enhanced the antiproliferative effect compared to either monotherapy in the ER+ cell
lines. This was associated with an increase in the number of cells in
G1 phase compared to the monotherapies. Of note the combination of
RAD001 with letrozole or tamoxifen enhanced nuclear accumulation
of p27 and increased p27 phosphorylated at Ser10. There was also a
marked decrease in cyclin D1 and enhanced phosphorylation of Rb
compared to cells treated with the endocrine agents alone. MCF7AROM1 xenografts were growth-suppressed with letrozole, tamoxifen
or RAD001 when used alone as compared to the vehicle-treated control.
However, whilst tamoxifen in combination with RAD001 provided no
added bene¿t compared with either agent alone, letrozole plus RAD001
resulted in the greatest reduction in tumor volume. Strikingly, treatment
of BT474-AROM3 xenografts, showed that RAD001 alone was equally
effective at reducing tumor volume as the combination therapies.
Conclusion: These data suggest that the tumor phenotype markedly
affects the response to the combination of RAD001 with endocrine
therapy, and may predict the effectiveness of the combination clinically
for the treatment of breast cancer.
1116
Combination therapy with tetramethoxystilbene and
phosphatidylinositol 3-kinase inhibitor is effective for killing
hormone-resistant breast cancer.
Park H, Aiyar SE, Kim S, Lee Y, Fan P, Santen RJ. Kyungpook National
University Hospital, Daegu, Republic of Korea; University of Virginia,
Charlottesville, VA; Seoul National University, Seoul, Republic of
Korea
Background:
Treatment of hormone-dependent breast cancer with tamoxifen,
faslodex and aromatase inhibitors can initially lead to tumor regression
but relapses usually occur after 12-18 months on average. Resistance
to these inhibitors occurs in part because of up-regulation of growth
factor pathways. Abrogation of these pathways with inhibitors of
MAP kinase, PI-3-kinase, mTOR EGF-R, IGF-R and HER-2 have
been used, but are not completely effective for preventing and treating
resistance. Targeted therapies also are not suf¿cient to control metastatic
breast cancer. Therefore, combination therapy has been suggested
as an alternative strategy. We have discovered that TMS (2,3’,4, 5’tetramethoxystilbene), a derivative of an herbal compound, modulates
microtubule polymerization and results in death of breast cancer cell
lines. TMS inhibited phosphorylation of focal adhesion kinase (FAK),
Akt, and mammalian target of rapamycin (mTOR), while stimulating
c-Jun N-terminal kinase (JNK) activity. We propose that TMS can be
used in combination with other inhibitors to induce potent cell death
while minimizing toxicity.
Methods: The following MCF7 ER (+) cell lines were used: parental,
tamoxifen resistant (TamR), long term estrogen deprived (LTED) and
ICI resistant (ICI-R). We examined TMS in the absence and presence of
the following inhibitors (PI3K, mTOR, MAPK, AKT, EGFR and IGFR)
S82
for both cell growth analysis and apoptosis measurements
Results: Treatment of MCF7 cells with TMS alone reduced MCF7 cell
counts by 70%. When used in combination with the PI3K inhibitor,
the cell counts were further reduced by 80% over PI3K inhibitor alone
(p=.00000117). Combination treatment increased apoptosis 1.7 fold
over TMS alone (p=.000218). In addition, E2 does not change the
apoptotic effect of TMS. The PI3K inhibitor was also the most effective
compound ( i.e 60% reduction in cell number ) in the hormone-resistant
cell line TamR. The combination of the PI3K inhibitor and TMS is
highly effective for decreasing the TMA R cell number. LTED cells
were most effectively killed by either a combination of TMS + Estradiol
or a combination of TMS + PI3K inhibitor. Immunoblot analysis
demonstrated that PARP is cleaved by single treatment with either
TMS or PI3K, while the combination of the two resulted in increased
cleavage. PARP cleavage can be blocked in the presence of zVAD.
Conclusion: TMS, when used in combination with another inhibitor,
reduced cell counts and increased apoptosis. Therefore, we suggest
that combination therapy with TMS may be an effective way to control
ER(+) hormone-resistant breast cancer.
1117
Inhibition of breast cancer growth with the combination of
lapatinib and an ADAM protease inhibitor.
Witters LM, Scherle PA, Friedman SM, Redman J, Fridman JS, Caulder
E, Lipton A. Pennsylvania State University College of Medicine,
Hershey, PA; Incyte Corporation, Wilmington, DE
The ErbB family of receptors, ErbB1 (EGFR) and ErbB2 (HER-2/
neu), has been shown to play a signi¿cant role in the proliferation of
human tumors. Many breast tumors overexpress these receptors and
this correlates with poor prognosis and resistance to therapy. These
receptors, when triggered by the binding of appropriate ligands, activate
multiple cellular downstream pathways that in turn lead to tumor growth
and survival. Although inhibitors of the ErbB family of receptors, e.g.,
Herceptin, have demonstrated clinical ef¿cacy in several solid tumors,
not all HER-2/neu positive tumors respond and many that respond
initially develop resistance, presenting the need for alternative therapies.
Proteolytic cleavage of both ErbB ligands and receptors has been shown
to be a critical event resulting in pathway activation. This cleavage is
necessary for the generation of soluble, functionally active forms of
the ligands and in the case of HER-2/neu, results in a shed extracellular
domain (ECD) and a membrane bound fragment (p95) containing a
kinase domain with signi¿cant constitutive activity. Importantly, the
presence of elevated HER-2/neu ECD in the sera of cancer patients
has been linked to poor response rates. Both ErbB ligand and HER2/neu cleavage have been shown to be mediated by the ADAM (a
distintegrin and metalloproteinase) family of zinc-dependent proteases.
We ¿rst examined the effect of combining a dual kinase inhibitor of
EGFR and HER-2/neu similar to lapatinib (GW2974) with an ADAM
protease inhibitor (INCB3619: Incyte Corp.) on the growth of MCF-7
and HER-2/neu-transfected MCF-7 cells. Exposure to INCB3619 (10
- 40 µM) produced minimal growth inhibition as a single agent in the
HER-2/neu-transfected MCF-7 cells (0-14% inhibition) and MCF-7
cells (22-38% inhibition). Addition of the EGFR/HER-2/neu inhibitor
(GW2974) resulted in a synergistic inhibitory effect in both cell lines.
Lower concentrations of INCB3619 (0.25 – 1 µM) (doses found to be
clinically achievable with the equipotent ADAM inhibitor, INCB7839,
currently in clinical trials) were also tested in the HER-2/neu-transfected
cells and produced synergistic growth inhibition when combined with
GW2974. Three days exposure to 10 µM INCB3619 signi¿cantly
reduced the amount of shed HER-2/neu ectodomain into the supernatant
of treated cells as measured by a HER-2/neu ectodomain speci¿c
ELISA (Oncogene Science). Combination of the clinical candidate
ADAM inhibitor, INCB7839, with lapatinib prevented tumor growth
in the BT474-SC1 human breast cancer xenograft model. These results
suggest that combining an ADAM inhibitor with kinase inhibitors of
the ErbB family may provide an improved result in the treatment of
1118
X3$5 gene ampli¿cation in breast cancer tissue: a rare
event.
Pintens S, Vanden Bempt I, Drijkoningen M, Van Belle V, Brouckaert
O, Christiaens M-R, Neven P, Peeters C. UZ Leuven, Leuven, Belgium;
ESAT KULeuven, Leuven, Belgium
Introduction: Overexpression of the urokinase Plasminogen Activator
Receptor (uPAR) has been associated with increased metastatic
potential and adverse prognosis in breast cancer. Recently, uPAR
overexpression has been associated with uPAR gene ampli¿cation on
chromosome 19q13 and was frequently found together with HER-2
gene ampli¿cation in isolated breast cancer cells.
Aims: We aimed to investigate the uPAR gene status in tissue sections
of breast cancer and to study its relation to the HER-2 gene status.
Materials and Methods: In total, we studied 57 high-grade primary
invasive breast carcinomas for which formalin-¿xed paraf¿n-embedded
material was available. The HER-2 and uPAR gene status were
determined by Fluorescence in situ Hybridisation (FISH) analysis.
For HER-2, a dual-probe kit was used including a probe for HER-2
and a control probe for chromosome 17 (PathVysion, Vysis): a HER-2/
chromosome 17 ratio greater than 2 was considered ampli¿ed for HER2. For uPAR, we used a dual-probe kit including a probe for uPAR and a
control probe for the opposite arm of chromosome 19 (19p13). A ratio
of uPAR/19p13 greater than 2 was considered ampli¿ed for uPAR.
Results: Out of 57 cases, 25 were ampli¿ed for HER-2. Only 1 of
these cases showed concurrent ampli¿cation of the uPAR gene (1/25,
4.0%). Thereby, the mean uPAR gene copy number was 10 compared
to 20 for HER-2. No uPAR gene ampli¿cation was found in non-HER-2
ampli¿ed breast carcinomas. While uPAR gene ampli¿cation was rare,
we frequently observed aneuploidy of chromosome 19 (35/57, 61.40%):
34 cases showed polysomy 19 and one case monosomy 19.
Interpretation and Conclusion: FISH analysis on tissue sections
indicates that uPAR gene ampli¿cation is extremely rare in breast cancer.
Whereas related to HER-2 gene ampli¿cation, it is unlikely to play an
important role in the pathogenesis of breast cancer.
1119
Targeting of mTOR is associated with decreased VEGF
expression and secretion in cancer cells.
Lackner EM, Krauth MT, Kondo R, Rebuzzi L, Eigenberger K, Vales A,
Kornek GV, Zielinski CC, Valent P. Medical University Vienna, Internal
Medicine I, Division of Oncology, Vienna, Vienna, Austria; Medical
University Vienna, Internal Medicine I, Division of Hematology and
Hemostaseology, Vienna, Vienna, Austria; Clinic for Int. Medicine and
Infectious Disease, Vienna, Vienna, Austria; Hanusch Krankenhaus,
Vienna, Vienna, Austria
Background: Cancer progression and metastasis are often associated
with increased angiogenesis and with the formation of malignant
effusions. Vascular endothelial growth factor (VEGF) is a major
regulator of angiogenesis, vascular permeability, and cell survival.
We examined the production and secretion of VEGF in various cancer
cell lines and primary tumor cells, and examined the regulation of
synthesis/secretion of VEGF in tumor cells.
Methods&Results: As assessed by ELISA, the VEGF protein was
detected in supernatants of cell lines derived from breast cancer
(MDA-MB231), pancreatic carcinoma (BxPC-3), lung cancer (A-427),
colon carcinoma (HCT8), and cholangiocellular carcinoma (EGI-1). In
addition, VEGF was detected in supernatants of primary tumor cells
obtained from malignant effusions in various malignancies (breast
cancer, n=5; pancreatic cancer, n=1; ovarial cancer, n=1; parotic
carcinoma, n=1; esophageal carcinoma n=1). In each case, the VEGF
protein was detectable in neoplastic cells by immunocytochemistry, and
was found to accumulate in supernatants of cultured tumor cells over
time, suggesting constant production and secretion. Correspondingly,
as assessed by RT-PCR, primary tumor cells as well as the cell lines
tested were found to express VEGF mRNA in a constitutive manner.
Since mTOR is a well known regulator of VEGF synthesis, we applied
rapamycin on neoplastic cells. Rapamycin (20-200 nM) was found to
counteract the production and secretion of VEGF in all tumor cells tested
(VEGF in supernatants in cultures supplemented with rapamycin at 100
nM on day 6: MDA-MB231: 11.8±0.2%; BxPC-3: 23.6±18.8%; A-427:
30.1±3.4%; HCT8 17.2±0.5%; EGI-1 28.4±1.1%; p<0.05). Neither
rapamycin nor VEGF were found to modulate growth of primary tumor
cells or tumor cell lines.
Conclusions: Various human tumor cells express and secrete VEGF.
The production of VEGF in tumor cells is mediated through mTOR.
These observations may have implications for the design of new
treatment approaches attempting to counteract VEGF production/
secretion and effusion-formation in solid tumors.
S83
S84
Abstracts – Poster Session II
2001
Elevated serum TIMP-1/HER-2 predicts decreased response
and survival in metastatic breast cancer.
Lipton A, Leitzel K, Chaudri-Ross HA, Evans DB, Ali SM, Demers L,
Hamer P, Brown-Shimer S, Pierce K, Guar V, Carney W. Penn State
University/Hershey Medical Center, Hershey, PA; Novartis Pharma AG,
Basel, Switzerland; Novartis Institutes for BioMedical Research Basel,
Basel, Switzerland; Penn State/Hershey Medical Center; Lebanon
VAMC, Lebanon, PA; Oncogene Science Biomarker Group/Siemens
Medical Solutions Diagnostics, Cambridge, MA
Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has
been shown to have diverse multifunctional roles in tumorigenesis
such as inhibition of the catalytic activity of MMPs, growth promotion,
inhibition of apoptosis and regulation of angiogenesis. Increased TIMP1 has been associated with an unfavorable prognosis in many cancers
including lymphomas, colorectal, gastric, head and neck, and lung
cancer. We have previously reported in separate analyses that elevated
pre-treatment serum TIMP-1 or HER-2 individually predict decreased
response to 1st-line hormone therapy and reduced survival in patients
receiving 1st-line hormone therapy.
Materials and Methods: Pre-treatment serum TIMP-1 and HER-2
levels were determined from 522 patients enrolled in a phase III 1st-line
hormone therapy trial comparing letrozole vs. tamoxifen (H Mouridsen
et al, J Clin Oncol; 19(10):2596-2606, 2001) and from post-menopausal
control females using the TIMP-1 and HER-2 ELISAs from Oncogene
Science Biomarker Group/Siemens Medical Solutions Diagnostics,
Cambridge, MA.
Results: The serum TIMP-1 levels from the post-menopausal control
group (n = 49) had a mean + SD of 315 + 117 ng/ml (range 175940 ng/ml). The upper limit of normal (ULN) was de¿ned as the 95
percentile (non-parametric method) of the control group (454 ng/ml).
Serum TIMP-1 values were elevated above this ULN in 120/522
patients (23 %). Serum HER-2 values were elevated above the ULN
of the control group (15 ng/ml, mean + 2SD) in 152/522 patients (29.1
%). In combined analysis for time to progression (TTP), patients with
elevated TIMP-1/normal HER-2 levels had signi¿cantly decreased TTP
(median 5.7 mo.) compared to patients with normal TIMP-1 and HER-2
levels (median 11.6 mo., p<0.0001). Within treatment arms, TTP was
signi¿cantly longer for letrozole compared to tamoxifen in biomarker
subgroups with normal HER-2 expression regardless of TIMP-1 levels,
but there was no signi¿cant difference between treatments in subgroups
with elevated HER-2. For overall survival, elevated vs. normal TIMP1 levels identi¿ed patients with signi¿cantly shorter survival in both
normal HER-2 (median 26 vs. 42 mo., p= 0.0006) and elevated HER-2
(15 vs. 25 mo., p= 0.012) patient subgroups. Conclusion: Combined
serum biomarker analysis of both TIMP-1 and HER-2/neu confers
additional ability to predict subgroups of patients with signi¿cantly
different clinical outcomes to hormone therapy as compared to using
either biomarker alone. These data suggest that patients with elevated
pre-treatment serum TIMP-1 and/or HER-2/neu levels may require
additional targeted therapies together with endocrine therapy.
2002
Plasminogen activator inhibitor-1 and tissue inhibitor of
metalloproteinases-1 are additive in predicting response to
chemotherapy in metastatic breast cancer.
Schrohl Rasmussen A-S, Meijer-van Gelder ME, Holten-Andersen
MN, Christensen IJ, Look MP, Mouridsen HT, Foekens JA, Brünner
N. University of Copenhagen, Faculty of Life Sciences, Copenhagen,
Denmark; Erasmus MC, Josephine Nefkens Institute, Rotterdam,
Netherlands; Hvidovre Hospital, Hvidovre, Denmark; Rigshospitalet,
Copenhagen, Denmark
Background: Predictive markers are urgently needed in breast cancer.
Here, we analyzed the predictive value of tumor tissue levels of
Plasminogen Activator Inhibitor-1 (PAI-1), which is an established
strong prognostic marker in breast cancer patients. Tumor levels of
Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) has previously
been determined in this patient group (Schrohl et al. 2006) and we
combined the present ¿ndings on PAI-1 with data showing that high
tumor tissue levels of TIMP-1 are associated with a poor response to
chemotherapy.
Materials and methods: The concentration of PAI-1 was measured by
ELISA in cytosolic extracts of primary tumors from 174 patients who
all developed metastatic breast cancer. Response to chemotherapy
for metastatic disease (cyclophosphamide-adriamycin/epirubicin-5Àuorouracil (CAF/CEF) or single-agent adriamycin) was evaluated
and it was analyzed whether this was related to tumor tissue PAI-1
levels. In addition, we investigated whether PAI-1 and TIMP-1 could
be combined for prediction of response to chemotherapy.
Results: In a test for trend, PAI-1 was not signi¿cantly associated
with response rate. However, it was possible to identify a cut point
that when used allowed us to identify two groups with signi¿cantly
different response rates. The group with high tumor tissue PAI-1 levels
consisted of 25 patients of which only two responded to chemotherapy
(8%). In the remaining group (149 patients), having low tumor tissue
PAI-1 levels, 62 patients responded to chemotherapy (42%). Combining
these results with our previous ¿ndings on TIMP-1 we divided patients
into a group having low tumor tissue levels of both markers and a
group having high levels of one or both markers. This resulted in two
patient groups; one group with low marker levels (142 patients) with
a response rate of 44% and one group (32 patients) with a high level
of one or both markers and with a response rate of 6% (p<0.001). In
total, 110 patients were non-responders and by using PAI-1 and TIMP1 we were able to identify 30 of these (27%), at the same time only
misclassifying 2 patients.
Conclusions: In the present study, by measuring tumor tissue PAI-1
and TIMP-1, we were able to identify 27% of all non-responders. In
the group having high levels of tumor tissue TIMP-1 and PAI-1 or both
markers, the response rate was 6% compared with a response rate of
44% in the remaining patient group (low levels of both markers). Thus,
this study generates the hypothesis that patients having high tumor
tissue levels of PAI-1, TIMP-1 or both markers should not be offered
chemotherapy with CMF and/or anthracycline-containing regimens but
should rather be offered an alternative treatment.
2003
17ß-hydroxysteroid dehydrogenase type 1 is a predictive
factor in premenopausal hormone receptor positive breast
cancer treated with tamoxifen.
Kallstrom A-C, Salme R, Ryden L, Gunnarsson C, Nordenskjold B, Stal
O. Helsingborg Hospital, Helsingborg, Sweden; University Hospital,
Linkoping, Sweden; University Hospital, Lund, Sweden
Background: 17ß-hydroxysteroid dehydrogenase (17HSD) are enzymes
involved in the local regulation of sex steroids. 17HSD type 1 enzyme
converts the weak estrone (E1) to the more potent estradiol (E2)
and 17HSD type 2 carries out the reverse reaction (E2 to E1). The
expression of these enzymes in breast cancer differs from that in the
normal mammary glad. Altered expression levels of these enzymes can
be responsible for the modulation of growth as well as responsiveness
to endocrine treatment. The aim was to investigate the levels of these
enzymes in premenopausal breast cancers and to determine if they have
any prognostic or predictive value.
Material and Methods: 564 premenopausal patients with invasive
breast cancer, stage II (UICC) were randomized to receive either 2
years of adjuvant tamoxifen (n=276) or no tamoxifen (n=288). Only
nine patients received adjuvant chemotherapy. The median period of
follow-up was 16 years and data were available for all patients. 396 of
the 564 tumors were available for analysis of 17HSD-1 and 373 tumors
for 17HSD-2. The analysis was done with immunohistochemistry using
tissue micro array from paraf¿n-embedded breast cancer. The enzyme
expression level was determined on a scale ranging from low (-/+/++) to
high (+++). Estrogen and progesterone receptors content were measured
in cytosols and with immunohistochemistry.
Results: Patients with hormone receptor positive tumors with lower
levels (-/+/++) of 17HSD type 1 showed a 43% reduced risk of
recurrence when treated with tamoxifen, HR=0.57 (CI 0.37-0.87). This
was statistically signi¿cant (p =0.0075). On the other hand patients with
high (+++) expression of 17HSD type 1 showed no signi¿cant difference
between the two treatment arms (HR=0.91, CI 0.43-1.95).
Discussion: It has been suggested that 17HSD type 1 predominates
in malignant cells and gives a higher conversion of E1 to E2, which
results in higher intratumoral E2 levels and increased tumor growth.
Our results suggest that tamoxifen may be unable to block the higher
levels of E2 in these tumors. Tamoxifen showed to signi¿cantly reduce
the risk of recurrence in tumors with low expression of 17HSD type 1.
Our data suggest that 17HSD type 1 may be used as a predictive factor
in hormone receptor positive breast cancer treated with tamoxifen but
this needs to be con¿rmed in further studies.
2004
A high ratio of 17HSD1/17HSD2 protein expression predicts
the outcome of tamoxifen treatment in postmenopausal
breast cancer.
Jansson A, Gunnarsson C, Persson L, Fornander T, Skoog L,
Nordenskjöld B, Stål O. Linköping University, Linköping, Sweden;
Karolinska University Hospital, Stockholm, Sweden
Background: After menopaus estrogen biosynthesis in peripheral tissue
has a major role. An enzyme group that affects the availability of active
estrogens is the 17b-hydroxysteroid dehydrogenase family (17HSD).
It is well known that 17HSD activity is responsible for the balance
between estrone and estradiol in breast tissue. There are multiple family
members expressed in breast tissue even though 17HSD1 and 17HSD2
seem to be the principal 17HSD enzymes involved in breast cancer this
far. 17HSD1 catalyzes reduction of estrone to estradiol with NADP(H)
as a cofactor, and 17HSD2 catalyzes oxidation from estradiol to estrone
with NAD(H) as a cofactor. In breast cancer high expression of 17HSD1
and low expression of 17HSD2 is associated to decreased survival in
estrogen receptor (ER) positive breast cancer. However, it remains
unclear if 17HSD-enzymes can predict the outcome of tamoxifen
treatment. The aim of this study was to investigate the prognostic and
predictive value of 17HSD1 and 17HSD2 expression in a group of
breast cancer patients randomized to tamoxifen treatment.
Material and Methods: A randomized tamoxifen trial comprising 1,780
low risk breast cancer patients was conducted in Stockholm, Sweden,
1976-1990. All patients had lymph node negative primary breast cancer
and were postmenopausal at the time of diagnosis. We analyzed the
protein expression of 17HSD1 and 17HSD2 with immunohistochemistry
using tissue microarrays, which were constructed from paraf¿n blocks
originating from 912 patients. 17HSD1 and 17HSD2 could be scored
in 871 (95.5%) and 858 (94%), respectively.
Results: Low expression of 17HSD1 was associated with signi¿cant
bene¿t of tamoxifen treatment (P=0.00045), whereas high expression
was not (p=0.15). For ER+ patients with a 17HSD1 score not exceeding
that of 17HSD2, tamoxifen decreased the risk of distant recurrencefree survival (DRFS) (RR=0.37, 95% C.I. 0.23-0.60) and breast cancer
survival (BCS) (RR 0.30 (0.16-0.54)), whereas no apparent effect was
observed when the score of 17HSD1 was higher that that of 17HSD2.
The interaction was signi¿cant for both DRFS and BCS (p=0.036,
p=0.014). In the cohort of systemically untreated patients no prognostic
importance for 17HSD1 or 17HSD2 could be found.
Discussion: In this study we could not con¿rm that high 17HSD1
expression is associated to shorter recurrence free survival among
systemically untreated patients. More interestingly, in this unique
series of breast cancer patients randomized to tamoxifen we found that
if the expression of 17HSD1 exceeded that of 17HSD2, there was no
bene¿t from tamoxifen treatment. This implicates that tamoxifen does
not completely block the estrogen receptor in these tumors and that the
cells respond to high estradiol levels.
S85
2005
723$ gene ampli¿cation and response to adriamycin
based therapy.
Tubbs R, Barlow W, Budd GT, Swain E, Porter P, Yeh I-T, Sledge
G, Shapiro C, Ingle J, Haskell C, Albain K, Livingston R, Hayes D.
Cleveland Clinic, Cleveland, OH; Seattle, WA; Fred Hutchinson Cancer
Research Center, Seattle, WA; University of Texas Health Science
Center at San Antonio, San Antonio, TX; Indiana University Medical
Center, Indianapolis, IN; Arthur James Cancer Center Hospital,
Columbus, OH; Mayo Clinic, Rochester, MN; UCLA Medical Center,
Santa Monica, CA; Loyola University Medical Center, Maywood, IL;
Arizona Cancer Center, Tucson, AZ; University of Michigan Medical
Center, Ann Arbor, MI
Introduction:
Reports have suggested that ampli¿cation and/or deletion of the TOP2A
gene are positive predictive markers of response to anthracycline-based
therapy. Using Àuorescence in situ hybridization (FISH), we determined
the status of the HER2 and TOP2A genes in a large cohort of breast
cancer patients treated with two regimens of doxorubicin (A) and
cyclophosphamide (C).
Tissue microarrays (TMA) were constructed from paraf¿n blocks
collected from SWOG study S9313/Intergroup0137. Survival was
similar in 3122 women with moderate-risk primary breast cancer
who received equivalent doses of either concurrent adjuvant highdose chemotherapy with A plus C (n = 1595) or high-dose, sequential
chemotherapy with A followed by C (n = 1527) (Linden, JCO. 25:656,
2007). FISH for TOP2A/CEP17 and HER2/CEP17 (Abbott Molecular)
were performed for 1637 and 1493 cases respectively, using automated
TMA core tracking and FISH tiling quanti¿cation (Metasystems).
Results:
An abnormal TOP2A genotype was identi¿ed for 150/1637 (9.1%) of
cases (3.7% ampli¿ed, 5.4% deleted). An abnormal HER2 genotype
was identi¿ed for 294/1493 (19.7%) of cases (18.1% ampli¿ed, 1.6%
deleted). All but one TOP2A ampli¿ed case were co-ampli¿ed for
HER2. Survival was marginally associated with HER2 ampli¿cation
(ratio>2) (OS hazard ratio (HR) = 1.32; p=.07; DFS HR=1.22; p=.12),
but was strongly associated for a ratio>4 (OS hazard ratio (HR) = 1.78;
p=.001; DFS HR=1.65; p=.001). No signi¿cant differences in either
overall or disease free survival were identi¿ed for TOP2A ampli¿cation
and deletion.
Conclusions:
TOP2A genotypic abnormalities were not associated with outcome in
this large prospective trial of patients treated with AC, consistent with
TOP2A abnormalities being associated with an adverse prognosis,
but balanced by greater responsiveness to anthracycline-based
chemotherapy. HER2 ampli¿cation remains a prognostic marker in
anthracycline-treated patients.
2006
Double staining chromogenic in situ hybridization is a
useful alternative to Àuorescent in situ hybridization: ¿rst
comparative study of HER2 and TOP2A gene ampli¿cation
in breast cancer.
Lacroix-Triki M, Mounie E, Charafe-Jauffret E, Jacquemier J.
Institut Claudius Regaud, Toulouse, France; Institut Paoli-Calmettes,
Marseille, France
Background : Analysis of gene ampli¿cation such as HER2 and
TOP2A in invasive breast cancer has now become a critical issue.
Chromogenic in situ hybridization (CISH), which uses the easier
bright¿eld microscopy, is an attractive alternative to Àuorescent in situ
hybridization (FISH), particularly since the recent development of a
dual-color CISH technique converting FISH signals to chromogenic
stainings. In comparison with FISH, we analyzed not only HER2 but
also TOP2A gene ampli¿cation using a new CISH conversion kit
allowing a two-probe co-hybridization.
Material and Methods: We selected 30 breast cancer samples with a
known HER2 status as determined by immunohistochemistry (IHC).
Cases were distributed in HER2-IHC score 1+ (n=2), score 2+ (n=16)
and score 3+ (n=12). For each case, we performed a double-staining
S86
CISH for HER2 and TOP2A genes, and a standard FISH for the same
genes. The CISH conversion kit (Dako Denmark A/S) allowed the cohybridization of two probes on the same slide with a two-color detection,
thus enabling centromere 17 (CEN17) analysis (blue signal) in addition
to HER2 or TOP2A detection (red signal). The two techniques were
performed in different institutions, and interpreted without knowing
the results of the alternative technique.
Results: The HER2 and TOP2A CISH slides showed contrasted and
well-balanced blue and red signals, which were clearly identi¿ed at
low magni¿cation and easily counted at high magni¿cation. Tumor
morphology was fully preserved, without any signal-fading overtime,
thus providing excellent reading conditions for the pathologist.
Preliminary statistical analysis for HER2 gene showed a high
concordance (95.6%) between double-staining CISH and FISH. Ongoing
studies are evaluating TOP2A concordance and detailed correlations
between HER2 and TOP2A gene copy numbers, HER2:CEN17 and
TOP2A:CEN17 ratios, as obtained by the two techniques.
Discussion: In addition to supporting the fact that dual-color HER2
CISH is a promising alternative to FISH, we described here the ¿rst
CISH conversion kit enabling extension of this innovating technique to
other genes such as TOP2A. Without the disadvantage of signal-fading,
double-staining CISH improves the ease and time needed for signal
enumeration and should be particularly valuable for routine practice
and high-throughput tissue microarray studies.
2007
Quantitative measurements of HER2 expression and HER2:
HER2 dimerization identify subgroups of HER2 positive
metastatic breast cancer patients with different probabilities
of response to trastuzumab treatment.
Huang W, Lipton A, Leitzel K, Ali SM, Fuchs EM, Weidler J, Chappey C,
Sperinde J, Tan Y, Jin X, Paquet A, Winslow J, Petropoulos C, Kostler
WJ, Bates M. Monogram Biosciences, Inc., So San Francisco, CA;
Penn State/Hershey Medical Center, Hershey, PA; Medical University
of Vienna, Vienna, Austria
Background: Immunohistochemistry (IHC) and Àuorescence in situ
hybridization (FISH) are currently used to determine patient eligibility
for trastuzumab therapy. However, not all HER2+ patients bene¿t from
trastuzumab. Reliable measures that indicate which HER2+ patients
will respond to trastuzumab have not been ¿rmly established. Here we
describe the correlation of quantitative measurements of total HER2
expression (H2T) and HER2:HER2 dimerization (H22D) using a novel
assay technology, VeraTagTM, with objective response rate (ORR),
time-to-progression (TTP) and overall survival (OS) in a cohort of
metastatic breast cancer (MBC) patients treated with trastuzumabbased regimens.
Methods: MBC patients received ¿rst-line trastuzumab alone or
combined with chemotherapy regimens. Selection of HER2+ patients
for trastuzumab treatment was based on IHC performed by a central
lab (Med Univ of Vienna). Formalin-¿xed paraf¿n-embedded (FFPE)
tissues from 58 patients were retrospectively measured for H2T and
H22D using VeraTag (Monogram), blinded to the outcome data.
Patients were categorized as high (> median) or low (< median) H2T
or H22D. Correlation of H2T and H22D with clinical outcome was
analyzed using the Kaplan-Meier method and Cox Proportional Hazards
regression analysis.
Results: Patients with high H2T showed signi¿cantly higher ORR than
those with low H2T (59.3% vs. 17.9%, p < 0.001). Similarly, patients
with high H22D had higher ORR than those with low H22D (55.6% vs.
21.4%, p < 0.01). Kaplan-Meier analysis revealed signi¿cantly longer
TTP for patients with high H2T as compared to those with low H2T
(median TTP 12.8 mo vs. 4.0 mo), and a relative risk of progression
nearly half for patients in the high H2T group compared with the low
group (HR=0.52, log-rank test p=0.013). A similar trend was observed
for H22D (median TTP 12.8 mo vs. 4.0 mo for high H22D vs. low
H22D, respectively), but did not reach statistical signi¿cance (HR=0.65
p=0.11). In separate multivariate Cox models where patients were
strati¿ed by age and number of distal metastatic sites, high H2T and high
H22D were independent correlates of TTP (H2T, p=0.007, and H22D,
p=0.009). The high H2T group showed a trend toward better OS in a
univariate Cox model (p=0.17). Further validation of H2T and H22D
using overall survival as an endpoint may require larger datasets.
Conclusion: In a population of MBC patients selected to receive
trastuzumab based on HER2+ IHC, higher HER2 expression and HER2:
HER2 dimerization were independently correlated with better objective
response and longer time to progression. The results suggest that more
precise methods of quantitating HER2 expression or measuring HER2
functionality (dimerization) will allow for improved strati¿cation of
MBC patients for trastuzumab treatment.
2008
Inter-observer interpretative reproducibility of HER2
genotyping of a consecutive series of primary breast
carcinomas by Silver In Situ Hybridization (SISH).
Tubbs R, Myles J, Papouchado B, Lloyd R, Oliveira A, McElhinny A,
Vladich F, Pestic-Dragovich L, Downs-Kelly E, Prescott N, Pettay
J, Loftus M, Roberts C, Grogan T, Roche P. Cleveland Clinic and
the Cleveland Clinic Lerner College of Medicine, Cleveland, OH;
Mayo Clinic, Rochester, MN; Ventana Medical Systems International,
Tucson, AZ
Introduction
Determination of HER2 status in breast carcinoma may be established
by Àuorescence in situ hybridization (FISH) as the primary method
of testing or for con¿rmation of equivocal immunohistochemistry
results. Requirements for specialized instrumentation and training,
overnight hybridization, manual rather than automated methods, and
workÀow issues may restrict routine implementation of FISH in many
pathology laboratories. Fully automated silver in situ hybridization
(SISH) provides permanently stained slides for determination of a
HER2 genotype in six hours and may reduce overall laboratory costs.
Preliminary studies have shown excellent performance against FISH as
the reference standard. We evaluated the inter-observer interpretative
reproducibility of HER2 SISH in a consecutive series of primary breast
carcinomas previously genotyped by FISH.
Patients and Methods
SISH HER2 was done using unstained paraffin sections of 292
consecutive primary breast carcinomas genotyped by FISH in the year
2006. The SISH procedure was fully automated and completed within
six hours, including on line deparaf¿nization, cell conditioning, target
denaturation, probe/target hybridization, and enzyme metallographic
signal detection. Interpretation was performed by standard bright ¿eld
manual signal enumeration of two representative ¿elds of invasive
carcinoma. Each observer was pre-trained using a standardized tutorial
and representative SISH preparations. Pathologists reviewed an H and
E slide, a SISH slide stained for HER2 using a repeat depleted DNP
labeled probe, and a SISH slide stained for chromosome 17 (CHR17)
using a DNP labeled centromeric oligonucleotide probe. The HER2 and
CHR17 signal counts were enumerated and the HER2/CHR17 ratio was
calculated. Overall agreement and kappa statistics were calculated for
each observer versus the consensus SISH score for all observers and
versus the reference HER2 status established by FISH.
Results
Overall agreement of HER2 amplification status among the five
pathologists interpreting the SISH preparations was excellent. Overall
agreement among observers ranged from 94.9 - 96.6%. The kappa
statistic correcting for chance agreement among observers ranged from
0.760 - 0.869; the agreement between consensus SISH and FISH was
94.2% and the kappa statistic was 0.775
Conclusions
Silver in situ hybridization (SISH) is a robust and rapid automated
method for determination of HER2 genotypic status. Interpretation
of SISH preparations by pathologists is reproducible and represents
a promising alternative to FISH testing for determination of HER2
status in breast carcinoma.
2009
HER2 tumors are heterogeneous, clinically, molecularly,
and in response to preoperative trastuzumab: pathway
analysis of gene expression pro¿les from three breast cancer
datasets.
Harris LN, Eklund AC, Carter S, Li X, Winer EP, Hilsenbeck S, Esteva
FJ, Symmans WF, Pusztai L, Szallasi Z, Chang J. Yale University, New
Haven, CT; Childrens Informatics Program, Boston, MA; Dana Farber
Cancer Institute, Boston, MA; Baylor University, Houston, TX; MD
Anderson Cancer Center, Houston, TX
HER2 ampli¿ed tumors cluster on transcriptional pro¿ling largely
driven by genes on the 17q12-21 amplicon, however this molecular
subtype is heterogeneous. We analyzed the inÀuence of pathways
signatures on response to preoperative trastuzumab-containing (trz)
therapy in HER2 ampli¿ed breast cancer.
Methods
Three cohorts of patients with HER2 3+/FISH+, stage II-III breast
cancer were included, summarized in Table. Extremes of response
were used to compare with gene expression signatures: resistance
was de¿ned as stable or progressive disease (SD+PD) using RECIST.
Pathologic complete response (pCR) was de¿ned as lack of invasive
disease in the breast and lymph nodes at the time of surgery. Raw data
from each of the three data sets were modeled separately with the RMA
algorithm. The relative expression of each signature in each sample was
estimated by taking the mean expression of all genes in the signature. We
used 14 published signatures said to characterize activity of e2f, myc,
ras, src, bcat, PI3K, hypoxia, chromosomal instability (CIN), spindle
checkpoint/assembly, genomic grade, DNA repair, BM1-1 and basal
gene signatures. The association between signature and outcome was
evaluated with Student’s t test.
Results
DFCI and Baylor cohorts were quite different with the majority of
tumors from the Baylor study being ER/PR- and T4. The DFCI and
MDACC cohorts were similar in T stage and ER status. Baylor and
DFCI cohorts had similar rates of pCR of 19% and 14% respectively,
compared to MDACC with 71% pCR, perhaps due in part to differences
in treatment duration. We evaluated the ability of fourteen published
signatures to predict response to therapy. While some of the signatures
were of signi¿cance in a particular cohort, no signature showed a
consistent correlation with pCR or resistance at a p>0.05. In fact, the
majority of the signatures correlated associated with resistance in the
opposite direction in the DFCI and Baylor cohorts. Higher levels of
basal signature was associated with resistance to trz in the Baylor dataset
(p=0.03) whereas the other two cohorts were not, although basal genes
were signi¿cantly associated with resistance in the DFCI cohort in a
separate analysis (p=0.03).
Conclusions
HER2 ampli¿ed tumors represent a heterogeneous group by lineage,
pathway activation and treatment response. HER2 tumors of basal
lineage may be less likely to respond to trz-containing therapy. Larger
studies are required to understand the variability in this breast cancer
subtype.
Trial
1
2
3
Site
Baylor
DFCI
MDACC
Subjects
38
48
30
Treatment
trz+docetaxel 12 wks
trz+vinorelbine 12 wks
trz+T>FEC 24 wks
Tissue
Core Bx
Core Bx
FNA
Platform
U133A
U133+2
U133A
Genechips
21
20
21
2010
Comparison of ERBB2 evaluation by immuno-histochemistry
and a quantitative RT-PCR method in primary breast
cancers.
Giacchetti S, Lehmann-Che J, De Roquancourt A, Cuvier C, Hocini
H, Bertheau P, De The H, Espié M, Turpin E. Hopital Saint-Louis,
Assistance Publique-Hopitaux de Paris, Paris, France; Hopital SaintLouis, APHP, Paris, France
Background: Immunohistochemistry (IHC) and Àuorescent in situ
hybridization (FISH) are currently the most commonly used methods
to assess ERBB2 status. They are semiquantitative methods. PCR-based
assays are sensitive, speci¿c and quantitative approaches to determine
ERBB2 ampli¿cation (DNA, Q-PCR) or over-expression (RNA, QRTPCR), but they mix tumor and stromal cells. Here, we performed
S87
a large study comparing IHC and Q-RTPCR. Discordant cases were
explored by Q-PCR and FISH.
Material and Methods: We analyzed 442 primary breast tumors
patients treated in St Louis Hospital from 2002 to 2007. Tissue samples
were formalin-¿xed paraf¿n-embedded for IHC (CB11 antibody) and
FISH. Tissues were frozen for Q-RTPCR and QPCR. IHC was positive
3+ if strong complete membrane staining was seen in ≥ 60% tumor
cells. Relative quanti¿cation (RQ) by Q-RTPCR was performed (with
a pathological control to ensure tumor cell density and the absence of
in situ carcinoma) for ERBB2 detection and TBP as endogen control.
Final results was expressed as a normalized ratio considered as low
over-expressed if ≥ 5 and high over-expressed if >10. DNA analysis
was performed with the LightCycler-HER-2/neu DNA Quanti¿cation
KIT (Roche) in a subgroup of discordant patients.
Results:
High RNA positive samples were all IHC positive. In IHC negative
cases, IHC / QRTPCR correlation was very high (97.5 %). In IHC3+
patients there are 16 discordant cases (14%). DNA analyses con¿rmed
the absence of ampli¿cation in 13 cases. In IHC2+, 14/16 were RNA
negative, 2 were low RNA positive. 1 out of these 2 was DNA positive.
FISH analyses are on going.
Conclusion:
The exact determination of ERBB2 status is crucial because of the
potential toxicity and the coast of Trastuzumab treatment. A quantitative
method as PCR-based assays could be more reliable and could allow
treatment according to the level of ERBB2 surexpression. This is a way
to optimize ERBB2 + breast cancer treatment.
2011
Development of novel proximity-based immunoassays for
the detection of HER heterodimerization in breast cancer
cell line lysates and formalin-¿xed, paraf¿n-embedded
tissue.
Eli* L, Shi* Y, Dao-Pick T, Bose J, Frankson K, Penuel E, Weston
J, Pidaprthi S, Mukherjee A, Nguyen X-T, Williams S, Goodman L,
Winslow J. Monogram Biosciences, South San Francisco, CA
Background: Trastuzumab, in combination with a chemotherapy
regimen, is the primary treatment for metastatic breast cancer patients
with tumors exhibiting HER2 protein over-expression. Of these patients,
approximately 30% initially respond to treatment, and subsets of
these patients demonstrate inherent or acquired resistance. Multiple
mechanisms of Trastuzumab resistance have been proposed, including
several that implicate HER receptor homo- and heterodimers as
potential escape pathways. Assays identifying such signaling pathways
could have clinical utility toward predicting response to Trastuzumab
as well as other emerging drugs that speci¿cally target HER signaling
pathways.
Materials and Methods: We have developed a set of novel proximitybased immunoassays (VeraTag) that measure proteins and functional
protein-protein interactions using two different formats: cell line/
tumor lysates and FFPE sections. To evaluate the importance of
HER heterodimer formation as a potential escape pathway, lysateformat assays were applied to measure levels of EGFR/HER1-HER2
heterodimers in cell lines derived from breast and ovarian tumors. A
matrix of positive and negative control cell lines, and HER antibodies,
were identi¿ed by several cross-validating technologies and evaluated
further by FFPE-format proximity immunoassays.
Results: Using our lysate-format proximity assay, we demonstrate
two-, three-, and ten-fold increases in EGFR/HER2 heterodimers in
SKBR3, AU565, and SKOV3 cell lines, respectively, following ten
minutes of stimulation with 100nM epidermal growth factor (EGF).
Control experiments indicate no signi¿cant change in the total amounts
of EGFR and HER2. These increases are further supported by the
EGF-dependent co-immunoprecipitation of HER1 and HER2 in these
cells. Additionally, we have generated stably transfected HEK-293 cell
S88
lines that over-express varying levels of EGFR and HER2, and we are
currently exploring the relationship between expression levels and
heterodimer formation. To initiate evaluation of HER1-HER2 cell lines
in the FFPE-format proximity assay, HER1 and HER2 antibodies were
identi¿ed and an assay format tested on EGF-stimulated SKBR-3 cells,
resulting in an increase in EGF-dependent heterodimer formation.
Discussion: We have established a HER2 total and a HER2 homodimer
assay (VeraTag) in FFPE breast tumors that is currently being validated
and is predictive of Trastuzumab response. We are also developing
VeraTag assays for other HER family members (for example, HER2HER3) and our preliminary evidence suggests that the use of this novel
technology to make these quantitative measurements in tumor biopsies
will be useful towards prediction of alternative or combination therapies
for the treatment of Trastuzumab-resistant tumors.
*Contributed equally.
2012
Characterization of a novel proximity immunoassay for
the quantitative determination of HER2 protein expression
and HER2 homodimerization in formalin-¿xed, paraf¿nembedded breast cancer tissue.
Winslow J, Shi Y, Tan Y, Jin X, Dua R, Penuel E, Mukherjee A, Sperinde
J, Pannu H, Chenna A, DeFazio-Eli L, Pidiparthi S, Chen L, Williams
S, Larson J, Goodman L, Whitcomb J, Petropoulos C, Huang W.
Monogram Biosciences, Inc., South San Francisco, CA
Background: Although present methods such as HER2
immunohistochemistry (IHC) and Àuorescence in situ hybridization
(FISH) are valuable for preliminary patient selection, both tests are
limited in that they fail to fully discriminate responding and nonresponding populations. There is a need to develop 2nd generation
diagnostic tests that will more effectively predict responses to HER2targeted drugs. We have utilized dual antibodies in a novel proximity
format, termed the VeraTag assay, to develop sensitive and quantitative
immunoassays measuring HER2 total and homodimerization levels
in FFPE breast cancer cell lines and tumor tissues for application to
predictive testing.
Methods. The characterized assay detects HER2 total protein and
HER2 homodimer protein-protein complexes by the release of novel
fluorescent electrophoretic tags conjugated to an analyte-bound
antibody. The release of Àuorescent tags requires proximity to a second
HER2 “scissors” antibody which is activated upon illumination. The
collected Àuorescent tags are separated and quantitated by capillary
electrophoresis, and normalized to tumor area.
Results. A HER2 monoclonal antibody proximity pair was selected
based on assay signals that parallel the relative HER2 expression levels
of human breast cancer cell lines (<103 to >106 receptors/cell). The
HER2 total eTag assay signal was linear with antigen concentration
over a 10-20-fold range of cell line section size and breast tumor area.
A comparison of HER2 total levels in 174 breast cancers demonstrated
a continuum over a wide dynamic range (>2 logs), in contrast with
conventional IHC categories. The correlation between HER2 total
levels and IHC categories was signi¿cant (p<0.0001). The VeraTag
assay signal correlates well with IHC Histoscore at lower HER2 total
levels, however, at high HER2 total levels the VeraTag assay provides
extended dynamic range. HER2 gene ampli¿cation measured by FISH
correlates loosely with IHC categories and HER2 total values. An
algorithm was developed to normalize for systematic assay variation,
generally <20-30%, allowing large scale processing of FFPE tumor
samples.Conclusions. The results demonstrate that the VeraTag
assay reliably measures HER2 total and HER2 homodimer levels
quantitatively in FFPE tissues. The continuum of HER2 total levels
over a wider dynamic range compared to conventional IHC and FISH
HER2 tests, the novel HER2 homodimerization measure, and studies
correlating HER2 levels with clinical responses to trastuzumab, suggest
that the VeraTag assay technology may provide better predictive tests
for targeted HER2 therapy.
2013
HER2 and SPARC status in tumors play an important role
in the relative effectiveness of nanoparticle albumin-bound
(QDE) paclitaxel versus polysorbate-based docetaxel.
Desai N, Trieu V, Hwang L, Wu R, Hawkins M, Soon-Shiong P,
Gradishar W. Abraxis BioScience, Inc., Los Angeles, CA; Northwestern
University, Chicago, IL
Background: HER2 overexpression in tumors is associated with a
more aggressive phenotype with increased disease recurrence and poor
prognosis. HER2 is overexpressed in about 25-30% of breast cancers,
as well as in other cancers such as ovarian (15-30%) and stomach
cancer (15-34%). The albumin-binding protein SPARC (Secreted
Protein Acidic and Rich in Cysteine), which is overexpressed in about
50% of breast cancers, is associated with increased tumor invasion and
metastasis and known to be a poor prognostic factor in breast cancer
(Watkins 2005). This has also been demonstrated in a number of other
cancers such as prostate, gastric, liver, lung, kidney, head and neck, and
brain tumors. Nab-paclitaxel (Abraxane®) is an albumin-bound 130-nm
particle form of paclitaxel that shows enhanced tumoral accumulation
by targeting SPARC in tumors through a SPARC-albumin interaction
(Trieu 2007). The goal of this study was to evaluate the importance of
HER2 and SPARC status in determining the relative ef¿cacy of nabpaclitaxel with polysorbate 80/ethanol-based docetaxel (Taxotere®).
Material and Methods: Maximum tolerated dose (MTD) of nabpaclitaxel and docetaxel were previously determined as >120mg/kg
and 15 mg/kg respectively on a q4dx3 schedule (Desai 2006).
HER2 and SPARC status in tumors was analyzed by RT-PCR and
immunohistochemistry (IHC). The antitumor activity of docetaxel
(15 mg/kg) was compared to nab-paclitaxel in breast tumor xenografts
MX-1 (equidose level of 15 mg/kg, qwkx3), MDA-MB-231 (120 and
180 mg/kg, q4dx3) and MDA-MB-231/HER2+ (50 and 120 mg/kg,
q4dx3). Additional tumor xenografts (LX-1 lung, PC3 prostate, and
HT29 colon) were also studied. Tumor volume and body weights
were monitored.
Results: Two of three breast cancer lines (MDA-MB-231 and MX1) were HER2 negative. Amongst the non-breast tumors, only LX-1
was HER2 negative. Two HER2 positive tumors HT29 and PC3 were
strongly SPARC positive with SPARC expression HT29>PC3>MB231/HER2+=MX1. MDA-MB-231 and LX-1 tumors had little to no
SPARC expression. Nab-paclitaxel, even at doses less than its MTD,
was a signi¿cantly more effective antitumor agent than polysorbatebased docetaxel administered at its MTD in the three HER2-negative
tumors (MX-1, MDA-MB-231, and LX-1) and relative ef¿cacy was
independent of SPARC expression. In HER2-positive tumors, the
antitumor activity of nab-paclitaxel was equal to or better than docetaxel
in two of the three tumors types (PC3, HT29, but not MB-231/HER2+)
and increased with increasing levels of SPARC expression.
Discussion: HER2 and SPARC expression may be of importance in
determining antitumor activity of taxanes and potentially serve as useful
as biomarkers for nab-paclitaxel effectiveness. The relative ef¿cacy
of nab-paclitaxel vs. polysorbate-based docetaxel was signi¿cantly
higher in HER2-negative than in HER2-positive tumors. In HER2
positive tumors, the relative ef¿cacy of nab-paclitaxel increased with
increasing SPARC expression.
2014
HER2 immunohistochemistry: comparison of image
analysis based interpretation of CB11 and 4B5 clones using
reference Àuorescence in-situ hybridization.
Fine JL, Bhargava R, Surti U, Dabbs DJ. Magee-Womens Hospital of
UPMC, Pittsburgh, PA
Background: Immunohistochemistry (IHC) testing for HER2/neu
is under increased scrutiny in terms of laboratory accreditation, to
ensure accurate and reproducible assessment of breast cancer patients
for potential trastuzumab therapy. Image analysis systems can help
pathologists provide improved HER2/neu IHC testing by: 1) reducing
inter-observer scoring variability; 2) reducing time required to score
IHC stains; and 3) increasing automation of both technical and
interpretation components of IHC testing. This study details validation
of image analysis for interpretation of HER2/neu IHC.
Methods: Breast cancer cases were stained for HER2/neu utilizing
CB11 and 4B5 antibody clones (Ventana Medical Systems, Tucson, AZ),
according to the vendor’s instructions, on a Benchmark XT automated
IHC platform (Ventana). Fluorescent in-situ hybridization (FISH) was
performed to assess for HER2/neu ampli¿cation (Vysis, Downers
Grove, IL). Image analysis of the IHC stained slides was carried out
using a commercially available image analysis system (VIAS, Ventana).
Using classi¿ers speci¿cally designed for each antibody, the system
assigned a numerical score (0 to 3.50), which was then automatically
rounded to the nearest whole number as a score (0, 1+, 2+, or 3+). These
scores are intended to be directly analogous to scores that would be
assigned by a pathologist: 0 or 1+ is negative; 2+ is weakly positive
(FISH required); and 3+ is positive.
Results: The image analysis system was able to differentiate tumor cells
from non-tumor cells in a given ¿eld of view; it could not differentiate
DCIS from invasive disease nor could it ¿nd a ¿eld automatically (i.e.
a pathologist had to “show” the system which ¿elds to analyze). All
CB11 analyses were 100% concordant with HER2/neu FISH results
(n=52). There was 95% concordance between 4B5 analyses and FISH
results; discrepancies were all weakly positive stains (i.e. over calls)
that were not HER2/neu ampli¿ed by FISH (3 discrepancies, n=56).
If a higher threshold for assigning a 3+ score was used instead of the
rounded score (i.e. the system maximum numerical score 3.50), then
100% concordance was obtained for 4B5 analyses.
Conclusion: There is excellent agreement between image analysis and
FISH, provided an appropriate reference range (i.e. 4B5 3+ cut-off)
is utilized. This validation study showed that this system can reliably
analyze HER2/neu IHC stains, thus assisting pathologists in scoring
these tests. This should reduce inter-observer variability in HER2/
neu IHC scoring, and future enhancements should seek to increase
automation by: 1) communicating with other laboratory information
systems; 2) improving ability to automatically ¿nd areas of invasive
disease without pathologist intervention; and 3) increasing accuracy
such that 2+ cases are reduced in number. Subsequent studies should
examine other impacts that image analysis have on HER2/neu testing,
such as number of required FISH tests, turn-around time, and error
rates related to slide misidenti¿cation.
2015
Expression of the microtubule-associated protein, tau,
predicts improved survival, but not response, to a
combination of docetaxel and vinorelbine in HER-2 negative
Gralow JR, Barlow WE, Gown AM, Goldstein LC, Porter PL, Yeh I-T,
Livingston RB, Hayes DF. University of Washington, Seattle, WA; Fred
Hutchinson Cancer Research Center, Seattle, WA; Phenopath, Seattle,
WA; UT San Antonio, San Antonio, TX; Arizona Cancer Center, Tucson,
AZ; University of Michigan, Ann Arbor, MI
Background
Drugs that poison the mitotic spindle, including taxanes and vinca
alkaloids, are active agents against breast cancer. Tumor expression
of beta-tubulin isoforms and microtubule-associated proteins (MAPs)
may predict outcomes of anti-tubulin therapy. In breast cancer, high
tau expression predicts for resistance to paclitaxel and sensitivity to
endocrine agents. SWOG conducted a phase II study of the combination
of docetaxel, vinorelbine plus ¿lgrastim as 1st or 2nd-line chemotherapy
in HER-2 negative metastatic breast cancer (S0102). This study
evaluates the predictive value of the MAP tau and class III beta-tubulin
in breast cancer patients receiving two anti-tubulin agents.
Methods
Immunohostochemistry using antibodies to tau, class III beta-tubulin,
ER, PR, p53, and Ki-67 was performed on a tissue microarray (TMA)
constructed from S0102 paraf¿n blocks. All markers were scored
from 0 to 3.
Results
Of the 95 patients registered, 92 were eligible and received treatment.
There have been 69 deaths and 83 progressions. Median overall survival
(OS) is 1.69 years with median progression-free survival (PFS) of 0.6
years. A total of 62 patents (67.4%) had a TMA constructed. There was
no difference in outcome for those with or without a TMA. Tau was
positively correlated with ER and PR, but not with class III beta-tubulin,
S89
KI-67, or age. Class III beta-tubulin was not signi¿cantly correlated
with any other marker. There was a signi¿cant effect of tau on OS
(HR=0.62, p=0.0002) and PFS (HR=0.67, p=0.0007), with higher tau
associated with longer survival. Higher tau was still associated with
improved OS and PFS when adjusted for age and ER/PR. Expression
of class III beta-tubulin was not associated with OS (HR=0.97, p=0.85)
or PFS (HR=0.86, p=0.29). We also analyzed the 42 tumor responses
among the 92 patients. There was no relationship of tau with tumor
response adjusting for age (p=0.33). There was also no relationship
of response with class III beta-tubulin (p=0.56), ER (p=0.32), PR
(p=0.07), or KI-67 (p=0.14). For the 29 patients who had tau values of
0-1, the response rate was 38%, compared to 47% for those who had
tau values of 2 or 3.
Discussion
High expression of tau was associated with improved survival in
patients with HER-2 negative breast cancer treated with docetaxel and
vinorelbine. Unlike previous studies with paclitaxel alone, increased tau
expression did not predict resistance to the combination of docetaxel
and vinorelbine. Further evaluation of the relationship between tau
expression and response to anti-tubulin agents is warranted.
This work was supported by a grant from the Breast Cancer Research
Foundation.
2016
Microtubule-associated protein tau is a marker of
pathological complete response in Her-2/neu positive
neoadjuvant treated breast cancer patients.
Rueckert S, Wirtz R, Lenhard M, Hasmueller S, Ditsch N, Ruehl I,
Kahlert S, Bauerfeind I, Untch M. LMU, Universtity of Munich, Munich,
Germany; Siemens Medical Solutions Diagnostics GmbH, Leverkusen,
Germany; Helios Klinikum Berlin-Buch, Berlin, Germany
Background: Microtubule-associated protein tau (MAPT) promotes
tubulin polymerization and stabilizes microtubules. Microarray
analysis of fresh breast cancer tissues revealed, that low expression of
MAPT is a predictive marker for response to anthracycline and taxane
based chemotherapy. In contrast, it has recently been shown, that high
expression of MAPT may indicate response to endocrine therapies.
Here, we have analyzed the RNA expression of MAPT in formalin
¿xed paraf¿n embedded breast cancer tumour tissues of patients treated
within two neoadjuvant chemotherapy trials to evaluate the prognostic
value in this setting.
Patients and methods: Breast cancer patients (≥cT2, N0-N3, M0)
received neoadjuvant chemotherapy of 4 cycles of epirubicin and
cyclophosphamide followed by 4 cycles paclitaxel (PREPARE
trial). In Her-2/neu positive breast cancer patients trastuzumab was
administered parallel to paclitaxel therapy and continued after surgery
(TECHNO trial). Samples of paraf¿n embedded core needle biopsies
obtained at diagnosis of an initial group of 57 patients (34 TECHNO /
23 PREPARE) were prepared for ¿rst analysis. RNA was successfully
isolated from the tissue samples by an automated system based on
magnetic beads (Siemens Medical Solutions Diagnostics GmbH).
RNA expression of ESR1, Her-2/neu and MAPT expression was
determined by quantitative RT- PCR. MAPT expression was correlated
to histopathological ¿ndings.
Results: RNA expression of MAPT signi¿cantly correlated with
ESR1 expression (Spearman r=0,677; p<0,0001), but not with Her2/neu expression. Median expression of MAPT was 4 fold higher
ESR1 positive tumors. Of the 57 patients included in the ¿rst analysis,
10 patients showed a pathological complete response, 4 in the
PREPARE and 6 in the Her-2/neu positive TECHNO group. There
was a signi¿cant difference of MAPT-RNA expression between those
patients with histopathologically complete response after neoadjuvant
chemotherapy and those with no or partial response in the ¿rst cohort
(Mann-Whitney-U, p=0.019). Patients with a complete response
showed signi¿cantly lower levels of MAPT-RNA. Interestingly, this
difference was prominent in the group of Her-2/neu positive tumors
(TECHNO trial) with all responding tumors exhibiting a 4 fold lower
median MAPT expression (Mann-Whitney-U, p=0.009). In contrast, no
statistically difference was seen in the PREPARE group with only half
of the tumors being below the median MAPT expression.
S90
Conclusion: These results validated the initial hypothesis that low
expression of MAPT indicates sensitivity to chemotherapy on RNA
level in clinical routine paraf¿n tissue. Moreover, low MAPT-expression
was particularly informative in Her-2/neu positive breast cancer patients
treated with anthracyclin-based chemotherapy containing paclitaxel
and trastuzumab.
2017
Cyclin-dependent kinase 2 to 1 specific activity ratio
predicts response to epirubicin and paclitaxel in human
breast cancer.
Kim SJ, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S, Tsukamoto F,
Akazawa K, Nakayama S, Matsushima T, Torikoshi Y, Ishihara H.
Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
Osaka Koseinenkin Hospital, Osaka, Japan; Sysmex Corporation,
Kobe, Hyogo, Japan
Background: We have reported that breast tumors with a high ratio of
cyclin-dependent kinase (CDK) 2 speci¿c activity (SA) to CDK1SA
(CDK2/1 ratio) are associated with high tumor cell proliferation and
poor clinical outcome. The aim of the present study is to evaluate the
correlation of CDK2/1 ratio with response to chemotherapy in breast
cancer.
Material and Methods: Of 76 primary breast cancer patients (pts)
(age: 25-71y, mean: 49.2y), 33 were treated with cyclophosphamide
+ epirubicin (CE) (600/60 mg/m2, q3w) for three or four cycles and
43 with paclitaxel (80 mg/m2, q1w) for 12 cycles in the neoadjuvant
setting. Frozen tumor tissues were obtained from core needle biopsy
before chemotherapy, and CDK2/1 ratio was examined by the Cell
Cycle Pro¿ling (C2P) assay as previously reported (Ishihara, et al:
Biochim Biophys Acta 1741: 226, 2005). Clinical response was
evaluated by MRI and patients were classi¿ed into responders (CR+PR)
and non-responders (NC+PD). Cut-off values of CDK2/1 ratio were
determined to best separate the responders and non-responders to CE
and paclitaxel, respectively.
Results: Pts characteristics were as follows: menopausal status: pre54%, post- 46%; Stage: II 41%, III 49%, IV 11%; Tumor size (cm):
2-5 cm 54%, > 5 cm 46%; histologic grade (HG): I 18%, II 41%, III
28%; ER: (+) 58%, (-) 42%; PR: (+) 41%, (-) 59%; HER2: (+) 29%, (-)
68%. In a CE treatment group, all 13 tumors with high CDK2/1 ratio
responded to CE while only 7 of 20 tumors with low CDK2/1 ratio
responded (positive prediction value (PPV): 100%, negative prediction
value (NPV): 65%, accuracy: 79%, p < 0.001). In a paclitaxel treatment
group, of 32 tumors with high CDK2/1 ratio, 29 responded to paclitaxel
while only 4 of 11 tumor with low CDK2/1 ratio responded (PPV: 91%,
NPV: 64%, accuracy: 84%, p = 0.0002).
Discussion: The CDK2/1 ratio is signi¿cantly associated with response
to CE and paclitaxel. The CDK2/1 ratio seems to have a potential to
be used as a new predictive factor for epirubicin and paclitaxel in
breast cancer.
2018
High pretreatment cyclin E levels may de¿ne a higher
risk subset of basal-like breast cancers: in depth
immunohistochemical analysis and clinical outcome of
neoadjuvantly treated basal-like breast cancers.
Osborne CR, Tripathy D, Allada N, Bian A, Xie X-J, Ashfaq R. UT
Southwestern Medical Center, Dallas, TX; Baylor University Medical
Center, Dallas, TX
Background: Gene expression pro¿ling has revealed several subsets of
breast cancer with distinct clinical outcomes. The basal-like subtype is
in part characterized as HER2 and hormone receptor (HR) negative.
We previously described a number of basal-like cases treated with
neoadjuvant chemotherapy. In this cohort, relapsing patients were
noted to have increasing Ki-67 values in their de¿nitive resection
specimens compared to their baseline biopsy. Here we present further
IHC characterization of neoadjuvantly treated basal-like cases.
Methods: 35 basal-like cases treated with neoadjuvant chemotherapy
were identi¿ed. Pre-chemotherapy and post-chemotherapy in depth
breast tumor IHC characterizations including; cyclin E, androgen
receptor (AR), survivin, EGFR, CK 5/6, CK 7, SPARC and Ki-67
expression were evaluated in relationship to relapse status. Wilcoxon
rank sum, Chi-square and Fisher’s exact tests were performed as
indicated.
Results: Of the 22 patients who relapsed, 18 are deceased, 1 has
progressive disease, 1 remains NED after surgery and 2 are lost to
follow-up. CK 5/6 was expressed in 61.1% of relapsed pretreatment
specimens but only 33.3% of non relapsed specimens, though this was
not statistically signi¿cant (p=0.83). Table 1 demonstrates IHC results
for the pre-chemotherapy specimens in relationship to relapsed vs. non
relapsed status. Of interest, cyclin E, survivin and Ki-67 were more
elevated in the relapsed cases compared with the non relapsed, though
only cyclin E was found to be statistically signi¿cant (p=0.013). Post
chemotherapy cases showed a signi¿cantly higher expression of Ki67 in the relapsed group as compared to the non relapsed group (65%
vs. 51% p=0.042). Cyclin E and survivin expression remained high
in the relapsed group (60% vs. 42% and 62% vs. 66% ) though these
values were not statistically signi¿cant. There was a trend for higher
AR expression in non-relapsing cases.
Conclusions: Basal-like breast cancers have more aggressive disease
and worse outcomes compared to other de¿ned subsets. Basal tumors
demonstrate rapid cell cycling as evidenced by high cyclin E and Ki67 and may have augmented anti-apoptotic mechanisms manifest by
elevated survivin levels which may allow for escape from cytotoxic
effect. Additionally, high pretreatment cyclin E levels may in particular
identify an even higher risk subset.
Table 1
Variable
AR
CK7
Cylin E
EGFR
Ki-67
SPARC
Survivn
Relapsed
NO
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
N
12
20
12
20
12
20
11
20
13
22
11
20
12
20
Mean
0.10
0.16
3.54
3.56
0.34
0.66
0.54
0.38
0.53
0.58
1.30
1.11
0.54
0.60
p Value
0.98
0.88
0.013
0.56
0.33
0.58
0.78
2019
Adding the estimation of cyclin D1 gene ampli¿cation to
the standard panel of predictors in breast carcinoma can
signi¿cantly improve identi¿cation of tumors resistant to
tamoxifen.
Petrakova K, Nenutil R, Vyskocil J, Fabian P, Palacova M, Hanzelkova
Z, KnoÀickova D. Masaryk Memorial Cancer Institute, Brno, Czech
Republic
Background: Despite of many recently published predictors of
resistance to tamoxifen, clinical practice lacks a simple, reproducible
and commercially widely available tool, routinely applicable to identify
patients, quali¿ed for adjuvant hormonal therapy, in which no bene¿t
of tamoxifen treatment can be expected. Here we attempted to ¿nd a
simple combination of predictors, recognizing most of tumors recurring
during the course of tamoxifen treatment, while exhibiting reasonably
low incidence in chronological series of unselected ER-alpha (ER)
positive carcinomas.
Material and Methods: Cases of ER positive breast carcinoma of clinical
stage I+II at the time of diagnosis exhibiting a documented locoregional
and/or distant tumor relapse during the adjuvant tamoxifen treatment
were retrieved from medical records. Tissue microarrays (TMAs) were
built from the archived paraf¿n blocks of primary (n=37) and secondary
, (if available, n=27), tumors of above patients. TMAs from unselected
cases of ER positive breast carcinomas (n=85) served as a control.
Her-2 and cyclin D1 ampli¿cation were analyzed using Àuorescence
in-situ hybridization (FISH) with Abbott probes. ER, progesterone
receptor A+B (PR), Bcl2, estrogen receptor beta (ER-beta), cyclin
A and cyclin D1 were estimated using immunohistochemistry with
commercially available antibodies (Labvision, Novocastra). Clinical
data, such as pT-stage, pN-stage, grade, patient’s age, and others, were
available for analysis.
Results: None of clinical parameters, neither Bcl2, ER-beta, cyclin D1
and cyclin A immunohistochemistry proved acceptably sensitive and
speci¿c. On the contrary, the combination of Her-2 and/or cyclin D1
ampli¿cation and/or PR negativity, was found in 92% of secondary
tumors growing during the tamoxifen treatment and in 66% of
corresponding primary tumors. The incidence of this combination in
consecutive cases was 28% only.
Her-2 and/or
Her-2
Cyclin D1
PR below 5% cyclin D1 ampli¿ed
ampli¿cation ampli¿cation
p<0,0001*
and/or PR below
p=0,008*
p=0,006*
5% p<0,0001*
Secondary tumors
26%
n=23
Primary tumors with
36%
relapse n=37
Control ER positive
12%
primary tumors n=85
* Pearson Chi-square probability
36%
68%
92%
23%
26%
66%
12%
8%
28%
Discussion: Cyclin D1 and Her-2 amplifications, as well as PR
negativity, are already recognized to predict resistance to tamoxifen.
FISH is in general better standardized and reproducible when compared
to immunohistochemistry. For this reason we suggest to add FISH
assessment of cyclin D1 gene status to the routine evaluation of breast
carcinomas, normally including ER, PR and Her-2 estimation. The
patients with ER positive tumors exhibiting Her-2 and/or cyclin D1
ampli¿cation and/or PR negativity may then be considered for adjuvant
hormonotherapy other than tamoxifen.
The study was supported from Czech Ministry of Health, No. NR
8270-3.
2020
Single agent in vitro drug sensitivity of molecular breast
cancer subtypes de¿ned by gene expression analysis.
Brase J, Schmidt M, Hengstler J, von Törne C, Kölbl H, Gehrmann M.
University of Luebeck, Luebeck, Germany; University of Mainz, Mainz,
Germany; University of Dortmund, Dortmund, Germany
Background: Breast cancer is a heterogeneous disease for which a
multitude of chemotherapeutic agents with different mechanisms of
action are available. In neo-adjuvant studies gene signatures predictive
for drug cocktails have been described. However, prediction with
high accuracy remains a major challenge. In order to unravel response
differences of individual drugs we combined gene expression pro¿ling
of primary tumor tissues with an in vitro drug sensitivity model.
Materials and Methods: Paclitaxel, Epirubicin, 5-Fluorouracil and
Carboplatin were tested as single agents in a clinically relevant range
of concentrations in an in vitro chemosensitivity assay (TCA-100; DCS,
Innovative Diagnostic System, Hamburg, Germany) on cells isolated
from 43 primary breast carcinomas. In addition, RNA was isolated
from the primary tumor and gene expression pro¿ling was performed
with Affymetrix HG-U133A microarrays. Unsupervised hierarchical
clustering and prinicipal component analysis were applied to identify
four molecular breast cancer subtypes. Drug sensitivity measured as
area under the dose response curve was compared between subtypes
by Kruskal-Wallis and Mann-Whitney tests.
Results: Unsupervised hierarchical clustering and principal component
analysis identi¿ed four major molecular subtypes, similar to the
previously described luminal A, luminal B, stromal like and basal
like subtype. We found that these subtypes could be classi¿ed with a
small set of characteristic genes. ANOVA analysis revealed signi¿cant
differences in drug sensitivity between the four molecular subtypes
for Epirubicin (p = 0.002), Paclitaxel (p = 0.002), 5-Fluorouracil (p
= 0.039) and Carboplatin (p = 0,025). The most striking difference
was observed between basal and luminal A subtype for Epirubicin (p
= 0.002) and Paclitaxel (p = 0.003). In contrast, these subtypes did
not differ in sensitivity for 5-Fluorouracil and Carboplatin. Luminal
B was more sensitive towards 5-Fluorouracil (p = 0.004) and slightly
more sensitive for Paclitaxel (p = 0.053) and Carboplatin (p = 0,076)
compared to the stromal like subtype. The inverse relation was seen
for Epirubicin (p = 0.011). Discussion: Striking differences in drug
sensitivity were seen between four major molecular breast cancer
subclasses. The basal subtype was most sensitive towards Epirubicin
and Paclitaxel but not 5-Fluorouracil, which was more active in the
luminal B subtype. A larger study is needed to identify more subtle
genetic differences and to elucidate the optimal combination of drugs
for a given tumor.
S91
2021
Tumour volume analysis. A better way than RECIST?
Gordon AB, Stebbing J, Coombes C. Charing Cross Hospital, London,
United Kingdom
Background: RECIST – Response evaluation and criteria in solid
tumours is the standard method of measuring complete response CR,
partial response PR, stable disease SD and progressive disease PD. It
utilises a single measurement as the longest diameter. Analysis of a
true sphere may be calculated as volume = 4/3 Π r3. Many tumours are
not truly spherical (one dimensional) but ellipsoid (two dimensional)
or have three known dimensions. In a one diameter sphere the volume
increases eight times when the diameter is doubled. This allows small
increases in tumour diameter to become large changes in tumour
volume. Volume becomes a more sensitive and accurate parameter to
assess tumour response to treatment.
Method: In partial response PR the RECIST guidelines are a 30%
decrease in tumour diameter to be signi¿cant. In the case of a 2.0 cm
diameter tumour (volume = 4.19 cm3) a 30% decrease is 6mm making
a 1.4 cm tumour (volume 1.44 cm3). In fact a diameter reduction of
6mm (30%) becomes a volume decrease of 2.75 cm3 (74%). We are
therefore underestimating the bene¿t of therapy. In the case of stable
disease SD many patients will be in this group because a diameter
change does not reach the RECIST 30%, although the volume would
decrease by 30%. These cases would not be eligible as a response in
Phase 2 clinical trials and the therapy discarded. In progressive disease
PD the RECIST guidelines are 20% increase in diameter, in the case of
a 2.0 cm tumour increases to become 2.4 cm. In fact the tumour volume
has greatly increased from 4.19 cm3 to 7.25 cm3 (42%).
New Material: A volume calculator is described for immediate
assessment of a mass in cubic centimetres following measurement of
diameter in centimetres. Tumour volume may be calculated in one, two
or three dimensions UK Patent Application No. 0618342.0. This corrects
for the clinical situation where few tumours are truly spherical.
Discussion: RECIST and the WHO guidelines that preceded it both used
diameter measurements in centimetres to assess response to therapy. It is
demonstrated that volume analysis in cubic centimetres underestimates
the bene¿t of therapy in partial response cases. Our treatments are more
bene¿cial than we realised. It is proposed we express data as volume
in cubic centimetres.
Diameter and volume ¿gures.
Diameter cm
Volume cm3
Diameter cm
Volume cm3
.4
.03
2.8
11.49
.6
.11
3.0
14.14
.8
.27
3.2
17.16
1.0
.52
3.4
20.58
1.2
.90
3.6
24.43
1.4
1.44
3.8
28.73
1.6
2.14
4.0
33.51
1.8
3.05
4.2
38.79
2.0
4.19
4.4
44.60
2.2
5.58
4.6
50.97
2.4
7.24
4.8
57.91
2.6
9.20
5.0
65.45
The volume has been calculated as: Vol = 4/3 r3
2022
Association of an extracellular matrix gene cluster with
breast cancer prognosis and response to tamoxifen.
Helleman J, Jansen MPHM, Sieuwerts AM, van Staveren IL, Ritstier
K, Look MP, Meijer-van Gelder ME, Klijn JGM, Foekens JA, Berns
EMJJ. Erasmus MC, Rotterdam, Netherlands
Background: The expression of an extracellular matrix (ECM) gene
cluster was previously found to be associated with response to ¿rstline tamoxifen therapy in metastatic breast cancer patients (Jansen et
al J Clin Oncol 2006). This ECM gene cluster comprises six genes,
collagen 1A1 (COL1A1), ¿bronectin (FN1), lysyl oxidase (LOX),
secreted protein acidic cysteine-rich (SPARC), tissue inhibitor of
metalloproteinase 3 (TIMP3) and tenascin C (TNC). In this study
S92
we determined if these ECM genes are associated with response to
tamoxifen monotherapy, metastatic potential, or both.
Material and Methods: We have measured the ECM gene expression
levels by real-time polymerase chain reaction in 1,286 primary breast
tumor specimens. Expression levels were normalized to housekeeper
gene levels and were analyzed as continuous variables in relation to
clinicopathologic factors for all patients. In addition, in a multivariate
analysis the expression levels were compared to traditional prognostic
and predictive factors (age, menopausal status, tumor size, grade, LN
status, ER, PgR, dominant site of relapse and disease-free interval).
Results: TIMP3, FN1, LOX and SPARC expression was signi¿cantly
associated with distant metastasis-free survival (MFS) in 680 lymph
node negative untreated patients (p<0.03) indicating a relation of these
ECM genes with metastatic potential, i.e. prognosis. The association of
FN1, LOX and SPARC with MFS remained signi¿cant in multivariate
analysis.
Increased expression of TNC and FN1 was signi¿cantly associated
with a shorter MFS in 145 lymph node and hormone receptor (ER and
PgR) positive patients adjuvant treated with tamoxifen (FN1: HR=1.21,
p=0.048, TNC: HR=1.42, p=0.004). For both genes multivariate
analysis showed that the association with MFS was independent of
prognostic factors.
Interestingly, increased expression of TNC was also signi¿cantly
associated with a shorter progression-free survival (PFS) in 298
patients who developed recurrent disease which was treated with
tamoxifen monotherapy (HR=1.20, p=0.000). Multivariate analysis
showed that the association of TNC with PFS was independent of
predictive factors.
Conclusion: High FN1, LOX and SPARC expression is associated
with a worse prognosis for lymph node negative patients which is
independent of traditional prognostic factors. Interestingly, TNC
expression was not associated with prognosis while high expression
did associate with resistance to tamoxifen treatment in the adjuvant as
well as the advanced setting. Moreover, this association is independent
of traditional prognostic and predictive factors. Additional studies are
needed to con¿rm this outcome.
2023
Increased b1 integrin expression is a predictor of
trastuzumab resistance in HER-2 overexpressing metastatic
Thoms J, Sabri S, Lesniak D, Lai R, Deschennes J, Mackey J, Murray
D, Abdulkarim B. University of Alberta, Edmonton, AB, Canada
%DFNJURXQG: Trastuzumab (Herceptin) based chemotherapy, is
standard of care in HER-2 (human epidermal growth factor receptor2) overexpressing metastatic breast cancer (MBC) patients. More than
50 % of HER-2 ampli¿ed MBC patients exhibit primary resistance
to trastuzumab. Thus, the identi¿cation of new predictive markers of
response to trastuzumab is crucial for appropriate patient selection
for trastuzumab-based therapy. b1 integrin plays a major role in
the proliferation, survival and invasion of carcinoma cells and its
overexpression has been reported in JIMT-1, a breast cancer cell line
established from a primary Trastuzumab resistant patient. To date, the
predictive value of β1 integrin expression in trastuzumab resistance has
not been investigated.
2EMHFWLYHV To investigate the value of β1 integrin expression in a
population-based study of HER-2 overexpressing MBC patients treated
with Trastuzumab-based therapy.
0HWKRGV We examined the expression of β1 integrin in a cohort of 85
MBC patients, treated in our institution with Trastuzumab-based therapy
in the setting of metastatic disease during the period of 1998 – 2005
(December2005) Formalin-¿xed, paraf¿n-embedded breast tumors
from these, specimens were analyzed by immunohistochemistry and
scored for membranous and cytoplasmic β1 integrin staining (percentage
of positive cells and intensity of staining) by two independent
pathologists blinded to clinical outcome). The association between b1
integrin staining, conventional histological features (tumor size and
grade, nodal status, hormone receptors, and lymphovascular invasion),
overall survival (OS) and the time to tumor progression (TTP) was
evaluated with univariate and multivariate analyses.
5HVXOWV The median OS is 17.8 months (14.6 - 20.3) and TTP is 6.7
months (5.6 - 8.5). High membranous β1 integrin staining (≥ 40% cells)
was associated with signi¿cant decrease in OS and TTP. The median OS
and TTP was 12.8 and 4.8 months in patients with high membranous β1
integrin staining versus 19.3 and 8.2 months, respectively in patients
with low membranous β1 integrin staining (P < 0.0015). In a multivariate
Cox proportional hazards model, membranous β1 integrin staining and
tumor size (> 2.0cm) were independent prognostic factors for time to
tumor progression (P = 0.0011). Strikingly, β1 integrin membranous
staining alone was an independent predictor for survival in HER-2
overexpressing MBC patients treated with Trastuzumab therapy
(P=0.001).
&RQFOXVLRQ Our results show that β1 integrin overexpression has
a powerful prognostic value to predict Trastuzumab response in
HER-2 overexpressing breast cancer patients. This may be of a great
signi¿cance, as HER-2 ampli¿cation/overexpression is currently the
only clinical marker used to select patients for trastuzumab-based
therapy.
2024
Preliminary results from I-SPY trial: tumor patterns on
pre-treatment MRI predict breast conservation therapy
eligibility.
Gomez R, Hylton N, Madhavan S, Leung E, Broadwater G, Herman
B, Esserman L, ISPY Radiology, Clinical & Pathology Investigators.
UCSF, San Francisco, CA; NCI, Bethesda, MD; CALGB, Durham,
NC; ACRIN, Providence, RI
MRI patterns have been described which characterize tumor containment
in women with locally advanced breast cancer (LABC). Previously,
these patterns were shown to predict eligibility for breast conservation
therapy (BCT) following neoadjuvant chemotherapy (NACT). Tumors
that were more contained at diagnosis tended to achieve BCT eligibility
more often. We sought to determine if MRI data from the I-SPY Trial,
a correlative science trial in which LABC patients underwent NACT
with serial MRI and biopsies, predicted BCT eligibility.
Methods: Eligible patients with new primary breast cancer >3 cm were
enrolled. All patients received anthracycline (AC)-based chemotherapy.
Some received further treatment with taxane (T) or other agents. All
patients had serial MRI at baseline (T1), after 1 cycle AC (T2), intraregimen (T3), and pre-surgery (T4). MRI patterns were de¿ned by a
5-point loss of containment (LOC) scale using the T1 MRI. Tumor
patterns were de¿ned as follows: 1) single, unicentric, 2) multilobular,
circumscribed 3) multinodular, 4) diffuse and 5) setpal. Eligibility for
BCT following NACT was determined by a longest diameter (LD) <4
cm on the T4 MRI. Actual surgical treatment was individualized based
on surgeon and patient preference.
Results: 237 patients were enrolled at 9 institutions between 6/02-3/06.
15 patients withdrew or failed to complete the study. 18 patients had
insuf¿cient data at the time of analysis on 5/14/07. 15 patients with
tumors <4 cm in LD on baseline clinical exam and on T1 MRI were
determined to be candidates for BCT prior to NACT and were not
included in the analysis. 189 patients had tumors >4 cm in LD on either
clinical exam or on T1 MRI (deeming them ineligible for BCT prior to
NACT) and were included in the analysis. Patients were assigned MRI
patterns according to the T1 MR. For patterns 1, 2, 3, 4, and 5 there were
28, 54, 60, 28, and 19 patients. After NACT, 65% patients were eligible
to undergo BCT based on a T4 MR LD <4 cm. For patterns 1, 2, 3, 4,
and 5, BCT eligibility was 21/28 (75%), 44/54 (81%), 34/60 (57%),
15/28 (54%), and 9/19 (47%). Only 61/189 (32%) eligible patients
underwent BCT. Actual BCT rates by MR pattern were 12/28 (43%),
27/54 (50%), 14/60 (23%), 8/28 (28%), and 0/19 (0%) for patterns 1,
2, 3, 4, and 5. The majority of eligible patients (52%) and those that
underwent BCT (61%) were patterns 1 or 2.
Conclusions: 65% of patients with tumors >4 cm at diagnosis became
eligible for BCT after NACT. MRI patterns were helpful in predicting
who would achieve BCT eligibility. Well-contained lesions (types 1 and
2) tend to undergo a concentric size reduction, thus making these lesions
more amenable to BCT. The lesser contained a tumor is on baseline
MRI, the lower the likelihood that the tumor will respond so as to allow
for BCT. This will help to set patient treatment expectations.
2025
Molecular markers as predictors of breast cancer response
to adjuvant epirubicin-CMF chemotherapy in the BR9601
trial.
Bartlett JM, Munro AF, Cameron DA, Thomas J, Prescott R, Twelves
C. University of Edinburgh, Edinburgh, United Kingdom; Western
General Hospital, Edinburgh, United Kingdom; University of Bradford,
Bradford, United Kingdom
Background: A number of studies have sought to identify which patients
gain most from the clear additional bene¿t seen with the adjuvant use of
anthracyclines. We tested the hypothesis that HER2, EGFr and HER3,
Ki67 (proliferation) or topoisomerase (TIIa) expression are predictive
of outcome on anthracycline-based chemotherapy in breast cancer.
Methods: Tissue microarrays from 322 patients recruited to the BR9601
trial which compared ECMF with CMF were analysed for protein
expression & HER2 ampli¿cation. Relapse free (RFS) and overall
survival (OS) was performed by Kaplan Meier and Cox’s multiple
regression tests identi¿ed treatment by marker interactions.
Results: HER2 normal cases exhibited improved RFS when treated
with ECMF vs CMF (HR = 0.49; p<0.01) vs. CMF. Tumors with
normal HER1, HER2 (FISH) or HER3 levels exhibited signi¿cantly
improved RFS (HR 0.37, p =0.005) & OS (HR 0.31, p<0.005) on ECMF
vs. CMF treatment. No difference in RFS or OS was seen in HER1-3
overexpressing cases treated with ECMF vs. CMF. Cox’s regression
established signi¿cant treatment by marker effects for RFS & OS
(p<0.05). Neither Ki67 nor TIIa showed predictive value.
Conclusion: Although these data con¿rm an interaction between HER2
(and HER1-3) status and anthracycline bene¿t, the results contrasts with
the DBCSG and MA5 studies. Differences in treatment regimens, total
anthracycline exposure and scheduling might be responsible, but what
these results do suggest is that caution is required before combining
different studies for meta-analyses and in interpreting results from
individual studies across different treatment regimens.
2026
Identification of molecular predictors of response of
advanced breast cancer patients to aromatase inhibition.
Haynes B, Ghazoui Z, Anderson H, Dunbier A, Dexter T, Mackay
A, Smith IE, Dowsett M. Royal Marsden Hospital, London, United
Kingdom; The Breakthrough Toby Robins Breast Cancer Research
Centre, London, United Kingdom
Background: Aromatase inhibitors (AI) have greater ef¿cacy than
tamoxifen in all stages of ER+ breast cancer in postmenopausal
women. However, whilst several gene expression studies have identi¿ed
markers of prognosis and response to tamoxifen, very few studies have
investigated gene expression in relation to the clinical response of
breast cancer patients to an AI. Our aim was to identify genes and gene
pathways that are differentially expressed in the primary tumours of
responders and non-responders to AI therapy for advanced disease.
Methods: Tumours were selected from our liquid nitrogen bank if they
were ER+ and the patient had received no neo-adjuvant therapy before
surgery and was treated with letrozole or anastrozole for advanced
disease. RNA was extracted and gene expression pro¿ling performed
on Breakthrough 20K cDNA microarrays. Patients were categorised as
responders (CR, PR or SD > 6 months) or non-responders. Genes that
were differentially expressed between the two groups were identi¿ed
by class comparison analysis. Proportional hazards models identi¿ed
genes whose expression was signi¿cantly related to time-to-treatment
failure. Gene ontology and pathway analysis was performed to identify
functional groups of genes that correlated with response. Quantitative
real-time PCR (QPCR) was used to con¿rm microarray ¿ndings for
selected genes.
Results: 58 tumours were analyzed (mean patient age at diagnosis 56
years, mean tumour size 2.6cm). Class comparison analysis identi¿ed
693 genes (at p < 0.01) that were differentially expressed between
responders and non-responders. The most signi¿cantly differentially
expressed gene was HSD17B7 which was con¿rmed by QPCR to
be 1.97-fold higher in responders. This gene encodes one of the two
isoforms of the 17β-hydroxysteroid dehydrogenase enzyme (17βHSD)
that is primarily responsible for the formation of estradiol from estrone
within the breast. AKR1C3 (aldo-keto reductase family 1, member
S93
C3), a gene which possesses 17βHSD activity and correlates with
aromatase expression, was also signi¿cantly up-regulated in responders.
Pathway analysis showed the androgen-estrogen metabolic pathway to
be signi¿cantly different between responders and non-responders (p <
0.0001). Other genes and pathways/molecular processes that showed
signi¿cance included antigen processing and presentation (PSMB5,
HLA-B), a lymphocytic signature (HPS5, ITGAL) and polyamine
metabolism (ASS1, SAT1).
Discussion: We have used an integrative approach to identify candidate
genes and gene pathways predicting response to AI in advanced breast
cancer and are subjecting these to further study in complementary
sample sets. The presence of multiple pathway members among the
signi¿cant genes suggests that global measures of activity of the
androgen-estrogen pathway may provide stronger predictors than the
individual genes.
Supported by the Breast Cancer Research Foundation and Breakthrough
Breast Cancer.
2027
Diet, lifestyle, and BRCA-related breast cancer risk among
French-Canadian.
Ghadirian P, Nkondjock A, Robidoux A, Narod S. University of
Montreal, Epidemiology Research Unit, Research Centre CHUM,
Hôtel-Dieu, Montreal, QC, Canada; CHUM, Hôtel-Dieu, Montreal,
QC, Canada; Women’s College Hospital – University of Toronto,
Toronto, ON, Canada
Background: Although the connection between diet, lifestyle and
hormones suggests that nutritional and lifestyle factors may exert an
inÀuence in the etiology of breast cancer (BC), it is not clear whether
these factors operate in the same way in women with BRCA1 and
BRCA2 (BRCA) gene mutations who already have an elevated BC
risk.
Methods: A case–control study was conducted within a cohort of 80
French-Canadian families with 250 members involving 89 carriers of
mutated BRCA gene affected with BC and 48 non-affected carriers.
A validated semi-quantitative food frequency questionnaire was used
to ascertain dietary intake, and a lifestyle core questionnaire, to gather
information on physical activity and other lifestyle risk factors. Odds
ratios (ORs) and 95% con¿dence intervals (CIs) were calculated in
unconditional logistic regression models.
Results: After adjustment for age, maximum lifetime body mass index
(BMI) and physical activity, a positive association was found between
total energy intake and BRCA-related BC risk. OR was 2.76 (95%CI:
1.10–7.02; p=0.026 for trend), when comparing the highest tertile
of intake with the lowest. The intake of other nutrients and dietary
components was not signi¿cantly associated with the risk of BC. Age
at the time the subjects reached maximum BMI was signi¿cantly
related to an elevated BC risk (OR=2.90; 95%CI: 1.01–8.36; p=0.046
for trend). In addition, a direct and signi¿cant relationship was noted
between maximum weight gain since both age 18 and 30 years and BC
risk. The ORs were 4.64 (95%CI: 1.52–14.12; p=0.011 for trend) for
weight gain since age 18 years and 4.11 (95%CI: 1.46–11.56; p=0.013
for trend) for weight gain since age 30 years, respectively. No overall
association was apparent between BRCA-related BC risk and BMI,
smoking, and physical activity.
Conclusion: The results of this preliminary study suggest that weight
control in adulthood through dietary energy intake restriction is an
important factor for the prevention of BRCA-related BC risk.
2028
Milk products are a source of dietary progesterone.
Goodson III WH, Handagama P, Moore II DH, Dairkee S. California
Paci¿c Medical Center Research Institute, San Francisco, CA
Much of the increase in breast cancer over the last 30 years is thought
to be hormone related. Menopause hormone replacement therapy
(HRT) explains some of the increase, but HRT does not explain other
hormone-related events associated with breast cancer risk, e.g. earlier
menarche. Thus, other causes of early or life-long feminization are
relevant to understanding breast cancer risk.
We reasoned that hormones in dairy products might be a lifelong
S94
source of feminizing hormones: in current dairy practice, milk cows
are maintained in the pregnant state; and elevated progesterone levels
in milk can be used to identify pregnant dairy cows (J Dairy Sci
1976;59:1528). To test whether progesterone absorbed from dairy
products might influence biological outcome, we measured bioavailable progesterone levels after short-term consumption of high-fat
dairy products.
Methods: With IRB approval, salivary progesterone levels were
measured in ¿ve healthy males (BMI 21.6 to 26.2, age 27 to 61 years)
before and after 24 hours of a high-fat dairy diet. We tested saliva
because a.) saliva progesterone levels reÀect bio-available hormone
not bound to serum proteins, and b.) repeated sample collection is free
from discomfort. We studied males because their baseline progesterone
levels are low and relatively constant. We focused on common highfat dairy products since milk hormones are known to partition into
the fatty components. After an evening saliva sample, subjects were
asked to consume similar amounts of butter with breakfast the next
day, cheese with lunch, and ice cream after lunch, prior to an afternoon
saliva collection. Sampling was repeated one week later. Samples
were collected in duplicate. Salivary progesterone was measured by
radioimmunoassay in a commercial laboratory.
Results: Salivary progesterone increased 22 to 116 percent in all subjects
both times after 24 hours of a high-fat dairy product diet (p=0.043).
Salivary progesterone decreased 48 hours after the end of the high-fat
dairy diet (p=0.22) and returned to baseline levels in most subjects by
one week (¿gure 1).
superoxide dismutase (SOD), catalase and lipid peroxidation of cardiac
tissue and plasma were determined using speci¿c assays. Caspase-3
activation and expression of alpha-actin, and HSP70 were determined
by western bloting
Results: GLN supplemented rats lost signi¿cantly less weight and
had reduced tumor weight and volume vs. water gavaged rats. The
pathohistological alterations increased with the increase of DOX dose
but were signi¿cantly less severe in GLN-supplemented rats. GLN
supplementation resulted in enhanced plasma antioxidant capacity,
increased GPx and higher GSH regardless of DOX dose. At the same
time GLN lowered cardiac lipid peroxidation and had no effect on on
SOD and catalase.
Conclusion: These results indicate that dietary GLN stimulates
the antioxidant property of both plasma and cardiomyocytes of a
tumor-bearing host treated with DOX. This effect of GLN is a result
mainly from the increased GSH synthesis and not by the other natural
antioxidants (such as SOD and catalase), supporting our hypothesis
that the bene¿cial effect of GLN supplementation during conditions of
oxidative stress is mainly through modulation of GSH metabolism. The
increased antioxidant capacity of cardiomyocytes is able to counteract
cardiac lipid peroxidation caused by DOX and thus can protect the heart
from the oxidative damages. This data further con¿rmed the safety of
GLN supplementation in a tumor-bearing host and its cardioprotective
effects during chemotherapeutic treatment with DOX.
Acknowledgements: This work was supported by a grant from Susan
G. Komen to VKT.
2030
Effects of Korean red ginseng on the concentration of
blood estrogen, leptin and urinary excretion of estrogen
metabolites in postmenopausal women.
Discussion: Early breeding of dairy cows was instituted in the mid
20th Century to increase production. We demonstrate that the resulting
progesterone in high-fat dairy products is rapidly absorbed leading
to a detectable increase in bio-available progesterone in individuals
consuming such products. Given the magnitude of milk use, we
must consider the possibility that a single change in food production
technology might have a major inÀuence on the health of young persons
who, with the best of intentions, are encouraged to drink milk.
2029
Cardioprotective effects of oral dietary glutamine in tumorbearing rats treated with doxorubicin.
Todorova VK, Kaufmann Y, Klimberg VS. University of Arkansas
for Medical Sciences, Little Rock, AR; Central Arkansas Veterans
Healthcare System, Little Rock, AR
Background: Previous data indicated that dietary glutamine (GLN)
could prevent cardiac lipid peroxidation of rats treated with doxorubicin
(DOX). The present study aimed to further examine the effect of oral
GLN on cardiotoxicity of DOX in rats with mammary carcinoma.
Materials and Methods: Female Fisher 344 rats (n=85) randomized
into 5 groups: (i)MatBIII implantation + DOX + GLN gavage (n=20),
ii)MatBIII implantation + DOX + water gavage (n=20), iii)DOX +
GLN gavage (n=20); iv)DOX + water gavage (n=20); v)naive control
(n=5), gavaged with GLN (1g/kg) or water were implanted with rat
mammary adenocarcinoma cells (MatBIII). After tumor development
the rats were treated i.p. with 4, 9, 12, 16 and 20 mg/kg DOX. Cardiac
histological damage was determined in H&E stained paraf¿n slides.
Total antioxidant capacity, GSH, glutathione peroxidase (GPx),
Kang SH, Lee SJ, Baek NW, Kim EM. Yeungnam University Medical
Center, Daegu, Korea
Purpose: To evaluate the effect of ginseng administration on the
endogenous hormonal environment, we measured blood estrogens,
hormones and urinary estrogen metabolites which proven to be linked
to breast cancer risk, in postmenopausal Korean women before and
after Korean red ginseng supplemental administrations.
Material and method: A randomized, blind, placebo-controlled crossover study was used. Forty three healthy postmenopausal women of
average age 56.9 year were recruited and 25 of these women completed
the study. The participants were randomly assigned to either ginseng
supplemental group or placebo control group. Ginseng group were
administered 1.2 gm of Korean red ginseng extracts per day and placebo
group were administered a placebo without ginseng daily for 8 weeks.
After a one month washout period with no medications, participants
were crossed over (into either the ginseng or placebo group), and
experimental procedure were repeated for 8 weeks. Serum and urine
samples were obtained at immediate before and after each 8 week
treatment period. Each samples were send to laboratory to measure
serum E1, E2, LH (leuteinizing hormone), FSH (follicular stimulating
hormone), SHBG (sex hormone binding globulin), TG (triglyceride),
insulin, leptin and urinary 2OHE1 (2-hydroxyestrone) and 16αOHE1
(16α-hydroxyestrone). The effects of Korean red ginseng extract on
blood estrogen and on urinary excretion of estrogen metabolites were
compared with placebo.
Results: There was no signi¿cant group difference for any demographic
parameter (age, height, body weight, body mass index, fat content) and
baseline level of serum E1, E2, LH, FSH, SHBG, TG, insulin, leptin
and urinary 2OHE1/16αOHE1. And there were no signi¿cant changes in
demographic parameters after both placebo and red ginseng treatment
periods. Compared with placebo condition, the concentration changes
of serum E1, E2, LH, FSH, SHBG, TG, insulin, leptin and urinary
metabolites are not signi¿cantly different in Korean red ginseng extracts
treatment group (p>0.05).
Conclusion: We found that supplemental administration of daily dose
of 1.2 gm of Korean red ginseng extract for 2 months did not change
the endogenous hormonal levels proven to be linked to breast cancer
risk signi¿cantly.
2031
Breast cancer survivors who use selected herbal supplements
have lower circulating estradiol and free estradiol: the
Health, Eating, Activity and Lifestyle study.
Wayne SJ, Koprowski C, Neuhouser ML, Ulrich CM, Bernstein L,
Gilliland F, Wiggins C, Baumgartner K, Baumgartner R, McTiernan
A, Ballard-Barbash R. University of New Mexico, Albuquerque, NM;
University of Southern California, Los Angeles, CA; Fred Hutchinson
Cancer Research Center, Seattle, WA; National Cancer Institute,
Bethesda, MD
A high proportion of breast cancer survivors use herbal supplements.
A number of these supplements have estrogenic properties that may
inÀuence serum hormone levels, although conÀicting evidence exists
about the magnitude and direction of this inÀuence. The estrogenic nature
of these herbs may increase serum levels of estrogen or, conversely,
may reduce circulating estrogen levels by inhibiting enzymes involved
in estrogen biosynthesis and metabolism. We evaluated the relationship
between estrogenic supplements and serum hormone levels among
participants in the Health, Eating, Activity and Lifestyle (HEAL) study,
a population-based, multi-center, prospective cohort study of breast
cancer prognosis. Questionnaire data from 541 postmenopausal breast
cancer survivors were obtained, on average, 31 months after diagnosis
of breast cancer. The questionnaire asked for information on use of
dietary supplements, including herbal preparations. Concurrently a
fasting blood sample was drawn. Serum hormone data were logtransformed, and women taking hormone replacement therapy were
excluded from these analyses. Seventeen supplements were identi¿ed as
having estrogenic properties: astragalus, alfalfa, black cohosh, burdock
root, cat’s claw, chaste berry, dehydroepiandrosterone, Àax, fo ti tieng,
ginseng, licorice, nettles, red clover, saw palmetto, soy, turmeric,
and yam. Thirty-¿ve percent of study participants reported use of at
least one estrogenic supplement. Use of estrogenic supplements was
signi¿cantly associated with younger age, higher education, increased
physical activity, and Hispanic or Black race/ethnic classi¿cation. After
controlling for these factors plus adjustments for tamoxifen use, body
mass index and number of ovaries, participants taking any estrogenic
supplement had signi¿cantly lower levels of estradiol (13.4 pg/mL v
15.4, p = 0.04) and free estradiol (0.30 pg/mL v 0.36, p = 0.01) than
participants not taking estrogenic supplements. Estrone, testosterone,
free testosterone, and dehydroepiandrosterone sulfate were lower and
sex hormone-binding globulin higher in participants taking estrogenic
supplements, but these differences were not statistically signi¿cant. It
is possible that women who took estrogenic supplements did so because
they had a lower level of some sex steroids and consequently had more
estrogen withdrawal symptoms. However, these data suggest that use of
estrogenic supplements may alter some sex hormone concentrations in
breast cancer survivors. Considering the high use of these supplements
among breast cancer patients, further research is needed to clarify the
relative estrogenicity/antiestrogenicity of these compounds and their
relation with prognosis.
2032
Toward individualized risk prediction: the clinical bene¿t
of risk reduction mastectomy and oophorectomy in %5&$
carriers with breast cancer.
Burke HB, Hoang A, Metcalfe K, Culver JO, MacDonald DJ, Grant
M, Thornton A, Robson M, Narod S, Weitzel JN. George Washington
University, Washington, DC; University of Toronto, Toronto, ON,
Canada; Memorial Sloan Kettering CA Ctr, New York, NY; City of
Hope, Duarte, CA
Background:Breast cancer patients with a BRCA mutation have a
markedly elevated risk for new cancers. Health care providers must
communicate complex information about risk-reducing surgeries. We
created models that provide individualized 5-year breast cancer survival
and contralateral breast cancer predictions and the bene¿t of risk
reduction mastectomy (RRM) and oophorectomy (RRSO). Method:
The study population was 491 women treated for stage I or II breast
cancer between 1975 and 2000 and who had a known mutation or were
from a family with a documented mutation (BRCA1, n = 327; BRCA2,
n = 152; both BRCA1 and BRCA2, n = 12). The independent variables
S95
were age (less than 50 years old vs. 50 years old or older), tumor size
(continuous variable), ER status (present vs. absent), and lymph node
status (present vs. absent). Logistic regression was used to create the
model. The output of one model was the probability of each outcome
for RRM, and the output of the other model was the probability of each
outcome for RRSO. Accuracy is assessed by the ROC. Results: See
Table Below. Conclusion: In this population of women who had breast
cancer and were BRCA positive, we found that, with the exception of
RRSO and risk of contralateral breast cancer, the models were highly
accurate predictors of the two outcomes. An unexpected ¿nding was
the bene¿cial effect of RRSO on breast cancer survival. These are
preliminary results and await validation on an independent dataset. The
individualized output of the predictive models will then be incorporated
into a decision support tool for use in cancer risk counseling.
Results
Risk reduction
Risk reduction
mastectomy (RRM)
salpingo-oophorectomy (RRSO)
5-year breast
Model ROC = 0.707 RRM
Model ROC = 0.804 RRSO
cancer-speci¿c survival was not signi¿cant
was signi¿cant
5-year contralateral
Model ROC = 0.749 RRSO Model ROC = 0.611 RRSO
breast cancer
was signi¿cant
was not signi¿cant
The 5-year breast and ovary cancer-speci¿c survival model did not differ signi¿cantly from
the 5-year breast cancer-speci¿c survival model and is not reported here.
2033
A BRCA1 or BRCA2 mutation and young age predict fast
breast cancer growth. Implications for screening?
Tilanus-Linthorst MM, Obdeijn I-M, Hop WC, Causer P, Leach
MO, Warner E, Pointon L, Hill K, Klijn JG, Warren RM, Gilbert FJ.
Erasmus University MC, Rotterdam, Netherlands; Sunnnybrook &
Women’s Health Sciences Centre, Toronto, Canada; Institute of Cancer
Research and Royal Marsden NHS, Sutton, Surrey, United Kingdom;
Addenbrooke’s Hospital and University, Cambridge, United Kingdom;
University of Aberdeen, Aberdeen, United Kingdom
Purpose
Breast cancers of young women with an inherited predisposition can
be detected at an early stage by MRI screening. Interval cancers were
described in BRCA1 mutation carriers, possibly because their tumours
grow fast. We investigated the inÀuence of a BRCA1 or BRCA2
mutation and age on the growth rate of breast cancers, as this inÀuences
the optimal screening frequency.
Methods
To assess tumour growth rate, we reviewed 100 invasive cancers
from the UK, Dutch and Canadian MRI screening trials for women at
hereditary risk, measuring tumour size at diagnosis and on preceding
MRI and/or mammography.
Results
In 43 BRCA1, 16 BRCA2 mutation carriers, and 41 women with high
familial risk we calculated tumour volume doubling time. Growth was
twice as fast in BRCA1 (p 0.003) and BRCA2 (p 0.03) mutation carriers
than in high risk patients of the same age. Growth slowed down with
increasing age (p 0.004) by a factor of 1.6 with each 10 years (range
27-67 yrs). With yearly imaging, pathological tumour size decreased
with increasing age (p 0.001). Median tumour size was 15 mm at or
below 40 years compared to 9 mm in older patients (p 0.003). In young
BRCA1 patients tumour size was largest
Conclusion
Tumours grow more quickly in younger women and in BRCA1 and
BRCA2 mutation carriers than in high risk women. With yearly
screening tumours were largest in young BRCA1 mutation carriers,
S96
therefore age and risk group should be taken into account when
recommending screening frequency and for follow-up imaging.
Numbers, geometric mean DT, average breast density and tumor pathology size of the 100
invasive cancers per age and risk group
40 years
41-50 years
> 50 years
p-value
n=31
n=42
n=27
Nr. BRCA1/2
23
24
12
Nr. High Risk
8
18
15
28
83
2.6
68
121
2.5
81
173
2.0
0.039
0.014
0.03
15 (4-40)
15 (4-40)
11.5 (4-20)
10 (4-42)
9.5 (4-35)
10 (6-42)
9 (4-27)
8.5 (4-25)
9 (5-27)
0.009
0.016
0.45
Mean DT
BRCA1/2
High Risk
Mean Density total group
Median Pathology size
Total group
BRCA1/2
High Risk
* p for the difference in geometric mean DT between the three age groups adjusted for study
center ** Mean density at a 4 point scale. Mean value would be 2.5 with equal numbers
50% and > 50% density.
2034
Breast carcinoma LQVLWX and the prevalence of %5&$ and
%5&$ mutations in a large commercial database.
Hall MJ, Reid JE, Noll WW, Frye CA, Burbidge LA, Wenstrup RJ.
Herbert Irving Comprehensive Cancer Center, New York, NY; Myriad
Genetic Laboratories, Inc., Salt Lake City, UT
Background: The prevalence of BRCA1/2 mutations in women with
breast carcinoma in situ remains controversial. The aim of this study
was to assess the prevalence of BRCA1 and BRCA2 mutations in women
with a diagnosis of breast carcinoma in situ who have undergone genetic
testing by a large commercial laboratory.
Methods: Between March 1996 and December 2006, full sequence
DNA analysis of BRCA1 and BRCA2 and, since August 2002, break
point analysis for five large genomic rearrangements in BRCA1
(exon13del3835bp, exon13ins6kb, exon14-20del26kb, exon22del510bp
and exon8-9del7.1kb) was performed on individuals referred to our
laboratory for genetic testing. For the current study, only individuals
who indicated a personal history of breast cancer in situ and no history
of breast or ovarian cancer were analyzed. Demographic, personal, and
family cancer histories were requested from each tested individual
and collected by way of a test requisition form (TRF) included in each
testing kit. Individuals were also required to have a de¿nitively positive
or negative familial cancer history in a ¿rst- or second-degree relative
(those with missing family history data were not included). Odds ratios
were calculated by Fisher’s Exact Test.
Results: In total, 4,452 individuals reported a personal cancer history
of only breast cancer in situ (3,435 Non-Ashkenazi, and 1,017
Ashkenazi(AJ)). Of these, 279/3435 (8.1%) women of non-AJ ancestry
had a deleterious BRCA1/2 mutation. In AJ, 65/1017 (6.4%) carried
a BRCA1/2 mutation. Non-AJ with in situ breast cancer <50 had an
increased risk of a BRCA1/2 mutation compared to those women without
breast or ovarian cancer [OR = 1.4, 95% CI 1.21-1.64, p<0.0001], but
this was not the case for women ≥50 [OR = 0.58, 95% CI 0.41-0.79,
p=0.0004]. Interestingly, BRCA2 mutations were seen more commonly
than BRCA1 (ratio 41% to 59% BRCA1 to BRCA2 for AJ and non-AJ
women combined). This is in contrast to the 67% to 33% ratio (AJ)
and 56% to 44% ratio (non-AJ) seen associated with invasive breast
cancer.
Conclusions: Breast carcinoma in situ is a manifestation of the
BRCA1/2-associated hereditary breast and ovarian cancer syndrome.
Women with breast cancer in situ referred for genetic testing are at
high risk for carrying a germline BRCA1/2 mutation. In light of these
¿ndings and a recent population-based study (Claus et al, JAMA 2005),
women <50 with breast cancer in situ and a family history of breast or
ovarian cancer should consider BRCA1/2 genetic testing.
2035
Lifetime risk for breast and ovarian cancer in postmenopausal
BRCA carriers: cause for concern?
Tice JA, Crawford B, Ziegler J, McLennan J, Beattie M. UCSF, San
Francisco, CA
Background: Older women who test for BRCA mutations commonly are
motivated by their concern for their children. Data regarding cancer risk
and uptake of risk-reducing surgeries in BRCA carriers who undergo
testing at age 55 and older is scant.
Methods: Participants in the UCSF Cancer Risk Program are recruited
from UCSF, satellite clinics, and from family members who attend
these clinics. All participants agree to a unique 20 year IRB approved
follow-up protocol. To investigate cancer risk, we preformed KaplanMeyer analyses for incidence of breast and ovarian cancer among known
BRCA carriers who are unaffected at age 55. Women were censored at
the time of mastectomy, oophorectomy, or death. The analysis presents
results to age 80, although the life expectancy of a 55 year old woman
in 2007 is greater than 25 years. To investigate uptake of risk-reducing
mastectomy and risk-reducing oophrectomy, we used Cox proportional
hazard analyses.
Results: Our cohort includes 152 BRCA carriers (97 BRCA1 and
56 BRCA2). The risk to age 80 for breast cancer was 35% for
BRCA1 carriers and 48% for BRCA 2 carriers who were unaffected
at age 55. Similarly the lifetime risk for ovarian cancer was 65% in
BRCA1 carriers and 35% in BRCA2 carriers. Uptake of risk reducing
mastectomy was 10% in women 55 and over, while uptake of risk
reducing salpingo-oophorectomy was 17% in women 55 and over.
Compared to women under 55, the relative hazard of RRM was 0.3
(0.1-.5) and the relative hazard to RRSO was 0.6 (.2-.9).
Conclusion: BRCA1 and 2 carriers who are unaffected at age 55 are
at very high lifetime risk for both breast and ovarian cancer. Intensive
screening and consideration of prophylactic surgeries are as relevant
for these women as they are for women at age 35.
2036
BRCA1- and BRCA2-associated breast cancer is more
sensitive to standard chemotherapy for metastatic disease
in comparison with sporadic breast cancer.
Kriege M, Seynaeve C, Meijers-Heijboer H, Collee M, Menke-Pluymers
MBE, Bartels CCM, van den Ouweland A, van Geel B, Hooning M,
Brekelmans CTM, Klijn JGM. ErasmusMC-Daniel den Hoed Cancer
Center, Rotterdam, Netherlands
Background: Preclinical as well as small, retrospective, neo-adjuvant
studies suggest that ovarian and breast cancer (BC) (cells) without
functional BRCA1- or BRCA2-protein are particularly sensitive
to DNA-damage based chemotherapy, such as anthracyclin- and
platinum-containing regimens. In this study we assessed the response
to chemotherapy of BRCA1- and BRCA2-associated patients with
metastatic breast cancer (MBC). Data hereon are not yet available.
Materials and methods: We selected 82 consecutive BRCA1- and 24
BRCA2-associated BC patients with MBC (treated between 1973 and
2006). Cases were matched for year of birth, year of BC diagnosis and
year of diagnosis of MBC (within 5-years periods) with sporadic BC
patients. Response rate (RR) and progression free survival (PFS) after
¿rst line chemotherapy for MBC in BRCA1- and BRCA2-associated
patients versus sporadic BC patients were assessed.
Results: Mean age at BC diagnosis was 40.4 years (range 23.8-65.7),
and at diagnosis of MBC 44.8 years (range 25.9-79.8), not being
signi¿cantly different between the three patient groups. Chemotherapy
for MBC was thus far administered to 64/82 BRCA1-associated (78%),
to 23/24 BRCA2-associated (96%), and to 91/106 sporadic patients
(86%). The mainly used chemotherapy regimens were CMF /CMF-like
(n=50), anthracyclin-based (n=108), taxane-based (n=12), platinumbased (n=4), and other regimens (n=4). RR and PFS were not evaluable
in 9 patients (5 BRCA1, 1 BRCA2, 3 sporadic), because of early stop
of treatment. The RRs to ¿rst line chemotherapy (see Table 1) were
higher in both the BRCA1- (71%; p=0.07) and the BRCA2-associated
group (86%, p=0.03) than in the sporadic group (51%).
Table 1. Response rate to chemotherapy
BRCA1
N
%
Response Rate
42
71
Stable Disease
10
17
Progressive Disease
7
12
Mixed Response
Unknown
BRCA2
N
19
2
1
%
86
9
5
Sporadic
N
43
18
21
2
4
%
51
22
25
2
PFS was better for BRCA1- and BRCA2-associated as compared to
sporadic breast cancer. Hazard Ratio (HR) for the risk of progressive
disease was 0.70 (95% con¿dence interval (CI) 0.49-0.99) for BRCA1-,
and 0.49 (95% CI 0.30-0.78) for BRCA2-associated, as compared to
sporadic MBC.
Conclusion: BRCA1- and BRCA2-associated BC patients have a higher
response rate to and a longer PFS on ¿rst line standard chemotherapy
modalities for MBC as compared to sporadic patients. Whether this may
result in a prolonged post-relapse overall survival is under analysis.
Further analysis will also stratify for different regimens and taking
administration to hormonal therapy in account.
2037
BRCA mutation in Chinese population: preliminary results
from the Hong Kong hereditary and high risk breast cancer
programme.
Kwong A, Wong CLP, Ma E, Ford JM. The University of Hong Kong;
Hong Kong Santorium and Hospital, Hong Kong; Stanford University,
CA
Background: Little is known about the frequency and spectrum of
BRCA 1/2 mutations among Chinese population. Previous research
suggests possible differences in the prevalence and penetrance of these
mutations among Asians versus Caucasians. Reports have suggested
earlier presentation of breast cancer in Asian population may have
more relevance to genetic causes. The Hong Kong Hereditary and
High Risk Breast Cancer Programme was established in January 2007.
This provides clinical testing, genetic counseling and research on the
prevalence and spectrum of the mutation in Chinese population. The
data will be entered in a newly established The Hong Kong Hereditary
Breast Cancer Family Registry.
Methods: Probands diagnosed to have breast cancer age 50 or below,
have a family/personal history of breast and/or ovarian cancer,
bilateral breast cancer, male breast cancer, and triple negative breast
carcinoma were recruited. Genetic counseling was given and consent
were obtained. Blood samples were collected and processed for DNA
and RNA extraction. The entire coding regions and Àanking introns
of BRCA1/2 were screened for germline mutations using full gene
sequencing and Multiplex Ligation –dependent Probe Ampli¿cation
(MLPA). RNA analysis was performed on suspicious variant to con¿rm
pathogenicity.
Results: 110 blood samples have been collected of which 29 has
been sequenced and analysed to date. 10 deleterious mutations were
identi¿ed. 2 were novel mutations. 7 of the 10 mutations found were
BRCA 2 mutations. 8 other variant of unknown signi¿cicance (VUS)
were also identi¿ed.
Conclusions: Approximately 1/3 of tested Chinese women carry a
deleterious mutation in BRCA1/2. In contrast to Caucasian data, a
majority (70%) were BRCA 2 mutations. 28% of the tested women
S97
carried VUS. With a highly selective inclusion criteria, a high yield
of BRCA mutations were found. Further research on these variants
and spectrum of the mutations in Chinese population has important
implications on clinical management.
Table1: BRCA1 and BRCA 2 deleterious mutation and VUS identi¿ed in Hong Kong
Chinese
FH of breast /ovarian FH of other
BRCA1/2
Age
BRCA1/2 VUS
cancer
cancers /type
Mutation Carriers
60
Breast
38
Breast
39* Ovarian
50* Breast
50
Breast
BRCA2 Exon 11,
c.3109C>T
BRCA2 Exon 11,
5164_5delAG
BRCA2 Exon 18,
Stomach, tongue,
8047-8054 dup
larynx
GCAAAAAAC
BRCA2 Intron
Stomach
c.7806-9T>G
BRCA 2 Exon11,
c.3109C>T
BRCA2 Exon 11,
c.5851_5854delAGTT
57
Breast
45
Unknown
-
65
Unknown
-
48
No
-
39
No
-
52
Breast
26
No
54
Ovary
33
Breast
26
No
36
No
37
No
-
Laryngeal
BRCA1 Exon 11,
c.2635G>T
BRCA2,
c.3337 C>T
BRCA1,
c.589delCT
BRCA1,
c.4491C>T
-
Liver, Cervix
-
BRCA1 Exon 18,
c.5271+66G>A
BRCA1 Exon 18,
c.5271+66G>A
BRCA1 Exon 18,
c.5271+66G>A
BRCA1 Exon 18,
c.5271+66G>A
BRCA1 Exon 11
c.2726A>T
BRCA2 Exon 5,
c.440A>G
BRCA2 Exon 5,
c.440A>G
*=Novel Mutation
2038
The CHEK2*1100delC variant: present in the west of
Ireland breast cancer population.
Colleran GC, Rowan A, Miller N, Sawyer E, Curran C, Kerin M,
Tomlinson I. National University of Ireland Galway, Galway, Ireland;
London Research Institute, Cancer Research UK, London, England,
United Kingdom
Background: As part of a population-based approach to breast cancer
genetics, a West of Ireland cohort is under study to elucidate inherited
variation which predisposes women to developing breast cancer. Due
to the West of Ireland’s geographical location on the western edge of
Europe the genetics of this population has been relatively undisturbed
by the demographic movements that have shaped variation on mainland
Europe and the USA.[1] Consequently, the West of Ireland population
is relatively homogenous and amenable to case-control analysis. It is
thought that several common low penetrance genes account for the
non-BRCA associated genetic susceptibility to breast cancer.[7] These
genes are likely to be inherited in a polygenic model whereby genes
interact with each other and/or with the environment to induce their
carcinogenic effects. CHEK2 has been identi¿ed as a low-penetrance
breast cancer susceptibility gene conferring a two fold elevated risk of
breast cancer in women and ten fold in men.[8] In addition, case-control
studies have identi¿ed that germline mutations in CHEK2 (*1100delC)
are associated with increased risk of breast, prostate and colorectal
cancer in Dutch [9] and Finnish [10] populations. Its prevalence varies
within ethnic groups and populations and its potential role in breast
cancer aetiology in Irish patients has yet to be elucidated.
Materials and Methods: To evaluate the prevalence of the
CHEK2*1100delC variant, DNA collected from 591 breast cancer
cases and 572 healthy controls was analysed. Patients were recruited
from 2 af¿liated hospitals in the west of Ireland. Female controls had
no personal history cancer, no family history of breast cancer and were
over 60 years of age. Male controls had no personal history cancer, no
family history of breast cancer. FAM (carboxyÀuorescein) labelled
PCR products were capillary separated on the ABI 3700 and fragment
analysis carried out using Genotyper v2.5. Normal PCR fragments
measures 168bp and the CHEK2*1100delC could be clearly seen at
S98
167bp. A sequenced control CHEK2*1100delC patient DNA was PCR
ampli¿ed for each test reaction.
Results: The CHEK2 *1100delC mutation was found in three cases.
The mutation was not found in any of the control samples. Of the three
mutation carriers, one had a sibling who was affected with colorectal
cancer.
Discussion:
We have established that the CHEK2*1100 delC variant is present in
the Irish population and is in excess in cases over controls. CHEK2
mutations confer a two fold elevated risk of breast cancer in women and
ten fold in men.[8] Our data are consistent with effect on risk. Given
the emergence of other low penetrance genes including BRIP1[11]
and ATM[12] their role in the clinical setting of screening and risk
assessment and the public awareness of these developments necessitates
revised guidelines in this area to assist clinicians managing breast
cancer patients.
References available on request.
2039
Addressing the needs of men in BRCA1/2 families.
Daly MB. Fox Chase Cancer Center, Philadelphia, PA
Male carriers of deleterious BRCA1/2 mutations have a 6% lifetime
risk of male breast cancer, and a 6%-14% lifetime risk of prostate
cancer. Despite these health implications, we have found a lack of
understanding of genetic test results among the men in these families.
As part of a larger study to explore family communication patterns of
genetic risk, we identi¿ed 24 male ¿rst-degree relatives whose proband
received a true positieve test result and reported telling the result to
her male relatives. Six (25%) of these male relatives reported that they
hadn’t received the results or had forgotten them. Of the remaining 18
(75%) who did report receiving the results, two (11%) reported tht it
was a negative result. Only two (11%) reported any level of dif¿culty
in understanding the test results, or indicated that they would like
more information. However, only ¿ve (28%) could correctly identify
their chance of being a mutation carrier. Seven (40%) did not believe
that the test results increased their own risk for cancer, reÀected in a
relatively low level (33%) of interest in genetic testing. Of the six men
who did express interest, half expressed interest primarily for their
children’s sake. And ¿nally, of the 14 men who expressed any level of
concern about the meaning of the test result, 11 directed their concern
toward other family members, primarily daughters and sisters. This
limited experience tends to con¿rm a level of cognitive and emotional
distance that men experience from the genetic testing process as it
applies to them.
2040
Identi¿cation of a recurring BRCA1 mutation in Bahamian
Donenberg T, Turnquest T, Lunn J, Curling D, Krill-Jackson E, Hurley
J. University of Miami/Jackson Memorial Hospital, Miami, FL;
Doctor’s Hospital, Nassau, Bahamas; Princess Margaret Hospital,
Nassau, Bahamas; Mount Sinai Comprehensive Cancer Center, Miami
Beach, FL
Background: As previously reported by our group, the age distribution
of women with breast cancer in the Bahamas is unusually early with
48% being under age 50 in an unselected group of 266 newly diagnosed
cases. The Bahamian population is a unique and culturally distinct
group originating in part from the African continent and likely harbors
a low level of genetic heterogeneity. These observations prompted
investigation into a common genetic etiology. The identi¿cation of a
founder mutation in this relatively isolated geographic population may
contribute to more ef¿cient cancer risk screening and prevention.
Methods: Sixteen women of Bahamian background underwent full
sequence analysis and limited large gene rearrangement testing for
BRCA1 and BRCA2 genes at Myriad Genetic Labs. Study criteria
included at least one parent born in the Bahamas, ovarian cancer or
breast cancer under age 50 in the proband or breast cancer at any age
and a ¿rst or second degree relative with breast or ovarian cancer.
Results: Four seemingly unrelated patients were found to carry the same
mutation (4730insG) in the BRCA1 gene. Two patients were found
to have the IVS13+1G>A mutation in BRCA1, a suspected founder
mutation reported in the African American population. Three patients
were found to have unclassi¿ed variants in the BRCA2 gene.
Discussion: Recurrent mutations in the BRCA1 gene may explain the
high prevalence of early onset breast cancer observed in the Bahamian
population. We aim to further characterize the mutational spectrum in
the Bahamas by testing additional patients with the above criteria. In
addition, haplotype analysis of those carrying the 4730insG mutation
may help identify a common ancestor that populated these islands.
The identi¿cation of a founder mutation can lead to simpli¿ed and less
costly genetic testing with increased accuracy and may allow clinicians
to serve this population better. Further investigation is needed to more
fully de¿ne the prevalence of founder mutations and the underlying
causes of early onset breast cancer in this population.
2041
%5&$ and %5&$ mutation carrier predictions using the
BRCAPRO model in clinic-based minority families.
Huo D, Senie RT, Terry MB, Daly MB, Buys SS, Ogutha J, Hope K,
Olopade OI. University of Chicago, Chicago, IL; Columbia University,
New York, NY; Fox Chase Cancer Center, Philadelphia, PA; University
of Utah Health Sciences Center, Salt Lake City, UT
Background: BRCA mutation prediction models, such as BRCAPRO,
are used in cancer risk clinics, but they were developed based on
mutation rates and penetrance observed in individuals of Ashkenazi
Jewish and European ancestry. Furthermore, in clinical counseling it is
not always clear whether to test additional family members for BRCA
mutations after the proband tests negative. The aim of this study is to
evaluate the performance of the BRCAPRO model among clinic-based
minority families and to evaluate the clinical utility of testing additional
family members in high risk families.
Methods: A total of 398 families with at least one member having been
tested for BRCA mutations were enrolled through the Breast Cancer
Family Registry and University of Chicago. Families of Ashkenazi
Jewish ancestry were excluded. Using the BRCAPRO model with
default penetrance and allele frequency for non-Ashkenazi Jewish
populations, the predicted likelihood of carrying either a BRCA1 or
BRCA2 mutations was generated. Sensitivity, speci¿city, and area under
the receiver operating characteristic curves (AUC) were calculated.
Results: There were 113 African American, 195 Hispanic, 54 Asian
American and 36 other minority families. The AUC was 0.808 (95%
con¿dence interval, CI: 0.767-0.847) for all minorities combined. At
a predicted probability of 10%, the sensitivity for identifying mutation
carriers was 72% and the speci¿city was 73%. The performance was
similar across the racial/ethnic groups (p=0.18). After taking into
account the mutation status of family members, the performance of
the BRCAPRO model was improved (p<0.001): the AUC increased to
0.883 (95% CI: 0.846-0.912) and the speci¿city at the 10% threshold
increased to 79%, while the sensitivity increased to 76%.
Discussion: The data support the use of BRCAPRO in pretest prediction
of BRCA1/2 mutations for minority families in high risk clinic settings.
Mutation status of family members provides additional predictive
value, which may help counselors decide whether to offer other family
members the test when one member has already tested negative, given
a positive family history of breast and ovarian cancer.
2042
Outcome in BRCA2 mutation carriers is superior to that of
high-risk women with sporadic breast cancer.
McLennan JL, Hwang ES, Moore DH, Crawford BB, Esserman LJ,
Ziegler JL. University of California, San Francisco, CA
Background: Breast cancer histology does not differ signi¿cantly
between BRCA mutation carriers and those with sporadic breast cancer.
We conducted this study to determine whether there existed a difference
in outcome between these two groups following a diagnosis of invasive
Methods: We performed a review of data collected from a prospectively
recruited cohort of BRCA2 mutation carriers and high-risk mutationnegative patients. All women in the cohort underwent genetic testing
for a BRCA mutation between 1996 and 2006 and had a diagnosis
of invasive breast cancer. Overall survival was compared using the
Kaplan-Meier survival method. Median survival was compared using
a log-rank test. A Cox proportional hazard model was used to compare
adjusted risk of mortality among BRCA2 mutation carriers and subjects
without BRCA mutations.
Results: 57 BRCA2 mutation carriers and 406 high risk, mutationnegative women were diagnosed with invasive cancer between 1954
and 2005. Median follow-up time was 49 months. BRCA2 mutation
carriers were slightly younger at diagnosis than those with sporadic
cancer (42.8 years and 45.7 years respectively, p=0.03), but less likely
to have node-positive disease (p=0.04) and more likely to have riskreducing salpingo-oophorectomy (RRSO) (67% versus 8.4%, p<0.001).
Mutation carriers had a signi¿cantly longer median survival after
diagnosis of IBC than non-carriers (median survival 90 months (95%
CI 49-122) vs. 49 months (95% CI 42-56), p=0.01). In a multivariate
model including age, BRCA mutation status and RRSO, only RRSO
was associated with improved survival (HR 0.72, p=0.02).
Conclusion: BRCA mutation carriers have longer median survival
following a diagnosis of IBC than similarly high-risk, mutation-negative
women. This observation may in large part be due to the higher use of
RRSO among mutation-carriers.
S99
breast cancer (AUROC=0.85). However, when the performance of
the BRCAPRO model was evaluated for women with bilateral breast
cancer strati¿ed by age at ¿rst diagnosis, it appeared that the BRCAPRO
model performed better in cases where the age at ¿rst diagnosis was
≤40 years (AUROC=0.90), compared to women whose age at ¿rst
diagnosis was >40 years (AUROC=0.76). Additionally, the carrier rate
of BRCA mutations was signi¿cantly higher (p=0.002, Fisher’s exact
test) in women with bilateral breast cancer whose age at ¿rst diagnosis
was ≤40 years (58%; 14/24), compared to women whose age at ¿rst
diagnosis was >40 years (18%; 8/42). When the same comparisons
were made for women with unilateral breast cancer, no statistically
signi¿cant differences were observed in either the performance of
the BRCAPRO model or in the carrier rate of BRCA mutations when
strati¿ed by age.
Conclusion: The BRCAPRO model appears to perform better in cases
of bilateral breast cancer where the ¿rst breast cancer is diagnosed ≤40
years. Furthermore, the carrier rate of BRCA mutations among women
with bilateral breast cancer is higher among those whose ¿rst breast
cancer is diagnosed ≤40 years. These results suggest that we may be
overestimating the relative contribution bilateral breast cancer has on
the likelihood of detecting a BRCA mutation. However, these results
should be validated in larger studies.
2044
Large genomic alterations in %5&$ in young women with
breast cancer participating in the breast cancer family
registry.
2043
BRCA mutations among women with bilateral breast
cancer: mutation carrier rate and sensitivity of the
BRCAPRO model based on age at ¿rst diagnosis.
Ready K, Vogel K, Atchley D, Amos C, Solomon K, Lu K, Arun B. The
University of Texas M.D. Anderson Cancer Center, Houston, TX
Background: Risk estimates for the likelihood of identifying a BRCA
mutation are calculated using the BRCAPRO risk assessment program.
However, the sensitivity of this program in patients with bilateral
cancer has not been determined. Furthermore, population based studies
suggest that there is a low proportion of mutation carriers among
patients with bilateral breast cancer whose age at ¿rst diagnosis was
>40 years. Therefore, our objectives were to determine the sensitivity
of the BRCAPRO model among women with bilateral breast cancer,
to determine the rate of BRCA1 and BRCA2 mutations among women
with bilateral breast cancer, and to determine if their mutation status is
dependent on their ¿rst age of diagnosis of breast cancer.
Methods: A retrospective chart review was performed. Women who
were diagnosed with either unilateral or bilateral breast cancer and who
had undergone comprehensive BRCA genetic testing were included.
The CancerGene program, version 4.3.1, was used to calculate the
BRCAPRO scores.
Results: Sixty-six women with bilateral breast cancer and 66 women
with unilateral breast cancer were identi¿ed. Of the bilateral cases, 33%
(n=22), and of the unilateral cases 14% (n=9) were carriers of a BRCA
mutation. The average BRCAPRO score among the bilateral cases was
52%, and the average BRCAPRO score among the unilateral controls
was 15%. Overall, there was no statistically signi¿cant difference
between the performance of the BRCAPRO model among women
with bilateral breast cancer (AUROC=0.86) compared to unilateral
Smith LD. Genetic Epidemiology Laboratory, The University of
Melbourne, Parkville, VIC, Australia
Large genomic alterations of BRCA1 represent a signi¿cant proportion
of clinically relevant BRCA1 mutations. Early studies of genomic
alterations used methods that were laborious, technically challenging
and usually required a large amount of DNA. Recently, tests to identify
large genomic alterations in BRCA1 have been successfully applied to
small amounts of DNA and larger scale screens for these alterations
have become possible. The proportion of women with breast cancer,
especially young women, whose cancers are attributable to large
alterations within BRCA1 is currently unknown in many populations
and clinical settings.
We selected 450 women from The Breast Cancer Family Registry
(BreastCFR) diagnosed with:
1) breast cancer before age 40 years with a strong family history (2 or
more ¿rst- or second-degree relatives affected with breast or ovarian
cancer) and/or
2) tumour morphology consistent with having a BRCA1 mutation (at
least 5 of the following: presence of necrosis, a marked lymphocytic
in¿ltrate, pushing margins, mitotic index >50 per 10 hpf, nuclear grade
III/III, trabecular growth pattern, syncytial pattern and/or poor tubule
formation).
These women had undergone extensive testing for BRCA1 mutations
via various methods. Women participating in the population-based
group of the BreastCFR were selected regardless of mutation status.
Women recruited via clinics were only selected for this study if prior
testing failed to identify a BRCA1 mutation.
We screened the germline DNA via Multiplex Ligation-dependent
Probe Ampli¿cation and found a variety of large alterations involving
the coding regions of BRCA1 and/or the promoter region that represent
∼25% of all BRCA1 mutations identi¿ed in this group. The prevalence,
penetrance and molecular nature of these changes, as well as the
relevance of this type of mutation screening in clinical genetics services
will be discussed.
2045
Clinical characteristics and choices regarding prophylactic
surgery in BRCA mutation carriers.
Stuckey A, Dizon D, Legare R, Wilbur J, Kent J, Tejada-Berges T, Gass
J. Women and Infants’ Hospital/Warren Alpert Medical School of Brown
University, Providence, RI
Background: BRCA mutation carriers are known to have a high lifetime
risk of developing breast and ovarian malignancies. As genetic testing
S100 Abstracts – Poster Session II
becomes widely available, preventative measures are a choice for
many of these women. The purpose of this study is to evaluate the
characteristics of BRCA mutation carriers who chose prophylactic
surgery (PS) compared to those who did not.
Methods: Eligible patients had a mutation in the BRCA1 or BRCA2
genes identi¿ed in our genetics program. Demographic data as well
as family history was collected by retrospective review. Patients who
opted for and those who chose not to proceed with prophylactic surgery
were compared.
Results: A total of 90 patients were included in this study. Forty-six
(51%) underwent PS and 44 (49%) did not. Prophylactic surgery
included 39 bilateral salpingo-oophorectomies (PBSO) and 13
mastectomies (PM). Of those undergoing PS, eighty-nine percent
of the pathology was benign. Among those undergoing PM, there
were two cases of DCIS (15.4%) and one case of in¿ltrating ductal
carcinoma (7.7%). Among those undergoing PBSO, there was one
case of adenocarcinoma of the fallopian tube (2.6%) and one case
of adenocarcinoma of the ovary (2.6%). Comparing the two groups,
PS was more often chosen among BRCA2 carriers versus those with
BRCA1 mutations (60.8% vs. 38.5%, p=0.06). In addition, being
married (62% vs. 40%, p<0.10), and employed (56% vs. 31%, p>0.1)
was associated with PS. However, a prior history of cancer was not
associated with PS in our cohort.
Discussion: Our study suggests a group of women who are more likely
to undergo prophylactic surgery—those who are BRCA2 mutation
carriers, employed, and married. Con¿rmation of the pro¿le of women
most interested in proceeding with preventative surgery as cancer
prophylaxis requires a larger data set. Furthermore, long-term follow-up
is required to describe the potential side effects of prophylactic surgery
on health-related quality of life.
Clinical characteristics of BRCA mutation carriers
Surgery
BRCA mutation
BRCA1
15 (38.5%)
BRCA2
31 (60.8%)
Employed
Yes
33 (56.0%)
No
5 (31.3%)
Married
Yes
31 (62%)
No
12 (40%)
Prior Cancer Diagnosis
Yes
29 (50%)
No
17 (53%)
No Surgery
P-value
0.059
24 (61.5%)
20 (39.2%)
0.21
26 (44.1%)
11 (68.8%)
0.09
19 (38%)
18 (60%)
0.9
29 (50%)
15 (46.9%)
2046
Cancer-predictive methylation patterns in hereditary breast
cancer.
Suijkerbuijk KP, Fackler MJ, Sukumar S, van Gils CH, van Laar T,
Vooijs M, van der Wall E, van Diest PJ. University Medical Center
Utrecht, Utrecht, Netherlands; Johns Hopkins, Baltimore, MD
Background: Promoter methylation is a common epigenetic mechanism
to silence tumor suppressor genes during breast cancer development.
Methylation of a selected set of genes was detected in ductal Àuids
of sporadic breast cancer patients. We investigated whether BRCAassociated breast tumors show cancer-predictive methylation patterns
similar to sporadic tumors.
Material and Methods: Quantitative Multiplex Methylation-Speci¿c
PCR (QM-MSP) of eleven genes involved in breast carcinogenesis
(APC, BRCA1, BRCA2, CYCLIN D2, CDH1, ERa, SCGB3A1,
p16, RARβ, RASSF1A, TWIST1) was performed on 40 BRCA1/2associated and 46 sporadic breast carcinomas, and on normal breast
tissue from 9 BRCA1/2 mutation carriers and 13 non-carriers.
Results: The median cumulative methylation index (CMI) of all studied
genes was signi¿cantly higher in tumors than in normal tissue. The
median CMI was signi¿cantly lower in hereditary than in sporadic breast
tumors and in lymph node negative compared to lymph node positive
tumors. Frequency of a positive methylation test was signi¿cantly
higher in tumors versus normals and in lymph node positive versus
negative tumors. The extent of cumulative methylation increased with
age. Malignancy was predicted with high accuracy using a panel of
genes in sporadic cases as well in hereditary cases.
Discussion: BRCA1/2-associated breast cancers show a lower extent
of promoter methylation compared to sporadic breast carcinomas.
Nevertheless, methylation status of a panel of breast cancer genes
is still highly associated with hereditary breast cancer, and should
be useful for early detection of cancer in nipple Àuids of genetically
predisposed patients.
2047
BRCA testing in underserved women: 5 years of followup.
Wilcox C, Lee R, Chan S, Crawford B, Luce J, Ziegler J, Beattie MS.
San Francisco General Hospital, San Francisco, CA; University of
California, San Francisco, San Francisco, CA
BACKGROUND: BRCA testing, to date, has not been widely available
to underserved populations. In 2002, San Francisco General Hospital
(SFGH) became the ¿rst public hospital in the US to provide BRCA
testing and follow-up, free of charge, to appropriate women, via an
Avon Foundation grant. The purpose of this research is to describe the
¿rst 5 years of experience of BRCA testing at SFGH and to compare
the SFGH satellite Cancer Risk Program to the UCSF/Mt. Zion Cancer
Risk Program.
METHODS: Patients at SFGH were referred through 3 main routes: a
family history questionnaire administered during mammography (50%),
hospital based clinics (34%) and community health centers (16%). 627
patients at SFGH have received “intake and education” visits for risk
assessment in the last 5 years. Of these, 122 have been offered BRCA
testing (2 declined). Using a similar testing threshold at UCSF/Mt. Zion,
1114 patients have been offered BRCA testing (77 declined).
RESULTS: Table 1 compares all patients at SFGH and UCSF/Mt.
Zion who have received BRCA testing. The ethnicity, employment,
and educational backgrounds of patients at SFGH differ considerably
from those at UCSF/Mt. Zion. The percent of patients from both sites,
however, who test BRCA positive is not clinically different. Table 2
compares patients at SFGH and UCSF/Mt. Zion who test positive.
Interestingly, SFGH has a higher ratio of BRCA2 positives than
UCSF/Mt. Zion. Choices for risk reducing surgeries at SFGH and at
UCSF/Mt. Zion do not differ clinically.
CONCLUSIONS: Although the demographics between SFGH and
UCSF/Mt. Zion populations are signi¿cantly different, the proportion of
positive results is not clinically different among these 2 populations. The
ratio of BRCA2:BRCA1 carriers is higher at SFGH compared to UCSF/
Mt. Zion, which may reÀect the more diverse ethnic population seen at
SFGH. Underserved and diverse women who carry BRCA mutations
appear as likely to choose risk reducing surgeries as frequently as
women who carry BRCA mutations from tertiary care centers.
Comparison of BRCA Testing Populations at SFGH and UCSF/Mt. Zion
SFGH
UCSF/Mt. Zion
Number Tested
121
1037
% Women
96%
97%
median age (range)
45 (30-84)
51 (20-82)
BRCA+
17%
22%
VUS
10%
7%
% Caucasian
49%
85%
% Black
15%
5%
%Asian
13%
6%
% Latina
23%
4%
% Ashkenazi Jewish
20%
26%
% with post high school education
66%
97%
% employed/spouse employed
50%
100%
Comparison of BRCA Carriers at SFGH and UCSF/Mt. Zion
SFGH
UCSF/Mt. Zion
BRCA2:BRCA1 ratio
1.5
0.8
% of eligible carriers choosing RRSO*
50%
51%
% of eligible carriers choosing RRM*
36%
23%
RRSO = Risk Reducing Salpingo-Oophrectomy, RRM = Risk Reducing Mastectomy,
“eligible carriers” must have tissue at risk and be free of metastatic disease
2048
Prophylactic surgeries among BRCA1/2 mutation carriers
in the Netherlands.
Hooning MJ. The Collaborative Group on Hereditary Breast and
Ovarian Cancer in the Netherlands (HEBON)
The purpose of this study was to estimate the uptake of prophylactic
surgeries in Dutch BRCA1/2 mutation carriers. Within the framework of
Abstracts – Poster Session II S101
a nationwide study (GEO-HEBON) on gene-environment interactions,
we invited 211 carriers for a survey on various preventive strategies, to
which 175 (83%) carriers responded (3% refused, 14% non-response).
Carriers were approached 7.7 ± 2.2 years after the DNA test. After
exclusion of carriers without intact ovaries at DNA test result, 150
carriers remained for analysis (123 BRCA1 and 27 BRCA2), of whom
67 had had breast cancer. The median age at DNA testing was 39.7
± 11.0 years. 104 carriers (69%) underwent bilateral prophylactic
oopho

Breast Cancer Research and Treatment

Transcription

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