Breast and Ovarian Cancer Testing and Diagnosis

Screening and Prevention
of Ovarian Cancer
Ellen M Hartenbach MD
Associate Professor
Vice Chair of Obstetrics & Gynecology
Division of Gyn Oncology
University of Wisconsin, Madison
Greetings from Madison, Wisconsin
Objectives
• Review the genetic basis of cancer as it relates to
breast and ovarian cancer
• Discuss which patients should be referred to
genetic counselors for possible hereditary breast
ovarian cancer
• Explain the risk reduction strategies available to
women once a breast/ovarian cancer (BRCA)
gene is detected
Conflict of Interest Disclosure
Dr. Ellen Hartenbach
None, nope,
nadda, nyet…
2011 Estimated US Cancer Deaths
Lung 28%
Colon
Men
300,430
Women
271,520
26%
Lung 11%
15%
Breast
Prostate
8%
9%
Colon Pancreas
6%
7%
Pancreas
Leukemia
4%
Liver 4%
6%
Ovary
Esophagus
4%
3%
Leukemia
Non‐Hodgkin 3%
3%
Uterus
2%
Liver lymphoma Bladder
3%
2%
Brain/ONS
Kidney
3%
27%
Other sites
Other sites 26%
American Cancer Society, 2011
The Development of
Hereditary Cancer
2 normal genes 1 damaged gene
2 damaged genes Tumor
1 normal gene
develops
In hereditary cancer, one damaged gene is
inherited.
1 damaged gene
2 damaged genesTumor
develops
1 normal gene
© 2004 Myriad Genetic Laboratories,
Inc.
Cancer risk with BRCA mutation
My Beloved Hometown, St. Louis…
What patients should be
referred to cancer genetic
counselors for evaluation?
“Red Flags” for
Hereditary Breast and Ovarian Cancer
•
•
•
•
•
•
Breast cancer before age 50
Ovarian cancer at any age
Male breast cancer at any age
Multiple primary cancers
Ashkenazi Jewish ancestry
Relatives of a BRCA mutation carrier
Criteria for Referral for BRCA Testing
• For non–Ashkenazi Jewish women:
– Two first–degree relatives with breast cancer, one relative in
whom breast cancer was diagnosed when younger than 50 years
– A combination of three or more first– or second–degree relatives
with breast cancer at any age
– A combination of both breast and ovarian cancer among first–
and second–degree relatives
– A first–degree relative with bilateral breast cancer
– A combination of two or more first– or second–degree relatives
with ovarian cancer at any age
– A first– or second–degree relative with both breast and ovarian
cancer at any age
– A male relative with breast cancer
• For women of Ashkenazi Jewish heritage:
– Any first–degree relative with breast or ovarian cancer
– Two second–degree relatives on the same side of the family with
breast or ovarian cancer
U.S. Preventive Services Task Force. Genetic risk
assessment and BRCA. Ann Intern Med 2005;143:355–61
Medicare criteria for BRCA testing
 Women with breast or ovarian
cancer (any age) and,
 A relative with breast cancer
<50, or
 A relative with ovarian
cancer, or
 A relative with male breast
cancer
 Women with breast cancer <50
 Women with ovarian cancer
any age
 Women with breast and ovarian
cancer any age
 Men with breast cancer
March, 2000…
Ov 74
Ov 44
Br 44
Ovarian cancer
Breast cancer
…June, 2011
Ov 74
Ov 55
Br 44
Ov 56
BRCA1
Ovarian cancer
Breast cancer
BRACAnalysis®
Myriad Genetic Laboratories, Inc
• Two ways to obtain a sample for analysis; small amount of blood can be drawn or oral sample can be taken using a buccal rinse
• Most health insurance plans pay for BRCA testing
• The Genetic Information Nondiscrimination Act or GINA adds additional protection to existing legal protections that are in place at both the federal and state levels. GINA is a federal law that protects Americans from being treated unfairly based on differences in their DNA. BRACAnalysis®
• Comprehensive BRACAnalysis®: BRCA1 and BRCA2 gene sequence analysis and a panel of large rearrangements for susceptibility to breast and ovarian cancer. • Single Site BRACAnalysis®: Single‐mutation analysis for susceptibility to breast and ovarian cancer for individuals with known BRCA1 or BRCA2 mutations in their family. • Multisite 3 BRACAnalysis®: Three‐mutation BRCA1 and BRCA2 analysis for genetic susceptibility to breast and ovarian cancer for Ashkenazi individuals. Clinical management of
BRCA positive women
Ovarian cancer risk reduction
 SURGERY:
 Risk reducing salpingo-oophorectomy
 CHEMOPREVENTION:
 oral contraceptives
 SURVEILLANCE:
 pelvic exam
 TV sonography
 CA125
Ovarian Cancer Screening
 NIH Consensus Conference on Ovarian Cancer
Screening, Treatment and Follow-up: 1995:
“There is no evidence available yet that the
current screening modalities of CA-125 and
transvaginal ultrasonography can be effectively
used for widespread screening to reduce
mortality from ovarian cancer nor that their use
will result in decreased rather than increased
morbidity & mortality.”
JAMA 1995; 273:491-497
Screening in high risk women?
• Five cancer genetics centers: UK, Netherlands, Norway.
• 3532 women, 1991-2007
• prospective observational study without a control group,
observed group stratified according to results of mutation testing
• annual TV sono and CA 125
Conclusion: annual screening with TV sono and CA125
is ineffective in improving survival in BRCA1/2
carriers (10 year survival no better than nonscreened population)
Evans et al, J Med Genet. 2009 Sep;46(9):593-7
GOG 199
 Large prospective study to assess high risk
women contemplating risk reducing salpingooophorectomy in US
 Evaluate a novel ovarian cancer screening
strategy (ROCA)
 Provide information related to quality-of-life
and health care practices related to managing
premature menopause after surgery
 Biological samples collected will be used to
help understand the mechanisms by which
hereditary ovarian cancer develops
 Accrual 2003-2006. 5 year results soon
Women at Increased Risk
of Ovarian Cancer
Risk Assessment
Enroll in Study
[Informed Consent]
Ineligible
Decline
Participation
BASELINE DATA
Questionnaires
Blood Samples
TVUS
CA-125
SURGERY
BSO Tissue
q 3 months:
CA-125
ROCA w/u
Q 6 months:
Q.O.L.
Cancer Events
Health Status
SCREENING
q 3 months:
CA-125
ROCA w/u
Q 6 months:
Q.O.L.
Cancer Events
Health Status
Yearly:
TVUS
Future of ovarian screening?
• CA 125 plus ovarian cancer symptom
index
• ROCA algorithm
• New biomarkers- HE4, mesothelin, OVX1,
LSA,…
• Proteomics
• Multiplex assays – Ovasure, others
Chemoprevention for BRCA positive women:
Oral Contraceptives? YES
Use of oral contraceptives for 4 or more years- 50%
reduction in ovarian cancer risk in the general
population
A majority of, but not all, studies also support oral
contraceptives being protective among BRCA1/
BRCA2 mutation carriers.
Meta-analysis of 18 studies including 4,358 BRCA
mutation carriers reported a 50% reduced risk of
ovarian cancer. Summary relative risk (SRR)=0.50;
95% confidence interval (CI, 0.33-0.75)
Meta-analysis. Eur J Cancer. 2010 Aug;46(12):2275-84
Benefits of salpingo-oophorectomy
 Potential benefits associated with RRSO in
genetically at-risk women:
 Reduction in the risk of ovarian cancer
 Reduced worry, anxiety and apprehension on the
part of the patient
 Reduction in the risk of subsequent breast cancer
[ ~ 50% ]
Burdens of salpingo-oophorectomy
 Potential risks associated with RRSO:
 It is not 100% effective:
primary peritoneal carcinomatosis
 It renders the premenopausal patient
immediately postmenopausal with potential
QOL issues (mood, sleep, sexual function)
 Must confront the issue of estrogen
replacement in women at high genetic risk
of breast cancer
 Surgical morbidity and mortality
Prevention and Observation of Surgical
Endpoints (PROSE) consortium.
• Participants were ascertained between 1974 and 2008, 22 centers
• 2482 known BRCA1/2 mutation carriers
• Risk-reducing salpingo-oophorectomy was associated with a
decreased risk of ovarian cancer. Women with no prior breast cancer,
(HR) in all BRCA1 mutation carriers was 0.31 (95% confidence
interval [CI], 0.12-0.82. 70% reduction in risk
• Salpingo-oophorectomy was associated with a decreased risk of
breast cancer in both BRCA1 mutation carriers (HR, 0.63; 95% CI,
0.41-0.96) 37% reduction and BRCA2 mutation carriers (HR, 0.36;
95% CI, 0.16-0.82) without prior diagnosis of breast cancer 64%
reduction
• Salpingo-oophorectomy was associated with significantly lower allcause mortality in those with no prior breast cancer (HR, 0.45; 95% CI,
0.21-0.95) and those with prior breast cancer (HR, 0.30 [95% CI, 0.170.52]
Domchek et al, JAMA. 2010 Sep 1;304(9):967-75.
Kaplan-Meier Estimated Probability of Ovarian Cancer
Among BRCA1 Carriers With and Without Intact Ovaries
Finch, A. et al. JAMA 2006;296:185-192.
Copyright restrictions may apply.
Risk of occult cancer at oophorectomy
AUTHOR
YEAR
CANCERS/RRSO
Salazar
1996
2/20
Deligdisch
1999
1/21
Morice
1999
1/27
Lu
2000
4/50
Colgan
2001
5/60
Rebbeck
2002
6/259
Leeper
2002
5/30
Lamb
2006
7/113
Finch
2006
11/490
43/1075 (4%)
When to perform RRSO?
 Decision analysis studies demonstrate the
greatest benefit if RRSO is performed after
childbearing before age 40
 May consider delay until natural
menopause in BRCA2 carriers as ovarian
cancer diagnosis is generally older
(average age =62)
HRT
 Short–term estrogen without progestins does not
mitigate the sharp reduction in breast cancer risk
achieved by premenopausal women with BRCA1 and
BRCA2 mutations who undergo risk–reducing salpingo–
oophorectomy
 Ideal dose, duration of therapy, estrogen compound, and
delivery method that maximizes quality of life while
minimizing breast cancer risk in women with mutations in
BRCA1 and BRCA2 have not been determined.
Rebbeck JCO 2005;23:7804-10
Surveillance for Breast Cancer in BRCA carriers
Procedure
Age to begin
Frequency
Breast self-exam
18-21 yrs
Monthly
Clinical breast
exam
25-35 yrs
6 months to a year
Mammography
25-35 yrs
Yearly
MRI
25-35 yrs
Yearly
Currently in clinical
trials
Currently in clinical
trials
Breast
Ultrasound
JAMA 1997; 277:997-1003
Cancer 2004;100:479-89
NEJM 2004;351:427-37
www.nccn.org
Great job.
Almost done with
this lecture!
Are there downsides to familial
cancer risk assessment?
Genetic Counseling: Benefits and Burdens
Benefits of DETECTING a mutation can include: • reduction of uncertainty and anxiety of "not knowing" • potential for reduced morbidity and mortality due either surveillance or to preventive measures
• opportunity to alert relatives to their potential risk and available services
• potential to participate in clinical trials and related research
Benefits of NOT DETECTING a mutation (when an affected relative has been found to have one) include: • reassurance and reduction of anxiety
• avoidance of unnecessary intensive monitoring strategies and prophylactic surgical measures
Genetic Counseling: Benefits and Burdens
Burdens of DETECTING a mutation can include: anxiety depression;
reduced self‐esteem;
frustration associated with the unproven effectiveness of available interventions;
the risks and costs of additional surveillance or prophylaxis
strained relationships with a partner or with relatives;
guilt about possible transmission to children;
stigmatization;
possible discrimination by health, life or disability insurance companies, by employers, or by others the potential (but as yet unproven) hazards of more frequent and earlier mammograms in BRCA1 and/or BRCA2 mutation carriers. Genetic Counseling: Benefits and Burdens
Burdens of NOT DETECTING a mutation include:
potential for neglect of routine surveillance due to the
mistaken belief that risk is zero
survivor guilt, i.e., feeling undeserving of negative test results
when other family members test positive
Burdens of a test result of "uncertain significance" include:
the need to evaluate other family members to determine its
significance;
the need to maintain intensive surveillance until the
significance of the genetic alteration is known
anxiety, frustration, and other adverse psychological
sequelae associated with uncertainty.
Is prevention surgery a good thing?
 846 high risk women: 44% RRSO & 56%
screening on nationwide, observational study
 QoL SF36 no difference between groups
 RRSO women had less cancer fear (p<.001)
 RRSO women worse endocrine sx’s (p<.001)
and worse sexual function (p<.05)
 86% would chose RRSO again
 63% would recommend it to others at risk
Madalinska et al, JCO 23:6890, 2005
Facing Our Risk of Cancer Empowered
FORCE is a national nonprofit
devoted to hereditary breast
and ovarian cancer. The
mission includes support,
education, advocacy,
awareness, and research.
http://www.facingourrisk.org/
Summary
 Ovarian cancer screening with CA125 and TV Sono is
ineffective in the general population, but needs further
study in the high genetic risk population
 Surgical “Risk-reducing salpingo-oophorectomy” is the
most effective prevention strategy for ovarian cancer
 ERT can be used in premenopausal patients after RRSO
 Annual breast cancer screening with mammography +/MRI is recommended for BRCA carriers
 Prophylactic mastectomy and RRSO are effective
strategies for breast cancer prevention
 Genetic counselors are recommended to evaluate
patients and conduct pre and post test counseling
Thank You!
Questions?