Adjuvant and Neoadjuvant Chemotherapy

Adjuvant and Neoadjuvant
Chemotherapy
2014 Situation
Dr Alexandre Bodmer
Centre du Sein
HUG Genève
Encouraging….
2014 challenge
Breast Cancer - Survival
Kaplan-Meier Survival Curves
Which Breast Cancers Return?
• We need to:
• Identify which patients
would benefit from
chemotherapy.
• Identify which patient
would not.
• Have reliable prognostic
factors
• Have clinically applicable
predictive factors
Risk assessment
Prognostic and predictive factors
•
•
•
•
•
•
•
Tumor size
Lymph node involvement
Grade
Proliferation Markers : Ki 67
Hormone receptors
HER2 status
Gene expression profiles
Stage : prognostic factor
91% at
5 years
98% at 5
years
80 %at
5 years
63% at
5 years
84% at 5
years
58% at 5
years
Molecular subtypes and prognosis
How can we do better?
• Better selection of patients for adjuvant
chemotherapy
• Treat only those patients who are most likely to recur
and who will therefore benefit most from the
addition of chemotherapy
• Take advantage of genomics
The PAM 50 risk of recurrence score
risk of recurrence score (ROR)
ABCSG-8 trial2
ATAC trial1
1Dowsett
M et al. Comparison of PAM50 risk recurrence (ROR) with Oncotype DX and IHC4 for predicting risk
of distant recurrence after endocrine therapy JCO 2013;31:2783
2Chia SK et al. A 50 gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant
tamoxifen. Clin Caner Res 2012M18:4465
21 gene recurrence score
Oncotype DX®
•
•
N = 675 patients ER+, N0, ttt Tamoxifen (NASBP-B14)
Risk of distant recurrence at 10yr, according to recurrence-score categories.
7%
14%
31%
HR 3.21 p <0.001
Paik et al, NEJM 2004
21 gene recurrence score
predictive factor
91%
90%
All
RS :< 18
NSABP B20
N= 651, ER+ N0
227 : TAM
424 : CT + TAM
Outcome : time to
distant recurrence
88%
RS : 18-30
60%
RS > 30
Paik et al. JCO 2006
21 gene recurrence score
predictive factor
•
•
Retrospective analysis, 1447 patients, menopausal , N+ (1-3/>4) , RE+
Tamoxifen vs CAF-Tamoxifen
60%
64%
P=0.97
HR 1.02
55%
43%
P=0.033
HR 0.59
Albain K et al. Lancet oncol 2010
21 gene recurrence score
issues unresolved in 2014
• Not clear at which RS cut off chemotherapy should or should
not be administrated ?
– Recently completed TAILORx trial will provide better data
– In this trial women with RS between 11 et 25 were randomly assigned
treatment either endocrin therapy vs chemotherapy followed by
endocrine therapy
• Data from SWOG study suggest role for RS in patients with
involved lymph nodes?
– We wait results from prospective study RxPONDER.
Adjvuant chemotherapy for HR+/- & HER2- BC
Adjvuant chemotherapy for HR+/-,HER2- BC
Anthracycline better than CMF
EBCTCG Comparison between different polychimiotherapy regimens for early breast cancer: metaanalysis of long term outcome among 100.000 women in 123 randomised trial. Lancet 2012;379:432
Adjvuant chemotherapy for HR+ /-,HER2- BC
Anthracycline + taxane better than anthracycline alone
EBCTCG Comparison between different polychimiotherapy regimens for early breast cancer: metaanalysis of long term outcome among 100.000 women in 123 randomised trial. Lancet 2012;379:432
Adjvuant chemotherapy for HR+/-, HER2- BC
No single standard regimen
• Intermediate risk
– ER+/PR- or low ER/PR or T>2cm or Grade 2-3 orKi67% >20%
– TC x 4 ( docetaxel 75mg/2 + Cyclophosphamide 600mg/m2)
• High risk
– N+
– 3xFEC – 3x docetaxel
• Alternative chemotherapy
–
–
–
–
–
–
AC /EC x 4
AC/EC x 4 –docetaxel x 4
AC / EC x 4-paclitaxel weekly x 12 weeks
4x AC( every 14 days) -paclitaxel dose dense
FEC 100 x 6
CMF x6
Adjvuant chemotherapy for HR+/-, HER2- BC
schedule / every 2 weeks treatment
Improvement of DFS and OS mainly seen for ER
/ PR negative BC
Bonilla L et al. Dose dense chemotherapy in non metastatic breast cancer: a systematic review and
meta-analysis of randomized controlled trials: J Natl Cancer Inst 2010;102:1845)
Adjvuant therapy for HR+/- & HER2+ BC
Adjvuant chemotherapy for HER2+ BC
benefit of adjuvant trastuzumab
• All trials establishing the benefit (DFS and OS) of adjuvant trastuzumab1
• pT1a ?
• Trastuzumab is, still in 2014, the only HER2 directed agent to result in
survival benefit when administered with chemotherapy in the adjuvant
setting
• Subcutaneous formulation?
• On the basis of pertuzumab in neoadjuvant and metastatic setting, NCCN
guidelines added: pertuzumab can be incorporated into adjuvant
treatment of HER2+, alongside trastuzumab and chemotherapy.
• However the benefit of this strategy for overall survival is not known
• Randomized trial evaluating th role of pertuzumab are ongoing.
• Other HER directed agent including trastuzumab-emtansine and lapatinib
remain area of clinical investigation.
1Moja L
et al. Trastuzumab containing regimens for early breast
cancer Cochrane Database Syst Rev 2012;4:CD006243
Adjvuant therapy for HER2+ BC
trastuzumab duration, HERA study
Women with locally determined HER2positive invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+ or FISH+
and LVEF ≥ 55%
Randomization
OBSERVATION
n=1698
After ASCO 2005,
option of switch
to Trastuzumab
1 year Trastuzumab
8 mg/kg – 6 mg/kg
3 weekly schedule
n=1703
2 years Trastuzumab
8 mg/kg – 6 mg/kg
3 weekly schedule
n=1701
HERA trial
DFS for 2 years vs 1 year trastuzumab at 8 yrs FU
Disease-free su
urvival (%)
100
89.1%
81.6%
75.8%
86.7%
80
81.0%
76.0%
60
Trastuzumab 2 years
Trastuzumab 1 year
40
Pts
20
Events HR (2 vs 1)
2 years
1553
367
1 year
1552
367
0.99
95% CI
p-value
(0.85-1.14)
0.86
0
0
1
2
3
4
5
6
Years from randomization
Trastuzumab 2 years
1553
1553
1442
1361
1292
1223
Trastuzumab 1 year
1552
1552
1413
1319
1265
1214
7
8
9
1153
1051
633
194
1180
1071
649
205
No. at risk
DFS
Adjuvant therapy for HER2+ BC
Choice of chemotherapy
• Several chimiotherapy regimens have been evaluated with
trastuzumab
• Anthracycline followd by taxane&trastuzumab regimen is
prefered: greater experience and limited data to suggest
greater efficacy for non-anthracycline based regimen
• No anthracycline based regimen: docetaxel+ carboplatine
+trastuzumab (TCH)(D. Slamon) = appropriate and effective
alternative
• Lower congestive heart failure (0.4% vs 2%)
Adjuvant therapy for HER2+ BC
Lapatinib ?
• Should not be administered in adjuvant setting
• Lack of benefit for the combined HER2 directed therapy
trastuzumab + lapatinib
• ALTTO study, 4.5 years follow up: combination lapatinib +
trastuzumab non impact on DFS
Piccart-Gebhart MJ et al. First results from the phase III ALTTO trial (BIG 2-06;
NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with
lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their
combination (T+L) in the adjuvant treatment of HER2-positive early breast
cancer (EBC). 2014 American Society of Clinical Oncology Annual Meeting;
Abstract LBA4.
Role of Neoadjuvant chemotherapy
Role of Neoadjuvant Chemotherapy
• Originally neoadjuvant chemotherapy was considered for
women with large toumors or inflammatory disease
• Actually commonly used for high risk (ER-/PR-) (HER2+),
operable, stage II and III, primary breast cancer.
• Associated with identical DFS and OS compared to same
treatment in the adjuvant setting1
• Additionnal benefit:
– Improvement surgical options
– Enhancement of breast conservation
• Attractive model for new drug investigation
1Mauri
D et al. Neoadjuvant verus adjuvant systemic treatment in
breast cancer: meta-analysis. J Natl Cancer Inst 2005;97:188-94
Role of Neoadjuvant Chemotherapy
Impact of pCR
• Assess clinical response of the primary tumor.
• Minimal response to pathological complet response (pCR)
• Definition of pCR/FDA1
– Absence of any residual invasive cancer
– Absence of invasive and non invasive cancer on hematoxylin and eosin
evaluation on the resected breast specimen, and all sampled
ipsilateral lymph nodes following completion of Neoadjuvant
chemotherapy
• pCR correlated with improved survival2
1Cortazar
P et al. Pathological complete response and long term clinical benefit in breast
cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13
2Von Minckwitz G et al. Impact of treatment charachterisitcs on response of different breast
cancer phenotypes:pooled analysis of the German neoadjuvant chemotherapy trials Breast
cencer Treat 2011;125: 145-56
Prognostic value of pCR
Cortazar P et al. Pathological complete response and long term clinical
benefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13
Prognostic value of pCR
by breast subtypes
Cortazar P et al. Pathological complete response and long term clinical
benefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13
Factors associated with pCR
• Adequate cumulative dose of anthracycline and taxane
• Concurrent use of trastuzumab
• ER-/PR-, G3, HER2+ : pCR rate up to 40%
Von Minckwitz G et al. Impact of treatment charachterisitcs on response of different breast cancer
phenotypes:pooled analysis of the German neoadjuvant chemotherapy trials Breast cencer Treat 2011;125:
145-56
Patients selection
• Locally advanced breast cancer, stage 2-3
• Inflammatory breast cancer
• Large operable tumor (> 5cm)1
• According tumor biology, likelihood of achieving a pCR
– HER2+/non luminal
– TNBC
– Luminal B
1Fisher
B et al. Effect of preoperative chemotherapy on locoregional disease in women with operable breast cancer:
findings from the NSABP B18. JCO 1997:15:2483
Patients selection
• Invasive lobular carcinoma:
– Better clinical behaviour compared with other histological types
– Lower pCR rates after neoadjuvant chemotherapy
• Offer neoadjuvant chemotherapy mainly to ILC patients with ER/PR
negative and high grade tumor
Loibl S et al. Response and prognosis after neoadjuvant chemotherapy in 1051 patients
with infiltrating lobular breast carcinoma. Berast Cancer Res Treat,2014;144:153-162
Systemic therapy
• Optimal regimen and duration of neoadjuvant chemotherapy
have not been established.
• General concensus: third generation regimen that contain
anthracycline and taxanes.
• NSABP B267 trial: AC x4 followed by docetaxel x4 was
associated with a higher clinical complete response rate (63%
vs 40.1% p< 0.001) compare to AC alone, and a higher pCR
rate (26.1% vs 13.7%p< 0.0001)
Bear HD et al. JCO 2003;21:4165
What we have learned?
• Early switch to a non-cross resistant regimen: GeparTrio study
– Specific treatment strategies for patients with or without response to
2 cycles of TAC ( docetaxel, doxorubicine, cyclophosphamide)
– Response guided ( switch to another chemotherapy in case of no early
response)
– Patient with response guided chemotherapy had a signigificant longer
DFS and OS.
– Regimen: TAC x 6 vs TAC x 8 /responder vs TAC-NX ( navelbine, xeloda)
Von Minckwitz G et al. Neoadjuvant chemotherapy adapted by interim response improves
overall survival of primary breast cancer patients: result of the Gepar Trio trial. Cancer Res
2011;72 (24suppl)53-2
What we have learned?
• NSABP B-40 : addition of bevacizumab to neoadjuvant
chemotherapy
Addition of capecitabin and gemictabine to docetaxiel .
What we have learned?
• EC (90/600mg/m2) with or without use bevacizumab 15mg/kg
GeparQuinto trial
• pCR rate breast and axilla 15.9%in chimiotherapie alone vs 18.4% in
bevacizumab group.
• With bevacizumab improvement of pCR rates but higher incidence of
toxicity
• Until results of other study ( biomarkers of response), bevacizumab is not
recommended to use in neoadjuvant setting
What we have learned?
Conclusion-I
• Incorporation of additional cytotoxic agent or antiangiogenic agent to anthracycline-taxane based
regimens:
– Has not offered significant additional benefit to breast
conservation or pCR rate
What we have learned?
Dual blockade of HER2 signaling
• Dual blockade of the HER2 receptor with trastuzumab and
lapatinib
• NeoALTTO study
• pCR :
• Combination of trastuzumab and lapatinib increase pCR rate
and pCR is associated with improved survival.
Piccart-Gebhart M et al. JCO 2014
• Not confirmed in adjuvant ALTTO trial1
1
Abstract LBA4
What we have learned?
Dual blockade of HER2 signaling
• Pertuzumab, monoclonal antibody inhibiting dimerization of HER2 with
other HER receptors
• NeoSPHERE phase II trial: evaluated efficacy of trastuzumab + pertuzumab
+ docetaxel
• FDA granted accelerated approval to pertuzumab for the use in
combination with deocetaxel for neoadjuvant treatment of patients
HER2+, locally advanced, inflammatory, early stage greater than2cm, or
with N+
Gianni L et al. Lancet Oncol 2012,13:25
What we have learned?
Gepar Sixto
•
Evaluate efficacy of carboplatin in combination with paclitaxel for HER2+ and
TNBC
•
•
Results : increase of the pCR rate (37.2 to 46.7%) by addition to carboplatin
Absolute increase by > 20% oberved in patients with TNBC (37.9% vs 58.7%)
but not increase in HER2+
Large biomarker program, including BRCA mutation in aim to identify
subgroup of TNBC that derive higher benefit from carboplatin
We have to wait until result of correlative studies before to decide carboplatin
as part of standard neoadjuvant therapy for stage 2-3 TNBC
•
•
Future perspective
• Patients who have no achieving pCR, currently no clear role
for adjuvant chemotherapy.
• Novel compounds are being investigated in post neoadjuvant
Future perspective
• Trastuzumab-emtansine (T-DM1)
– Post neoadjuvant without pCR: treatment with T-DM1 compared with
continuation of trastuzumab in HER2+ patients (Katherine Study)
• Novel cyclin D kinase 4/6 inhibitor: palbociclib
– Cyclin D kinase inhibitor explored in addition to endocrine therapy in
patients without pCR after neoadjuvant treatment (PENELOPE study)
• Olaparib:
– Phase III evaluating efficacy and safety of PARP ihibitors as adjuvant
treatment in patients with germline BRCA1/2 mutations and high risk
HER2- primary breast cancer.Have completed surgery and
(neo)adjuvant chemotherapy
CONCLUSIONS
• Current consensus opinion for use of neoadjuvant chemotherapy
recommends anthracycline and taxane based therapy
• Several data suggest that neoadjuvant anthracycline and taxane based
therapy is associated with the highest response rate.
• As similar survival benefits have been demonstrated for the administration
of chemotherapy before or after surgery. More frequently recommended
for women with primary operable stage 2-3 disease
• Neoadjuvant chemotherapy is an attractive area for research by
identifying new effective treatment strategies
• As we enter in an era of « personalized » therapy, the identification of
surrogate predictive and prognostic biomarkers are essential in order to
aid treatment decisions.
Thank you for your attention