Update on Management of Triple Negative Breast Cancer
Transcript of Update on Management of Triple Negative Breast Cancer
Update on Management of Triple Negative Breast Cancer
Banu Arun, M.D. Professor, Breast Medical Oncology Co-Director Clinical Cancer Genetics
The University of Texas MD Anderson Cancer Center
August, 2015
Basal-like 1: cell cycle, DNA repair and proliferation genes
Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R)
IM: immune cell processes (medullary breast cancer)
M: Cell motility and differentiation, EMT processes
MSL: similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers)
LAR: Androgen receptor and downstream genes, luminal features
TNBC is Not One Disease
Lehmann et al. J Clin Invest 2011
Characteristics of TNBC
• At least 15% of breast cancers
• Higher incidence in AA and Hispanic women
• Germline BRCA mutation rate 11-37%
• Etiologic risk factors not known (except BRCA1 germline mutations carriers and ? AA women who did not breastfed)
• Sensitive to standard chemotherapy (pCR 35-40%)- but ↓DFS/OS
• Early relapse (2-3 yrs); after relapse time to death shorter • Significantly heterogeneous disease
• No targeted therapy currently available
Lehmann et al. J Clin Invest 2011, Kwon & Arun JCO 2010
Clinical Questions
• Specific type of chemotherapy? – Metastatic – Neoadjuvant, adjuvant
• BRCA-associated breast cancer, role of HRD assay in
sporadic TNBC (BRCAness)
• Role of antiangiogenic agents? • What are the targets in subsets of TNBC?
How does TNBC respond to available
chemotherapeutic agents?
-Anthracyclines
-Taxanes
-Capecitabine
-Ixabepilone
-Eribulin
Anthracyclines for TNBC
Trial Phase/no. TNBC pts
Setting Regimen Outcome in TNBC
Di Leo (2008) Meta-analysis
III (n=157) Adjuvant Anthracycline vs CMF
23% reduction in risk of relapse
Bidard (2008) II (n=120) Neoadjuvant CEF x 4-6 pCR: 17%
Gluz (2008) III (n=66) Neoadjuvant DD EC or CMF vs HD EC-ECThiotepa
5-yr EFS with HD 71% vs 26% with DD
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
• Meta-analysis, stage IV, first-line trials
• Taxane-based vs anthracycline-based
• Results: Taxane better, ER-negative ~ ER-positive – HER2 not evaluated
TNBC and Taxanes
Piccart-Gebhart et al, JCO 2008
28-day cycle: Paclitaxel 90 mg/m2 D1, 8, and
15. Bevacizumab 10 mg/kg D1 and
15.
Paclitaxel +/- Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast
Cancer (E2100)
R A N D OM I Z E
Paclitaxel+ Bevacizumab
Paclitaxel
Miller et al. N Engl J Med 2007
0
20
40
60
80
100
Months
Pro
gres
sio
n-f
ree
surv
ival
est
imat
e
0 10 20 30 40
6.7 13.3
HR=0.48; p<0.0001 13.3
6.7
99% increase
in median PFS
Med
ian
PFS
(m
onth
s)
15
10
5
0 bevacizumab +
paclitaxel
Paclitaxel
Paclitaxel (n=354)
bevacizumab + paclitaxel (n=368)
HR = hazard ratio; bevacizumab Summary of Product Characteristics (SmPC)
Progression-free survival
Miller et al. N Engl J Med 2007
Paclitaxel +/- Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer (E2100)
Miller et al. N Engl J Med 2007
CALGB 40502/NCCTG N063H Randomized phase III Trial, first-Line therapy for locally recurrent
or metastatic breast cancer
Rugo H et al, ASCO 2012
Paclitaxel vs nab-paclitaxel vs Ixabepilone
- -
Control
1
Exp 2
N = 799 Untreated Stage IV Strata: Adj taxanes ER/PR status
nab-paclitaxel 150 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks2
ixabepilone 16 mg/m2 weekly +
bevacizumab 10 mg/kg q 2 wks3
Restage q 2 cycles until
disease progression
paclitaxel 90 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks1
CALGB 40502 Subset Analyses
Triple Negative Disease
Months From Study Entry
Pro
port
ion A
live
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1
PacNabIxa
Triple Negative Disease
Comparison HR P-value 95% CI
nab vs. pac 0.93 0.7354 0.62 – 1.40
ixa vs. pac 1.46 0.0647 0.98 – 2.18
Pro
po
rtio
n P
rog
ressio
n F
ree
paclitaxel nab-paclitaxel ixabepilone
• 40502 overall findings: - Weekly paclitaxel > ixabepilone - Weekly paclitaxel less toxic
than either (in general)
• TNBC Subset: - No real difference from
parent trial - 98% received bevacizumab
• Women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009
• 25% were positive for BRCA mutations
• Treatment with T+A or A, or T only
Arun et al JCO 2011
Pathologic Complete Response
Arun et al JCO 2011
Further improvement with PARP inhibitors, Platinums?
Efficacy of Eribulin in Women with Metastatic Breast Cancer: A Pooled Analysis of two Phase 3 Studies
Twelves Breast Can Res Treat 2014
TNBC: BRCA Germline associated vs BRCAness
• Sporadic TNBC (without germline BRCA mutations), shares clinical and molecular features with BRCA-associated cancers including defective DNA repair: – methylation-induced silencing of BRCA
– mutations in other genes that encode proteins involved in DNA repair
• Opportunity for DNA damaging agents: Platinums
• DNA repair inhibitors: PARPi
Foulkes NEJM 2010; Lips BrJ Ca 2013; Maxwell KN JCO a1510, 2014; Turner N Nat Rev Can 2004; Lehmann BD JCO 2011
TNBC and Platinums in Stage IV
Stage IV Trials Population Results
Control arm BALI-1 (CDDP) Sporadic TNBC 10% RR
Control arm Phase III iniparib (Gem/carbo) Sporadic TNBC 30% RR
TBCRC 001 (Cetuximab/Carbo) Sporadic TNBC 17% RR
TBCRC 009 (Carboplatin or Cisplatin) Sporadic TNBC 30% RR
Baselga, ESMO’10; O’Shaughnessy, ASCO’11; Carey et al, JCO’12; Isakoff, ASCO’11
Platinums:
Reasonable in sporadic TNBC – but what line?
TNT: Phase III Carboplatin versus Docetaxel in Metastatic TNBC or BRCA1/2 Breast Cancer
Institute of Cancer Research, UK
Tutt et al. SABCS 2014
Trial Type n Drugs Population pCR
DFCI1 Single arm Ph 2 21 CDDP x 4 TNBC 21%
DFCI2 Single arm Ph 2 51 CDDP+bev TNBC 15%
Polish Retrospective 13 CDDP x 4 BRCA+ 83%
GEICAM Randomized Ph 2 94 EC-D EC-D+carbo
Basal-like (IHC) 30% 35%
GeparSixto Randomized Ph 3 315 wP/LDox/bev +/- Carbo
TNBC (subset) 43% 57%
PreCOG0105 Single arm Ph 2 80 G/Carbo/iniparib TNBC 36%
CALGB 40603 Randomized Ph 2 455 T-AC(bev) T/carbo-AC(bev)
TNBC 41% 54%
Neodjuvant Platinum in TNBC
Silver et al, JCO’12; Ryan et al, ASCO’09; Byrski et al, JCO’10; Alba et al, BCRT’12; von Minckwitz et al, Lancet Oncol ‘14; Telli et al, ASCO a 1003’13; Sikov et al, SABCS’13
Schema of randomized phase II CALGB 40603 Trial
Sikov W M et al. JCO 2015;33:13-21
©2015 by American Society of Clinical Oncology
Pathologic complete response in breast
and breast/axilla
©2015 by American Society of Clinical Oncology
Sikov W M et al. JCO 2015;33:13-21
Do we add carboplatin to every TNBC?
• Addition of either carboplatin or bevacizumab to NACT increased pCR rates; ↑DFS/OS??
• Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely
• Role of carboplatin could be evaluated in definitive studies in biologically defined patient subsets most likely to benefit from this agent (BRCA?)
• Decreased rate of completing all taxol and all AC cycles
Bevacizumab and Response in Metastatic HER2-Negative Breast Cancer
Trial Regimen RR Bev arm RR placebo
Initial Ph 3 Capecitabine + B 20%* 9%
E2100 Paclitaxel + B 37%* 21%
AVADO Docetaxel + B 64%* 46%
RIBBON-1 Chemotherapy + B 35%* 24%
RIBBON-2 (TNBC subset)
Chemotherapy + B 41%* 18%
Miller et al, JCO‘05; Miller et al, NEJM‘07; Miles et al, JCO’10; Robert et al, JCO’11 Brufsky et al, BCRT’12
*statistically significant
Bevasuzumab: Neoadjuvant and Adjuvant in TNBC
Trial Setting Outcome P value
Gepar-Quinto Neoadjuvant pCR:33% → 43% 0.007
NSABP-B40 Neoadjuvant pCR:47% → 52% NS
BEATRICE Adjuvant No DFS benefit
E5103 Adjuvant No DFS benefit
Von Minckwithz NEJM 2012; Bear NEJM 2014, Cameron Lancet Oncol 2013; Miller JCO 2014)
• Metastatic setting: increases RR when added to chemotherapy, but has no impact on OS- therefore, when response is the endpoint, adding Bev is an option
• Neoadjuvant setting: Increase pCR; but DFS/OS impact is unknown
• Adjuvant setting: No impact on DFS and OS
Bevacizumab: Practical Conclusions
Principles of Cancer Biology: DNA Repair
Adapted from Carey L. Oncologist 2010 (In Press)
Chemo, XRT and Other Insults
DNA DAMAGE
Normal cell BRCA loss PARP deficient BRCA loss + PARP deficient
VIABLE VIABLE VIABLE DEAD
HR BER HR BER HR BER HR BER
HR: Homologous Recombination BER: Base Excision Repair
X X X X
“Synthetic Lethality”
PARP Inhibitor Trials – Activity Seen Only in BRCA1/2 Mutation Carriers
Agent Author BRCA1/BRCA2 TNBC Response Rate
Olaparib (phase I; mixture tumor
types)
Fong 60 patients 37% -BRCA1/2
mutations
N/A 63% clinical benefit rate
(only in BRCA associated cancers)
Olaparib 400 mg po BID
Tutt 27 patients BRCA1 67% BRCA2 33%
50% 41%
ABT888 +temozolomide
Isakoff 41 patients BRCA1: 7.3% BRCA2: 12%
56% BRCA 1 and 2: 37.5%
No response in normal BRCA status
Fong et al. N Engl J Med 2009 Tutt et al. Lancet 2010 Isakoff et al. ASCO 2010
• Non-BRCA ovarian cancer responds to olaparib…Evidence of BRCAness.
Breast Cancer, Ovarian Cancer and PARPi
• Not seen with non-BRCA breast cancer.
– Triple negative
Gelmon K et al, Lancet Oncol 2011
Identifying BRCA Deficiency
• Major consequence is homologous recombination (HR) DNA repair defect
• Functional assays in development
Birkbak NJ et al. Cancer Discovery 2012
HRD score
Non-responders
BRCA1/2 intact responders
BRCA1/2 mutant responders
Telli M et al, SABCS 2012
Immunomodulatory TNBC
Lehmann et al. J Clin Invest 2011
IM: immune cell processes (medullary breast cancer)
• - 10-15% of TNBCs
• - enriched in immune
cell processes
• -medullary breast
cancers
• - ?BRCA1 carriers?
• - p53 mutant
•
Other targets for triple-negative breast cancer
Hudis C A , and Gianni L The Oncologist 2011;16:1-11 ©2011 by AlphaMed Press
Chemo-insensitive (prediction & interim imaging)
Vimentin + (mesenchymal)
AR+ Other (Enriched for Basal-like)
mTORi + chemo
Improved rate of pCR/RCB-I?
ARi + chemo
PDL-1i + chemo
*comparison to control ‘predictor unknown’ group
BRCA1/2 +
PARPi+ chemo
• Single arm phase II trials • pCR improvement: 5%20% • N=37 • Two stage design; close if
pCR/RCB-I not seen in >1 of 14 patients
EGFRi + chemo
• TNBC is heterogeneous
• Stage 4: Chemotherapy is mainstay and (at the moment) is the same as for other subtypes.
– First-line taxanes or platinum appropriate
– Second+ lines: Eribulin to other options
• Neoadjuvant: Platinums ? Toxicity- clinical benefit ratio? No ↑EFS, BCS rate- additional markers needed: HRD score, TILs….more studies ongoing
• Residual disease ?: EA1131 phase III ECOG-ACRIN: Evaluate platinum after Tax based NAST. Endpoint: EFS
• BRCA1-associated TNBC may be different:
Platinums, PARP inhibition
• Subtype specific studies and novel study designs are ongoing
Conclusion