Se ha denunciado esta presentación.
Utilizamos tu perfil de LinkedIn y tus datos de actividad para personalizar los anuncios y mostrarte publicidad más relevante. Puedes cambiar tus preferencias de publicidad en cualquier momento.

Update on Management of Triple Negative Breast Cancer

5.168 visualizaciones

Publicado el

Update on Management of Triple Negative Breast Cancer. Dr. Banu Arun

Publicado en: Educación
  • Sé el primero en comentar

Update on Management of Triple Negative Breast Cancer

  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. 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?
  5. 5. How does TNBC respond to available chemotherapeutic agents? -Anthracyclines -Taxanes -Capecitabine -Ixabepilone -Eribulin
  6. 6. 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
  7. 7. • 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
  8. 8. 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 O M I Z E Paclitaxel+ Bevacizumab Paclitaxel Miller et al. N Engl J Med 2007
  9. 9. 0 20 40 60 80 100 Months Progression-freesurvivalestimate 0 10 20 30 40 6.7 13.3 HR=0.48; p<0.0001 13.3 6.7 99% increase in median PFS MedianPFS(months) 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
  10. 10. Paclitaxel +/- Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer (E2100) Miller et al. N Engl J Med 2007
  11. 11. CALGB 40502/NCCTGN063H 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
  12. 12. CALGB 40502 Subset Analyses Triple Negative Disease Months From Study Entry ProportionAlive 0 5 10 15 20 25 30 Pac Nab Ixa 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 ProportionProgressionFree 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
  13. 13. • 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
  14. 14. Arun et al JCO 2011 pCR: BRCA 1+: 46% Negative: 22.4%
  15. 15. Pathologic Complete Response Arun et al JCO 2011 Further improvement with PARP inhibitors, Platinums?
  16. 16. Efficacy of Eribulin in Women with Metastatic Breast Cancer: A Pooled Analysis of two Phase 3 Studies Twelves Breast Can Res Treat 2014
  17. 17. 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
  18. 18. 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?
  19. 19. TNT: Phase III Carboplatin versus Docetaxel in Metastatic TNBC or BRCA1/2 Breast Cancer Institute of Cancer Research, UK Tutt et al. SABCS 2014
  20. 20. Tutt et al. SABCS 2014
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. Sikov W M et al. JCO 2015;33:13-21
  25. 25. 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
  26. 26. Antiangiogenic Drugs Added to Chemotherapy?
  27. 27. 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
  28. 28. 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)
  29. 29. • 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
  30. 30. PARP Inhibitors
  31. 31. 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”
  32. 32. 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
  33. 33. • 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
  34. 34. 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
  35. 35. What is next for TNBC? Targets Within Triple Negative Subsets?
  36. 36. 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 •
  37. 37. Novel agents in clinical trials
  38. 38. Other targets for triple-negative breast cancer Hudis C A , and Gianni L The Oncologist 2011;16:1-11 ©2011 by AlphaMed Press
  39. 39. MDACC Moonshot Triaging Platform
  40. 40. 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
  41. 41. • 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
  42. 42. Thank you