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Do we have a “ better ” chemotherapy regimen?

São Paulo, August 2014. Triple Negative Breast Cancer. Do we have a “ better ” chemotherapy regimen?. Carlos H. Barrios, M.D. | PUCRS School of Medicine | Porto Alegre, Brazil. Potential Conflicts of Interest. No financial conflicts to declare Consulting and r esearch support

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Do we have a “ better ” chemotherapy regimen?

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  1. São Paulo, August 2014 Triple Negative Breast Cancer Do we have a “better” chemotherapy regimen? Carlos H. Barrios, M.D. | PUCRS School of Medicine| Porto Alegre, Brazil

  2. Potential Conflicts of Interest • No financial conflicts to declare • Consulting and research support • Roche, Astra Zeneca, Sanofi, Merck.

  3. Terminal Duct Lobular Unit (TDLU) Luminal Epithelial Cells Low molecular wt CK 7, 8, 18 and 19 Mucin, BCL2, Hormone Receptors Basal Cells (Myoepithelial cells) High molecular wt CK 5, 6, 14 and 17 SMA, Calponina, p63, P-caderin Perou C, et al. Nature 460:747-752, 2000 Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844

  4. Gene Expression of Breast Cancer Basal- like Group • Low HER2 cluster expression • Low ER (and related genes) expression Usually “triple negative” • High basal cluster • basal CK (5, 6, 14, 17) • EGFR, c-kit • others… • Very proliferative • Often p53 mutant • Evidence of genomic instability HER2 cluster Basal gene cluster Luminal (hormone receptor-related) cluster Proliferation cluster

  5. Basal-like Breast Cancer and Genomic Instability Array CGH in 89 LABC: % DNA copy number alterations Red=gain Green=loss Genome-wide aberrations Chromosome Bergamaschi et al, Genes Chromosomes Cancer, 2006.

  6. Triple-Negative vs. Basal-Like: Definitions ~75% of TNBC have Basal gene expression ER- / PR- / HER2- ~15% of all breast carcinomas Poorly differentiated Express CK 5/6, 17, EGFR (+) • Triple negative but not basal • Definition by IHC • Includes other histologies (medullar, adenoid cystic) • 10-30% can also include “claudin-low,” a subtype notable for high expression of stem cell markers • 90% of TNBC do not have BRCA mutations • Basal but not triple negative • Definition by gene expression • Includes most BRCA1 mutated tumors • 15-40% are ER+, PR+ or HER2+ Triple Negative Basal BRCA 1-2 • BRCA1-2 mutated tumors • ~5% of Breast Cancer • 50% BRCA-1 carriers are basal-like • Pal & Mortimer. Maturitas 2009; • Gluz et al. Ann Oncol 2009; • Anders & Carey. Oncology 2008. • Young et al. BMC Cancer 2009 • Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018

  7. Deconstructing the Molecular Portraits of Breast Cancer: TNBC gene expression profiles Prat A, Perou C. Molecular Oncology, Nov 24, 2010 (PMID: 21147047)

  8. Genomic Analyses of Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity 55% of Basal-like breast tumors were found more similar to SQCLC than to non-basal breast cancers. Luminal A (76%), Luminal B (72%) and HER2-enriched (17%) breast tumors. Prat A, et al. Sci Rep 2013

  9. Lehmann B, et al. JCI, 121:2750, 2011

  10. Clinically targetable pathways in TNBC ~90% of all patients had an aberration in at least one of these pathways PI3K/mTOR inhibitors DNA-repair targeting agents RAF/MEK inhibitors Cell cycle/mitotic spindle inhibitors Targeted RTK inhibitors Arteaga C, et al. Vanderbilt

  11. Take Home • TN Breast cancers represent an heterogeneous group of diseases • Highly complex and genetically unstable • Should consider the challenge of a molecular vs. a histological classification

  12. Basal-like BC Responds to Conventional Chemotherapy Pathologic Complete Response: • Basal-like / triple negative breast cancer responds to primary chemotherapy. Explanation of higher response but worse outcome? Rouzier, et al. Clin Cancer Res, 2005 Carey LA, et al. Clin Cancer Res 2007

  13. TNBC: Responsiveness to Neoadjuvant Conventional Chemotherapy • TNBC is responsive to conventional NAC with good outcome similar to other subtypes • < pCR = poorer outcome 1.0 98% 94% P = .24 0.9 88% 0.8 P = .0001 Probability of Being Alive 0.7 68% 0.6 pCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC 0.5 0.4 7 3 6 2 4 5 1 Yrs After Surgery Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281.

  14. TIL are prognostic in TNBC treated with adjuvant chemotherapy (BIG 02-98) RCT 2009 patients (256 TNBC) A-CMF vs. AC-CMF Highest TIL in HER2 and TNBC Prognostic correlation in TNBC (not in the other subtypes) Continuous: better with each 10% Binary: LPBC (>50% better) Loi S et al. JCO 2013

  15. Take Home • TN Breast cancers respond to conventional chemotherapy • Strong prognostic value of Response to Neoadjuvant Chemotherapy • Strong prognostic value of TIL

  16. Bevacizumab for TNBC *Median PFS vs non-TNBC subgroup. No Survival data available in the TNBC subset

  17. EGFR Inhibition for TNBC Efficacy data from phase II trials • TNBC is strongly associated with EGFR expression • EGFR inhibitors combined with platinum • Current data are conflicting Carey et al. ASCO 2008; abstr 1009; O’Shaughnessy et al. SABCS 2007; abstr 308. NR=not reported; PFS=progression-free survival; RR=response rate; TBCRC=Translational Breast Cancer Research Consortium

  18. I-Spy 2 Trial Neoadjuvant Veliparib/Carboplatin followed by wPac/AC Rugo H, et al. SABCS 2013

  19. CALGB/Alliance 40603pCR in Breast and Axilla TNBC Patients ER 1-10% (6%) Age <60 83% T2-T3 86% LN+ 55% Grade III 86% Sikov W, et al. SABCS 2013

  20. The Role of Carboplatin in TNBC (Neo) Sikov W, et al. SABCS 2013. Rugo H, et al. SABCS 2013. Von Minckwitz G, et al, The Lancet Oncology 15:747, 2014.

  21. Platinum-sensitivity of BRCA1mut TNBCs • Neo-adjuvant setting: • Retrospective trials suggest platinum-based regimens activity; • Data from prospective trials on TNBCs are controversial; • Metastatic TNBCs: • control arm in BALI-1 study with DDP alone – 10% RR Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010

  22. Phase II Trial of Olaparib in BRCA Deficient MBC • Multicenter POC phase II, single-arm sequential cohort • Confirmed BRCA1 or BRCA2 mutation • Advanced refractory breast cancer(stage IIIB/IIIC/IV after failure of ≥1 prior CT for advanced disease) MTD, maximum tolerated dose (determined during Phase I evaluation) Audeh et al. ASCO 2009. Abstract #5500

  23. TNBC recent perspectivesLooking for a target... • Other Chemotherapy? • Androgen Receptor • PI3K pathway alterations • EGFR inhibitors • Anti-angiogenics • Src inhibitors • C-Kit alteration • Clinical Trail • Likely will need combos

  24. TNBC: Conclusions • TNBC is a recognized distinct subtype of BC • ER, PR, HER2-negative by IHC • Surrogate of basal-like BC • More aggressive biology (morphology, clinical, molecular) • TNBC responds to a variety of CT agents although no specific standard regimen or agent can be singled out • TNBC has no identified specific therapeutic target • Represents an heterogeneous group of tumors probably with different response patterns to different treatments • Introduction of novel agents (PARPi, others) ? • Biomarkers: RAD-51, Neuropilin ?

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