Subtype-directed therapy of TNBC Global Breast Cancer Conference 2015 & 4th International Breast Cancer Symposium Jeju Island, Korea, April 2015 Ruth M. O Regan, MD Visiting Professor and Division Chief Hematology and Medical Oncology, Department of Medicine, University of Wisconsin
Challenges of TNBC Aggressive cancer with high propensity for distant metastases within a shorttime of diagnosis Chemotherapy is the only approved therapy but is ineffective in many cases Currently no definitive drugable targets have been identified Goal of personalized therapy not close to being achieved
Probability of Progression Free Survival Probability of Survival The challenge of treating unselected metastatic TNBC 1.0 0.9 PFS Median PFS, mos (95% CI) GC (N=258) 4.1 (3.1, 4.6) GCI (N=261) 5.1 (4.2, 5.8) HR (95% CI) 0.79 (0.65, 0.98) p-value 0.027 Pre-specified alpha = 0.01 1.0 0.9 OS Median OS, mos (95% CI) GC (N=258) 11.1 (9.2, 12.1) GCI (N=261) 11.8 (10.6, 12.9) HR (95% CI) 0.88 (0.69, 1.12) p-value 0.28 Pre-specified alpha = 0.04 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0 0 2 4 6 8 10 12 14 16 Months Since Study Entry No. at risk GC 258 171 116 63 38 18 6 1 0 GCI 261 187 138 83 53 11 2 0 0 0.1 0 0 2 4 6 8 10 12 14 16 Months No. at risk GC 258 239 214 181 151 99 38 11 0 GCI 261 248 230 204 169 111 52 15 0 O Shaughnessy PASCO 2011
Most TNBC are basal-like Claudin-low 2% HER2 4% Basal Basal-like 87% Sikov SABCS 2014 Normal 7% Basal Sorlie et al PNAS 2003
TNBC subtyping (Vanderbilt) 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) Lehmann et al JCI 2011 LAR: Androgen receptor and downstream genes, luminal features
Vanderbilt subtypes according to basal-like status Masuda et al Clin Cancer Res 2013
Implications of TNBC subtyping Can molecular profiling be used to predict which patients will benefit from chemotherapy? Can we select individual chemotherapeutic agents based on subtypes? Identification of new targets?
San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 PCR is a robust predictor of prognosis in unselected TNBC Neoadjuvant Chemotherapy for TNBC pcr (ypt0/is N0) rate: 34% (meta-analysis) Cortazar et al SABCS 2012
Relationship between TNBC subtypes and response to chemotherapy (anthracycline-taxane) Masuda et al Clin Cancer Res 2013
5-years DFS for TNBC based on AR and PCR AR + PCR 100% AR + RD 80% AR - PCR 79% AR - RD 59% Loibl et al Breast Cancer Res Treat 2011
Implications of TNBC subtyping Can molecular profiling be used to predict which patients will benefit from chemotherapy? Not ready for prime time but emerging differences which?could allow the avoidance of chemotherapy in the future Can we select chemotherapeutic agents based on subtypes? Identification of new targets?
San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 CALGB 40603: pcr Breast/Axilla (ypt0/is N0) 41% (35-48%) 54% (48-61%) 44% (38-51%) 52% (45-58%) N=212 N=221 Odds ratio: 1.71 p = 0.0029 N=218 N=215 Odds ratio: 1.36 p = 0.0570 This presentation is the intellectual property of William Sikov, MD. Contact at wsikov@lifespan.org for permission to reprint or distribute.
TNT trial 90% TNBC
Implications of TNBC subtyping Can molecular profiling be used to predict which patients will benefit from chemotherapy? Can we select chemotherapeutic agents based on subtypes? Convincing data supporting platinums in BRCA-related cancers Taxanes in non-basal requires confirmation Identification of new targets?
TNBC subtyping 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) Lehmann et al JCI 2011 LAR: Androgen receptor and downstream genes, luminal features
New approaches for targeting EGFR in TNBC EGFR is expressed in 50% of TNBC 1 Despite success in other cancers, treatments targeting EGFR have not been effective in TNBC 2 ~20% TNBC- abnormal localization of EGFR in nucleus (negfr) Wheeler laboratory showed a Src family kinase inhibitor (dasatinib) Mobilizes negfr back to the surface Re-sensitizes to anti-egfr antibodies Window study proposed in new diagnosis TNBC prior to surgery Neilsen et al CCR 2004 Baselga et al JCO 2013 Brand et al MCT 2014
Phase 2 trial of bicalutamide in AR+ ER- PR- MBC Screening 452 patients with TNBC: 51 (12%) were AR+ 26 patients were treated with bicalutamide 150mg daily No responses, stable disease > 6-months in 5 patients Median PFS 12-months Gucalp et al Proc ASCO 2012 Abstract 1006
Pre-operative approach in TNBC PCR Good prognosis Early stage triple negative breast cancer Pre-operative chemotherapy BX Residual disease Trials with novel agents/ approaches SX
Implications of TNBC subtyping Can molecular profiling be used to predict which patients will benefit from chemotherapy? Can we select chemotherapeutic agents based on subtypes? Identification of new targets? Getting closer!
Conclusions: sub-typing of TNBC Clearly heterogeneous with several distinct subtypes which will require different therapeutic approaches Role of TNBC sub-typing is evolving as a means of personalized therapy The use of sub-typing to identify therapeutic targets is ongoing