Triple negative breast cancer 21st Annual NOCR Meeting Las Vegas, NV, March 2015 Ruth M. O’Regan, MD Visiting Professor and Division Chief Hematology and Medical Oncology, Department of Medicine, University of Wisconsin

TNBC: Topics to cover Optimal pre-operative therapy for patients with TNBC Management of metastatic TNBC Sub-typing of TNBC Goal of personalized therapy in TNBC Residual disease following pre-operative therapy in TNBC

Importance of PCR in TNBC San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 Importance of PCR in TNBC Neoadjuvant Chemotherapy for TNBC pCR (ypT0/is N0) rate: 34% (meta-analysis) Given its prognostic importance, how can we increase pCR rate in TNBC? Cortazar et al SABCS 2012

CALGB 40603: pCR Breast/Axilla (ypT0/is N0) 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 N=218 N=215 Odds ratio: 1.71 p = 0.0029 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.

CALGB 40603: Select Grade >3 Toxicities San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 CALGB 40603: Select Grade >3 Toxicities Chemo Chemo + Bev Chemo + Carbo Chemo + Carbo + Bev Neutropenia 22% 27% 56% 67% Thrombocytopenia 4% 3% 20% 26% Febrile neutropenia 7% 9% 12% 24% Hypertension 2% 0% 10%* Nausea / Vomiting 4% / 2% 3% / 2% 8% / 4% Fatigue 10% Stopped treatment due to toxicity 6% Difficult to give weekly paclitaxel without growth factors This presentation is the intellectual property of William Sikov, MD. Contact at wsikov@lifespan.org for permission to reprint or distribute.

Addition of carboplatin to standard chemotherapy increases PCR rate but.. Toxicity, particularly myelosuppression, is problematic resulting in decreased dose intensity of paclitaxel Use of G-CSF is generally required Could other schedules be effective? Which sub-types of TNBC benefit from the addition of carboplatin? Are there additional chemotherapeutic options?

Protocol Design CP-CEF R P-CEF Paclitaxel 80 mg/m2 qwk x 12 CEF q3wks x 4 HER2 (-) BC Stage II/IIIA 18-70 years PS 0/1 Good Organ function Written IC Carboplatin AUC5 q3wks x 4 R S U R G E R Y P-CEF Paclitaxel 80 mg/m2 qwk x 12 CEF 500/100/500 mg/m2 q3wks x 4 Tamura Proc ASCO 2014

pCR rates by sub groups (%) TNBC Primary Endpoint P =0.04 P =0.02 Odds ratio 0.46 0.30 0.15 Tamura Proc ASCO 2014

Adverse Events Treatment arm CP-CEF P-CEF *12% in CALGB trial   All CP phase P phase Adverse events G3% G4% Anemia 18.2 1.1 14.8 Neutropenia 46.6 19.3 52.3 5.7 17.6 20.9 8.8 Thrombocytopenia Febrile neutropenia 20.5 2.3* 15.4 Nausea 3.4 2.3 2.2 Vomiting Fatigue Infection 4.4 Sensory neuropathy *12% in CALGB trial Tamura Proc ASCO 2014

Pre-operative therapy of TNBC Addition of carboplatin to paclitaxel – anthracycline backbone increases PCR rate in TNBC (BL and non-BL) but.. Toxic, resulting in decreased dose intensity of paclitaxel without growth factors Other schedules should be investigated ? Assess response to anthracycline before adding carboplatin Substitution with nab-paclitaxel may be an option

Management of metastatic TNBC Highly aggressive course with propensity for visceral and brain mets Progression-free survival approximately 6-months to first-line therapy with overall survival in the range of 12-months Chemotherapy only approved therapy but TNBC is either inherently resistant or rapidly acquires resistance to available agents Unclear if any one agent is better than another

Capecitabine 1250 mg/m2 BID orally Days 1-14, q21 days Eribulin 301 Global, randomized, open-label phase III trial (Study 301) Patients (N = 1102) Locally advanced or MBC ≤ 3 prior chemotherapy regimens (≤ 2 for advanced disease) Prior anthracycline and taxane in (neo)adjuvant setting or for locally advanced or MBC Co-primary endpoint OS and PFS Secondary endpoints Quality of life ORR Duration of response 1-, 2-, and 3-year survival Tumor-related symptom assessments Safety parameters Population PK Eribulin mesylate 1.4 mg/m2 2- to 5-min IV Day 1 & 8 q21 days Randomization 1:1 Capecitabine 1250 mg/m2 BID orally Days 1-14, q21 days Kaufman PA, et al. SABCS December 7, 2012. Abstract S6-6.

Eribulin 301: Overall Survival By Receptor Status Subgroup HR (95% CI) Eribulin Capecitabine Median (months) Overall 0.879 (0.770, 1.003) 15.9 14.5 HER2 status Positive 0.965 (0.688, 1.355) 14.3 17.1 Negative 0.838 (0.715, 0.983) 13.5 ER status 0.897 (0.737, 1.093) 18.2 16.8 0.779 (0.635, 0.955) 14.4 10.5 Triple negative Yes 0.702 (0.545, 0.906) 9.4 No 0.927 (0.795, 1.081) 17.5 16.6 N = 755 N = 449 N = 284 0.2 0.5 1.0 2 5 Favors eribulin ITT population Favors capecitabine Kaufman PA, et al. SABCS December 7, 2012. Abstract S6-6. Kaufman et al, SABCS– December 7, 2012

TNT trial 90% TNBC

Click on image to magnify. Basal-like 1: cell cycle, DNA repair and         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 Lehmann et al JCI 2011

Vanderbilt TNBC trials AR- positive Bicalutamide + GDC0941 (PI3K inhibitor) Met TNBC AR- negative Cisplatin +/- GDC0941 (PI3K inhibitor)* *NCT01918306

Pre-operative approach in TNBC PCR Good prognosis Early stage triple negative breast cancer 25 to 30% Pre-operative chemotherapy 70% BX Trials with novel agents/ approaches Residual disease SX

Deep sequencing of the residual disease in NAC-treated TNBC San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec. 10-14, 2013 Deep sequencing of the residual disease in NAC-treated TNBC 182 oncogenes and tumor suppressors in a CLIA certified lab (Foundation Medicine, Cambridge MA) Data were evaluable for 81 tumors, with a sufficient coverage to determine CNAs in 72/81 * Balko et al, Cancer Discovery, in press. This presentation is the intellectual property of the authors/presenters.  Contact them at justin.balko@vanderbilt.edu for permission to reprint and/or distribute

JAK2 copy number increases with treatment and metastatic progression San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec. 10-14, 2013 JAK2 copy number increases with treatment and metastatic progression JAK2 gains and amplifications were more frequent in NAC-treated TNBC than in primary untreated BLBC (TCGA) Ongoing randomized trial of JAK TKI in HER2-negative metastatic breast cancer

Targeting growth factors in chemo-resistant TNBC Mouse “clinical trial” Residual Chemo-resistant TNBC Gene expression (Vanderbilt subtypes) Pre-operative Chemotherapy (Phase 2 clinical trials) TNBC Theranostic Nanoparticles (EGFR/IGF1R) Human TNBC Xenografts Supported by Glenn Family Pilot Grant

Conclusions TNBC Use of pre-operative therapy is a consideration for most patients with TNBC Addition of carboplatin to paclitaxel or substitution of paclitaxel with nab-paclitaxel increase PCR rate Role of TNBC sub-typing is evolving as a means of personalized therapy