10/15/2012. Inflammatory Breast Cancer vs. LABC: Different Biology yet Subtypes Exist

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1 Triple-Negative Breast Cancer: Optimizing Treatment for Locally Advanced Breast Cancer Beth Overmoyer MD Director, Inflammatory Breast Cancer Program Dana Farber Cancer Institute Overview Inflammatory breast cancer vs. LABC Prognosis is different Subtypes exist Importance of a pcr TNBC vs. other Utilizing optimal chemotherapy Platinum agents The need to target TNBC Angiogenesis JAK-STAT pathway Inflammatory Breast Cancer vs. LABC: Different Biology yet Subtypes Exist 1

2 IBC vs. LABC: Different Prognosis OS: HR=1.98 for IBC v LABC Median OS: 2.9yr v 6.4yr 5 yr OS: ER+ : 50% ER : 25% Seer : 2-yr BCS IBC = 84% LABC = 91% P < % higher risk of breast cancer death in IBC vs. LABC IBC LABC Dawood S Cancer May 1, 2011; Anderson WF, JCO 21:2254, 2003 IBC: Rate of Local/Regional Recurrence According to Breast Cancer Subtype. 39% 8% Li J et al. The Oncologist 2011;16: IBC: Overall Survival According to Breast Cancer Subtype. 3.2 yr 2.0 yr Li J et al. The Oncologist 2011;16:

3 Neoadjuvant Treatment of TNBC: Importance of a pathologic complete response TNBC Paradox TNBC: If pcr achieved = outcome is similar to non- TNBC TNBC: If residual disease = poorer outcome c/w non-tnbc MD Anderson total = 255 TNBC v. 863 non-tnbc JCO 2008;26:1275 Cytotoxic Therapy for TNBC: Effective Current Treatment 3

4 Advances in Chemotherapy Have Dramatically Improved Outcomes in ER-Negative Breast Cancer ative Risk nce Reduction in Rela of Recurre Corresponds to an absolute improvement in 5 year DFS of 23%, and to an absolute improvement in 5 year OS of 17% in ER negative subset 55% 26% ER- ER+ 0 CALGB Trial Overall Optimizing Adding taxane Optimizing anthracycline taxane Berry et al, JAMA 2006 DFS With or Without Paclitaxel in CALGB 9344 According to ER/HER2 Status Hayes et al, N Engl J Med 2007 Prognostic Impact of pcr on DFS According to Breast Cancer Intrinsic Subtype von Minckwitz G et al. JCO 2012;30:

5 Optimal Cytotoxic Therapy for TNBC: Platinum Agents BRCA1 Cell Lines Exhibit Differential Chemotherapy Sensitivity Cisplatin Doxorubicin Paclitaxel Increased sensitivity to DNA damaging agents like cisplatin Tassone P et al. Br J Cancer (8):1285 Cisplatin As Preoperative Therapy in Patients With BRCA1 Mutations 10 patients with BRCA1 mutations Stage I-III disease Treatment: Preoperative Cisplatin 75 mg/m 2 q 3 weeks x 4 Mastectomy AC x 4 Path CR = No invasive tumor in breast or nodes Path CR rate = 9/10 = 90% Byrski T Br Ca Res Treat 2009;115:359 5

6 DF/HCC Preoperative Cisplatin in TNBC > 2cm, Stage II/ III ER/PR/Her Neg Research Core Biopsy N=28 Cisplatin 75mg/m 2 q3wks x 4 cycles S U R G E R Y Standard Adjuvant Therapy per MD Pathologic CR 6 (22%) Clinical CR 4 (14%) Clinical PR 10 (36%) Silver et al, JCO 2010 Stable Disease 5 (17%) Predictors of Response to Pre-operative Cisplatin in TNBC Silver et al, JCO 2010 Randomized Phase II trial: Neoadjuvant Cisplatin vs AC in Women with Newly Diagnosed Breast Cancer and Germline BRCA Mutations 6

7 Schema Randomized Phase 2: 166 patients Targeting Triple Negative Breast Cancer Angiogenesis in TNBC: Targeting VEGF 7

8 Is There a Role for Angiogenesis Inhibition in TNBC? Perou, C. M. Oncologist 2010;15(Supplement 5):39-48 Pre-operative Cisplatin/Bevacizumab for TNBC Triple Negative Breast Cancer Stage II/III N=51 Research bx CISPLATIN 75 mg/m 2 x 4 BEVACIZUMAB 15mg/kg x3 S U R G E R Y RESULTS Path CR (Miller-Payne 5) 8/51 = 16% Almost path CR (Miller-Payne 4) 10/51 = 20% Ryan et al, ASCO /51 = 36% German Breast Group: addition of bevacizumab to chemotherapy ECT: ECT 633- ECT-B: 956 Epirubicin 90 mg/m 2 IV + cyclophosphamide 600 mg/m 2 IV q3w x4 Epirubicin 90 mg/m 2 IV + cyclophosphamide 600 mg/m 2 IV q3w x4 Bevacizumab 15 mg/kg IV q3w x 8 Docetaxel 100 mg/m2 IV q3w x 4 Docetaxel 100 mg/m2 IV q3w x 4 Von Minckwitz NEJM 2012;366:4 8

9 Pathological Complete Response (pcr), According to Subgroup. von Minckwitz G et al. N Engl J Med 2012;366: Intergroup/CALGB 40603: Triple Negative Pre-operative Trial (Sikov, PI) N=400 ER/PR/HER2- Stage II-IIIB Paclitaxel Paclitaxel Carboplatin No carboplatin Carboplatin No carboplatin Bevacizumab Dose-dense AC S U R G E R Y RT prn Breast imaging Blood MUGA Tumor Biopsy* Breast imaging Blood Breast imaging Blood MUGA mtor-akt Pathway: Targeting mtor 9

10 10/15/2012 mtor Is a Central Regulator of Growth and Metabolism IGF 1R, EGFR ER RAS PI3K E AKT ER RAF TSC2 TSC1 MEK mtor ERK E ER intracellular intracell lar serine/threonine kinase mtor regulation can affect Angiogenesis Cell growth Nutrient uptake, utilization Metabolism Cell Proliferation Reprinted from J Steroid Biochem Mol Biol. 106/1-5, Yue W et al, Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells, Pages , Copyright 2007 with permission from Elsevier. Testing mtor Inhibitors in Combination Therapy with other p73-inducing Drugs DNA Damage Cisplatin (CDDP) (Wang; Shaul; Kufe; 1999) Apoptosis Tumorigenesis TAp73 Np63 Basal phenotype (22%) Cisplatin (CDDP), Taxol (Sidransky; Ellisen; 2008) mtor Inhibitors (Pietenpol; 2008,2009) p73 CDDP/Rapamycin Taxol/C CDDP//Rapamycin CDDP Puma PARP * p63 actin mycin Rapam Con CDDP/Rapamycin Taxol/C CDDP Taxol/C CDDP mycin Rapam Con Testing mtor Inhibitors in Combination Therapy with other p73-inducing Drugs actin Taxol + Cisplatin + mtor inhibitor = p73 induction, P63 suppression Apoptosis Maria Pino, Lucy Tang (CDDP = Cisplatin; Puma = p73 target gene) 10

11 Vanderbilt: RAD001 Neoadjuvant Study Design 1 week 11 weeks Stage II and III triple negative breast cancer Arm 1 (2:1) Cisplatin + RAD001 Cisplatin + Paclitaxel + RAD001 Surgery Arm 2 Cisplatin + Placebo Cisplatin + Paclitaxel + Placebo Baseline Day 3 5 of week 1 Week 12 Cisplatin 25 mg/m2 weekly Paclitaxel 80 mg/m2 weekly Core biopsy Core biopsy Core biopsy Proliferation/ Proliferation/ Proliferation/ apoptosis markers (IHC) apoptosis markers (IHC) apoptosis markers (IHC) Pathway activity markers (IHC) Pathway activity markers (IHC) Pathway activity markers (IHC) RNA microarrays RNA microarrays Path CR analysis Ultrasound Ultrasound JAK-STAT Pathway: JAK2 Inhibition Identification of IL6-JAK-STAT Pathway as Relevant in Breast Cancer Intra-tumoral heterogeneity CD44+/CD24 cells with stem cell-like characteristics Found in ~70% of luminal, ~50% of HER2+, ~100% of basal-like tumors Associated with poorer outcomes even after controlling for ER status and grade Hypothesis: Targeting this cell population may be clinically beneficial 11

12 STAT Signaling Mechanisms: Integration of E-Cadherin, Stem Cell Features & STAT3 Activation in IBC 1. Devarjan E, Huang S. Curr Mol Med. 2009;9: Preferential Activation of IL6-JAK2-STAT3 Pathway in Basal-Like BC Cells 1 IL-6 secreted by basal-like BC cell lines IL-6 secretion accompanied by elevated pstat3 levels Autocrine growth regulatory loop appears to be interrupted by JAK inhibitor, as demonstrated by reduction of pstat3 levels upon treatment 1. Marotta LLC et al. J Clin Invest. 2011;121: Increased cell density is associated with increased activation of STAT3 Evidence that E-cadherin stimulates IL-6 via Rac1/Cdo42: activation of JAK2 autocrine loop Slide curtesy of Kornelia Polyak MD, PhD 12

13 Importance of JAK2-STAT3 Signaling Pathway in Tumor Growth Images provided courtesy of Kornelia Polyak, MD, PhD. Preoperative Treatment with Standard CT + JAK2 Inhibitor (ruxolitinib) in TN IBC Phase 1: Metastatic BC ddac + ruxolitinib OR Weekly paclitaxel + ruxolitinib Phase 2: Untreated TN IBC Biopsy 1 Biopsy 2 Cycle 1 ddac + ruxolitinib Cycle 2 ddac + ruxolitinib Cycle 3, 4 ddac + ruxolitinib Assess proportion of patients with pstat3+ disease Association with pcr rate Assess percent reduction of pstat3 following 1 week of ruxolitinib run-in phase Cycle 5-8 Weekly paclitaxel x 12 + ruxolitinib Biopsy 3 MRM Key Questions Concerning TN - LABC Are all TNBC alike? Do we need to perform microarray on all breast cancers to understand each patient s disease? How do we choose appropriate chemotherapeutic agents? Do not forget traditional agents in light of newer regimens current focus on platinum agents. Are there other targets in TNBC that can be used in directed therapy? Angiogenesis inhibitors are they best for TNBC? Explore new targets mtor inhibitors JAK2 inhibitors 13

14 Summary The pathologic response to neoadjuvant chemotherapy can be used prognostically in TNBC Standard anthracycline/taxane combinations are effective in TNBC Current research focus on DNA-damaging agents (platinum) and angiogenesis inhibitors final analysis is still pending Encouraging pre-clinical data supports investigation of other targeting agents: mtor inhibitors and JAK2 inhibitors 14