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Future therapeutic approaches for metastatic triple negative breast cancer 18 th Annual Perspective in Breast Cancer New York, August 18 th, 2012 Ruth M. ORegan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University, Chief of Hematology and Medical Oncology, Georgia Cancer Center for Excellence, Grady Memorial Hospital

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Copyright 2003 by the National Academy of Sciences Triple negative breast cancers have a high recurrence rate following initial diagnosis with a poor survival Sorlie et al PNAS 2003 Basal/TN

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Triple negative breast cancers High grade aggressive cancers with a high propensity to distant metastases in short-term Poor outcome is associated with Chemo-resistance (only about one-third respond to chemotherapy) Lack of molecular targets towards which novel agents can be developed

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Triple Negative Tumors (%) By Age Lund Breast Cancer Res Treat 2008

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Topics to be covered Triple negative breast cancers represent a heterogeneous group of cancers which likely require different therapeutic approaches Potential therapeutic targets Chemo-resistance how can we manage patients with early stage breast cancer who have resistant cancers

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0246810121416 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Months Since Study Entry Probability of Progression Free Survival No. at risk GC258171116633818610 GCI261187138835311200 No. at risk GC2582392141811519938110 GCI26124823020416911152150 Iniparib does not improve outcome in unselected metastatic triple negative breast cancer 0246810121416 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Probability of Survival Months Pre-specified alpha = 0.04 PFS GC (N=258) GCI (N=261) Median PFS, mos (95% CI) 4.1 (3.1, 4.6) 5.1 (4.2, 5.8) HR (95% CI)0.79 (0.65, 0.98) p-value0.027 Pre-specified alpha = 0.01 OS GC (N=258) GCI (N=261) Median OS, mos (95% CI) 11.1 (9.2, 12.1) 11.8 (10.6, 12.9) HR (95% CI)0.88 (0.69, 1.12) p-value0.28 OShaughnessy PASCO 2011

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Sub-types of triple negative breast cancer Evaluated gene expression profiles from 21 breast cancer data sets (14 training and 7 validation = 587 cases of TNBC) Used cluster analysis to sub-divide TNBC into 6 sub-types displaying unique gene expression and ontologies Identified breast cancer cells lines representative of each subtype Lehmann et al JCI 2011

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Click on image to magnify. 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

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Click on image to magnify. Cell lines correspond to the 6 triple negative subtypes Lehmann et al JCI 2011

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Click on image to magnify. Sub-types demonstrate differential response to therapies in vivo Lehmann et al JCI 2011 Vehicle Cisplatin Anti-androgen P13K/mTOR inhibitor

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EGFR/HER1 GRO1 TCF4 Laminin gamma 2 c-KIT Keratin 5 Keratin 17 P-Cadherin Frizzled 7 K-Ras Is EGFR a viable target for triple negative breast cancer?

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Randomized Phase II: Cetuximab +/- Carboplatin for Triple-Negative MBC Carey et al. J Clin Oncol 2012 RANDOMIZERANDOMIZE Cetuximab N=31 Cetuximab + Carboplatin at Progression N=22 Cetuximab + Carboplatin N=49 Arm 1 Cetuximab Cetuximab + carboplatin Arm 2 Cetuximab + carboplatin Arm 1b + 2 N31247195 ORR CR PR 2 (6%) 0 2 (6%) 4 (17%) 0 4 (17%) 12 (17%) 1 (1%) 11 (15%) 16 (17%) 1 (1%) 15 (16%) SD5 (16%)6 (25%)16 (23%)22 (23%)

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EGFR inhibitors in TNBC R Cisplatin + Cetuximab (n=114) Cisplatin (n=57) PD01-01 Met TNBC 1 chemo for mets Cis + EGFRCisp Response (%)20100.5 PFS (mo)3.71.50.032 Baselga et al SABCS 2010

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+ + + + + + + MDA-MB-468 Rapamycin Erlotinib Lapatinib mTOR inhibition sensitizes triple negative breast cancer cells to EGFR inhibition Liu et al Mol Cancer Ther 2011 p-EGFR pMAPK p-S6 -actin p-Akt

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Phase 2 trial of Lapatinib and Everolimus in metastatic TN breast cancer Metastatic TN breast cancer prior taxanes and anthracyclines Second/third-line n = 40 TN in metastatic setting Lapatinib 1250mg daily RAD001 5mg daily BX CT Primary endpoint: response rate

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ER HER2/neu MDA-MB-468 (BL1) HCC1806 (BL2)HCC70 (BL2)MDA-MB-231 (MSL) Hs578t (MSL)BT549 (M)BT474MCF7 -actin Triple Negative Breast Cancer Cells IGF1R IRS-1 Parent EV IGF1R-/- MDA-MB-468MDA-MB-231 IGF1R -actin Expression of IGF1R in triple negative breast cancer cell lines Taliaferro-Smith et al SABCS 2011

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E-cad Vimentin GAPDH EV IGF1R-/- MDA-MB-468MDA-MB-231 EV IGF1R- /- Empty VectorIGF1R-/- MDA-MB-468 Empty Vector IGF1R-/- MDA-MB-231 EV IGF1R-/- MDA-MB-468MDA-MB-231 E-cad Vimentin GAPDH Knock-down of IGF1R changes morphology of triple negative breast cancers cells Taliaferro-Smith et al SABCS 2011

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MDA-MB-468 E-cadherin DAPIMerge Empty Vector IGF1R(-/-) VimentinDAPIMerge Empty Vector IGF1R(-/-) E- cadherin DAPIMerge VimentinDAPIMerge MDA-MB-231 Knock-down of IGF1R induces mesenchymal to epithelial transition in MDA-231 triple negative cells Taliaferro-Smith et al SABCS 2011

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MDA-MB-231 MDA-MB-468 EV IGF1R-/- ** * Matrigel Invasion IGF1R knock-down affects invasive properties of triple negative breast cancers dependent on underlying morphology MDA-231 cells with IGF1R knock-down compared to WT cells also exhibit decreased colony formation Taliaferro-Smith et al SABCS 2011

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MDA-MB-468 MDA-MB-231 UNT 0.175 M PPP Pharmacologic inhibition of IGF1R alters morphology of triple negative breast cancer cells Taliaferro-Smith et al SABCS 2011

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Incidence of pCR by Breast Cancer Subtype 107 patients treated with neoadjuvant AC and hormone therapy if HR+. Response Type All Patients N=107 (%) Basal Like N=34 (%) HER2 N=11 (%) Luminal B N=26 (%) Luminal A N=36 (%) CR14291086 PR4756605033 SD3815304258 PD10003 pCR162736150 Carey et al; Clin Cancer Res 2007; 13(8)

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Importance of Pathologic CR Liedtke et al. JCO 2008; 26(8): 1275-81 Overall Survival

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Log-rank P = 5.5 x 10-7 RCB 0 (n = 16) RCB I (n = 2) RCB II (n = 17) RCB III (n= 9) Among Basal-like Tumors

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Chemo-resistance is a significant issue with TNBC PCR is clearly a very robust prognostic factor for outcome in TNBC How can we increase PCR rate? How should we manage patients with residual cancer following pre-operative chemotherapy?

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Neoadjuvant Chemo plus Carboplatin +/- Bevacizumab in Stage II-III TNBC (Phase II CALBG 40603) Paclitaxel 80mg/m 2 wkly x4 ddAC x4 Paclitaxel 80mg/m2 wkly x4 ddAC x4 Bevacizumab 10mg/kg q2w x 9 Paclitaxel 80mg/m 2 wkly x4 ddAC x4 Carboplatin AUC 6 q3w x 4 Paclitaxel 80mg/m 2 wkly x4 ddAC x4 Bevacizumab 10mg/kg q2w x 9 Carboplatin AUC 6 q3w x 4 Surgery 4-8 wks after last ddAC XRT No adjuvant chemo planned Sikov WM, et al. J Clin Oncol. 2010;28:15s (Abstract TPS 110).

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Phase II Neoadjuvant Trial of Sorafenib in combination with Cisplatin followed by dose dense Paclitaxel for ER-, PR-, HER2- (Triple Negative) Early-stage Breast Cancer Early Stage Triple Negative BreastCancer Surgery Biopsy Cisplatin 75 mg/m 2 q3wk x 4 cycles Paclitaxel 175 mg/m 2 q2wk x 4 cycles Sorafenib 400 mg po bid PET Sorafenib 400 mg po bid x 4 weeks PET Biopsy PET Biopsy

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Triple negative cancers Behave very aggressively Develop (chemo)-resistance rapidly In clinical trials, many patients experience disease progression before their first staging scan 1 Maybe micro-metastatic disease is a better way of evaluating novel agents in triple negative disease 1. Carey et al Proc ASCO 2008

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

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Pre-operative trial in triple negative breast cancer (PI: Zelnak) Early Stage TNBC (not LABC) Surgery Biopsy CISPLATIN PACLITAXEL SORAFENIB PET SORAFENIB PET Biopsy PET Biopsy PCR Residual cancer Gene expression Focused on EGFR, IGF1R, Wnt, Vimentin

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Conclusions Triple negative breast cancers have an aggressive natural history with a poor outcome due to intrinsic or rapid onset of resistance There is an urgent need for new therapies Triple negative breast cancers do not represent a single entity and individual subtypes will require different treatment approaches Pre-operative or post-operative residual disease settings may be optimal for evaluation of novel agents