1. 1 Approaches to Metastatic Disease in Breast Cancer Anne F. Schott, MD University of Michigan

2. The Goals Prolonged survival Palliation of symptoms primarily by decreasing disease bulk Not cure in the vast majority of patients How to optimally use the tools we have to maximize patient quality of life and lengthen survival?

3. Patient Case #1 46 year old woman, breast cancer 1998, postmenopausal due to TAH, presents with a supraclavicular lymph node Biopsy – ER positive, PR negative, Her-2 negative Prior therapy AC x 4 and tamoxifen x 5 years, completed two years ago Staging evaluation with CT scan shows pleural metastases, several small lung metastases, and slightly enlarged mediastinal lymph nodes

4. Options in this case Chemotherapy Chemotherapy combined with hormonal therapy Hormonal therapy Clinical trial

5. Chemotherapy vs Tamoxifen vs Concurrent Therapy TamACTam + AC Response22.1%45.1%51.3% Clinical Benefit80%88%91% Median Survival22.8 mo22.5 mo19.04 mo Although median survival not improved for chemo over tamoxifen, RR increased: patients did not all cross over Led to recommendation of hormonal therapy first – retest in modern day? ANZ BCTG 7802

6. Concurrent chemotherapy and hormonal therapy No survival benefit seen in metastatic setting with combined tamoxifen with cytotoxic chemotherapy Adjuvant setting suggests similar outcome (SWOG 8814), again with tamoxifen Would this hold true for aromatase inhibitors?

7. Why Use Hormonal Therapy Alone Metastatic Disease? ER rich tumors less responsive to chemotherapy –less likely to have pCR in neoadjuvant setting –less likely to benefit in adjuvant setting Hormonal therapy can be used longer than chemotherapy with fewer side effects Minimal disease, asymptomatic disease, non- life-threatening disease if ER or PR positive should get hormonal therapy –bone-only metastases, bone/pleura, lymph node

8. Selection of Hormonal Agents- Postmenopausal Aromatase inhibitors superior to tamoxifen first line Fulvestrant equal to anastrozole, following tamoxifen failure Hormonal Therapy for Metastatic Disease Post-Menopausal ONLY Aromatase Inhibitor Aromatase inhibitorFulvestrant Aromatase inhibitorFulvestrantMegestrol acetate Androgens 2nd aromatase inhibitor Megestrol acetate Tamoxifen Fulvestrant

9. NCI-sponsored clinical trials for hormone responsive metastatic disease (Luminal A and B) What is the role of combination endocrine therapy in metastatic disease? –CALGB 40302: fulvestrant +/- lapatinib –CALGB 40301: letrozole and tipifarnib –ECOG: hormone + /- bevicizumab –S0226: anastrozole +/- fulvestrant What new agents can be used in hormonal combinations to overcome endocrine resistance?

10. Patient case #2 38 year old diagnosed 2003, Stage II ER-, PR-, Her-2 neu – Received AC-Taxol, lumpectomy and RT Recurred in breast, bone, liver, lymph nodes biopsy confirmed same receptor profile Highly symptomatic

11. Active single agents in breast cancer Taxanes –Docetaxel, paclitaxel Anthracyclines –Doxorubicin, epirubicin, liposomal doxorubicin Alkylating agents Fluoropyrimidines –5-FU, capecitabine Vinorelbine Ixabepilone (epothilone) Gemcitabine Platinums

12. Additive Synergistic Antagonistic Concept of Additive, Synergistic, and Additive Combination Regimens +

13. Commonly Used Combination Therapies: Preclinical Predictions Doxorubicin + cyclophosphamide Doxorubicin + Docetaxel Docetaxel + capecitabine Platinums + taxanes Gemcitabine + taxanes Gemcitabine + cisplatinum Vinorelbine + docetaxel Vinorelbine + capecitabine Cyclophosphamide + capecitabine Additive Antagonistic Synergistic Additive Synergistic Additive Synergistic

14. Table 2 – Main characteristics of randomized controlled trials testing chemotherapy regimens reported 2000-2007 Total number of trials (n < 150 excluded)63 Median trial size305 Main research questions Combination versus combination20 Combination versus single agent13 Single agent versus single agent3 Combination versus sequential single agent3 Dose questions High-dose therapy3 Dose4 Dose intensity2 Dose schedule3 Drug formulation9 Duration3 Statistically significant benefit In response rate19 (30%) In PFS22 (35%) In OS8 (13%) QOL Measured in19 (30%) Cochrane Review: Wilcken, Dear European Journal Of Cancer 4 4 ( 2 0 0 8 ) 2 2 1 8 – 2 2 2 5

15. Author # patients Arm AArm BOS AOS Bp-ValueToxicity/QOL Feher, O410EpirubicinGemcitabine19.111.80.0004Toxicity similar O’Shaughnessy511 Docetaxel/ capecitabine Docetaxel14.511.50.0126 Arm A more toxic but trend to less decrease in QOL. Cost effective Jassem, J267 Doxorubicin/ paclitaxel FAC23.318.30.013 Arm A neutropaenia. Arm B emesis Albain, KS529 Paclitaxel/ gemcitabine Paclitaxel18.515.80.018Arm A more toxic Bontenbal, M216 Docetaxel/ doxorubicin FAC22.616.20.019Arm A more FN Stockler, M325 Intermittent or continuous capecitabine CMF22.018.00.02 Capecitabine HFS. CMF FN Jones, S449DocetaxelPaclitaxel15.412.70.03 Docetaxel more toxic. QOL same Icli, F201Oral etoposide/ cisplatin Paclitaxel14.09.50.039Toxicity similar 8/63 Trials With Survival Benefit None of these trials included a sequential crossover design

16. Combination A-Taxol vs. Single Agent Sequential: E1193

17. Combination Capecitabine + Docetaxel Crossover in only 25% of patients (non-US population)

18. Gemcitabine-Paclitaxel Combination

20. Combination vs. Single Agent Chemotherapy Consistent increases in response rate with combination vs. single agent therapy Consistent increase in toxicity as well Increase in response rate could be seen with either synergistic, additive, OR ANTAGONISTIC combinations The only true test of a survival benefit (for combination vs use at all) in patients who are not gravely ill includes a “crossover” design

21. Selection of chemotherapy agents in metastatic disease Prior therapy (anthracycline, taxane) Residual toxicity (neuropathy) GI function (capecitabine) ?Triple negative phenotype and platinum combinations ?Expression profiling?

22. June 26, 200722 New Agents in Metastatic Breast Cancer

23. June 26, 200723 N Engl J Med Volume 355(26):2733-2743 December 28, 2006 Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer Charles E. Geyer, M.D., John Forster, M.Sc., Deborah Lindquist, M.D., Stephen Chan, M.D., C. Gilles Romieu, M.D., Tadeusz Pienkowski, M.D., Ph.D., Agnieszka Jagiello-Gruszfeld, M.D., John Crown, M.D., Arlene Chan, M.D., Bella Kaufman, M.D., Dimosthenis Skarlos, M.D., Mario Campone, M.D., Neville Davidson, M.D., Mark Berger, M.D., Cristina Oliva, M.D., Stephen D. Rubin, M.D., Steven Stein, M.D., and David Cameron, M.D.

24. Cumulative Incidence of Disease Progression or Death from Breast Cancer According to the Assessment of the Independent Review Committee (Panel A) Kaplan-Meier Estimates of Overall Survival (Panel B) Cumulative Incidence of Disease Progression or Death from Breast Cancer According to the Site Investigators' Assessments (Panel C) Geyer CE et al. N Engl J Med 2006;355:2733-2743

25. Efficacy End Points in the Intention-to- Treat Population

26. Adverse Events Geyer CE et al. N Engl J Med 2006;355:2733-2743

27. Conclusion Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab

28. From the Ixabepilone Drug Label

29. From the Ixebepilone Drug Label

30. Ixabepilone Summary As monotherapy, ixabepilone produced a modest response rate of 12.4% in patients with locally advanced or metastatic breast cancer whose tumors had progressed following treatment with anthracyclines, taxanes, and capecitabine in a single-arm, multicenter clinical trial (n=126). However, ixabepilone did improve progression-free survival when combined with capecitabine compared to capecitabine alone in patients who were previously treated with anthracyclines and taxanes in an open-label, multicenter, randomized clinical trial (n=752) (Prod Info IXEMPRA(TM) IV injection, 2007).

31. Bevacizumab in breast cancer E2100 722 patients randomized First line chemotherapy + weekly Taxol Taxol aloneTaxol + bevacizumab Response21.2%36.9% PFS5.9 months11.8 mo

33. Conclusion Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone. FDA approval of bevacizumab withdrawn in November 2011.

34. Measuring the benefit of therapies for metastatic disease Improved quality of life and survival are the goals Are there surrogate markers for these? –Response rate –Time to progression –QOL measurements –Others?

35. Measuring treatment benefit – clinical trial methodologies focus on tumor “response” Plain films CT scan Bone scan MRI PET scan MUC-1 based tumor antigens CEA, CA 125 Circulating Tumor Cells Other biological markers of response

36. % Probability of Progression Free Survival 0 5 10 15 20 2530 3540455560657075 80 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 50 ~7 mos ~2.1 mos CTC at 1st Follow-up predict PFS 1 st Follow-up (3 - 4 wk) N = 163 Log rank p < 0.0001 Time from Baseline (Weeks) <5 CTC (n=114) ≥5 CTC (n=49) ~7-8 mos ~5-6 WEEKS First Followup

37. S0500 Trial Schema Metastatic Breast Cancer Starting 1 st Line Chemotherapy N = 350 Metastatic Breast Cancer Starting 1 st Line Chemotherapy N = 350 End 1 st cycle / blood draw 5-7 days prior to next cycle Group B - Randomized N = 104 Group B - Randomized N = 104 End Therapy / Final Blood draw Analysis & Report 1º End Points = PFS (Progression / RECIST) & OS (12 month follow-up) 2º End point = QOL (SWOG Method) Analysis & Report 1º End Points = PFS (Progression / RECIST) & OS (12 month follow-up) 2º End point = QOL (SWOG Method) Arm 2 – Δ Therapy N = 52 Arm 2 – Δ Therapy N = 52 Arm 1- same therapy N = 52 Arm 1- same therapy N = 52 Group A – Same Therapy N = 246 Group A – Same Therapy N = 246 <5CTC ≥5CTC *2 x 8ml CellSave tubes 1 x 10mL EDTA Processed at: Immunicon Impath Labs *2 x 8ml CellSave tubes 1 x 10mL EDTA Processed at: Immunicon Impath Labs *Baseline blood draw / begin new therapy