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Challenging Cases in Cancer: Advanced Breast Cancer

Challenging Cases in Cancer: Advanced Breast Cancer. Linda T. Vahdat, MD Medical Director, Breast Cancer Program Weill Medical College of Cornell University New York Presbyterian Hospital New York, NY. Goals of Program. Review approach to goals of therapy in advanced breast cancer

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Challenging Cases in Cancer: Advanced Breast Cancer

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  1. Challenging Cases in Cancer:Advanced Breast Cancer Linda T. Vahdat, MD Medical Director, Breast Cancer Program Weill Medical College of Cornell University New York Presbyterian Hospital New York, NY

  2. Goals of Program • Review approach to goals of therapy in advanced breast cancer • Integrate existing clinical data in the day-to-day management of advanced breast cancer

  3. Management of Advanced Breast Cancer: Efficacy vs. Toxicity

  4. Options for Advanced Breast Cancer Hormonal Therapy Chemotherapy Oral meds- capecitabine, Vincas, taxanes, camptothecins, liposomal preparations, nanoparticle preparations (ixabepilone, eribulin) Tamoxifen, SAIs, fulvestrant (2ME) Biologics Trastuzumab, bevacizumab, Lapatinib (sunitinib, tipifarnib) Non-FDA approved drugs in parentheses

  5. Advanced Breast Cancer • No standard approach • Many options • QOL important endpoint • Site specific palliation (i.e. VAT, bisphosphonates) • Many clinical trials available • Improvement in survival • Median 4.3 years

  6. Chemotherapy for Stage IV Breast Cancer • Options: • Taxanes- vary the schedule to re-induce response, use of different delivery systems • Capecitabine + • Vinorelbine + • Anthracyclines + liposomal preparations, epirubicin • Gemcitabine + • Irinotecan

  7. Stage IV Breast Cancer Chemotherapy • Modest differences in response rates • No real effect on overall survival • Toxicity issues important when palliation the goal

  8. Common Regimens for Stage IV Breast Cancer Jones, JCO 2005,Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005

  9. Common Regimens Used in MBC: Grade 3/4 Hematologic Toxicity Jones, JCO 2005,Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005

  10. 30 25 20 paclitaxel docetaxel 15 nab-paclitaxel 10 capecitabine gemcitabine 5 navelbine 0 N/V Asthenia stomatitis PN-Motor PN- Sensory Common Regimens Used in MBC: Grade 3/4 Non-hematologic Toxicity Jones, JCO 2005,Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005

  11. Case Studies • Real patients • No wrong answer • Integrate goals of patients and physician into final decision

  12. Case #1: DG • 72-year-old woman with a h/o bilateral breast cancer • 1978 RMRM: T = 2.cm, N = 0/24, ER/PR+ • No further therapy • 1990 LMRM: T = 1.0 cm, N = 0/12, ER/PR+ • Tamoxifen x 5 years • 1998 CW nodule excised: c/w ILC, ER/PR+, HER2- • EOD: sub-centimeter pulmonary nodules • Anastrazole started with resolution of pulmonary nodules

  13. Case #1: DG • 2006: routine follow-up physical exam: • Noted to have large pre-sternal mass • Asymptomatic • CT chest abd pelvis: 8 cm mass adjacent to sternum abutting but not invading pericardium

  14. Case #1: DG What treatment would you recommend? • Hormonal therapy • Chemotherapy • Radiation therapy • Hospice

  15. Case #1: DG What treatment would you recommend? • Hormonal therapy • Chemotherapy • Radiation therapy • Hospice Recommended Approach: • All options are appropriate but would favor hormonal therapy

  16. Reasons to Consider Hormonal Therapy for This Patient • Elderly • Asymptomatic from current cancer • Long natural history of breast cancer • 9-years of benefit from an aromatase inhibitor • RT will only manage CW mass and large area to irradiate

  17. Hormonal Options • Another aromatase inhibitor • Exemestane • Letrozole • Estrogen receptor down-regulator • Fulvestrant

  18. Clinical Data • Use of fulvestrant after an aromatase inhibitor: • Fulvestrant in women with advanced breast cancer after progression of prior aromatase inhibitor: NCCTG Trial 0032. Ingle JN et al. JCO 2006 • Use of an aromatase inhibitor after failure of an aromatase inhibitor: • Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors. Lonning et al. JCO 2000 • Sequential use of aromatase inactivators and inhibitors in advanced breast cancer. Bertelli et al. Proc Amer Soc Clin Oncol 2002

  19. Fulvestrant in Women with Advanced Breast Cancer After Progression of Prior Aromatase Inhibitor: NCCTG 0032 Eligibility criteria • ER and/or PR+ breast cancer • Measurable disease • Progressive disease after a 3rd generation AI in addition to another hormonal agent • One prior chemo regimen for MBC Treatment: Fulvestrant 250 mg IM Q 28 days Evaluation on study: Month 1 and then Q 3 months Ingle JN et al. JCO 2006

  20. NCCTG 0032 • Entered: 80 patients • Evaluable: 77 patients • Disease sites: • 88% visceral predominant disease • 73% 2 prior hormone therapies • 32% prior chemotherapy Ingle JN et al. JCO 2006

  21. NCCTG 0032: Results • Partial responses: 11/77= 14.3% • Stable disease ≥ 6 months16/77 = 20.8% • Clinical benefit rate: 35% • Median TTP = 3 months • Median duration of response 11.4 months • Clinical benefit rate 54% in those who had not received prior tamoxifen Ingle JN et al. JCO 2006

  22. Clinical Benefit of Fulvestrant in Post Menopausal Women with Primary or Acquired Resistance to Aromatase Inhibitors: Final Results of Phase II Swiss Group for Clinical Research Trial (SAKK 21/00) • Two groups of patients: • Group A (N = 70)AI responsive disease • Group B (N = 20) AI resistant disease • Treatment: fulvestrant 250 mg IM Q 28 days Perey et al. Annals of Oncology 2007

  23. SAKK 21/00: Results • Patient characteristics: • AI pretreatment: 100% • Tam/toremifene pretreatment: 84% • Bone mets: 64% • Liver mets: 45% • Clinical Benefit rate (CR,PR, SD ≥ 6 months): 30% • No difference by prior AI response Perey et al. Annals of Oncology 2007

  24. Activity of Exemestane in Metastatic Breast Cancer After Failure of Nonsteroidal Aromatase Inhibitors • Phase II trial: N = 242 pt • Exemestane: 25 mg QD after failure of AI • Response rate: 16/242 6.6% • Stable disease rate ≥ 6 months: 42/242 (17%) • Clinical benefit rate: 24.3% • Median duration of response: 54 weeks • Median duration of treatment: 10 weeks Lonning PE et al, JCO 2000

  25. Summary of Fulvestrant or Aromatase Inhibitor After Failure of an AI AI= aromatase inhibitor, RR= response rate, SD= stable disease, CBR= clinical benefit rate ( CR,PR and SD≥6 mos); TTF= Time to treatment failure (ie. median duration of response)

  26. Case #1: Outcome • Patient in an ongoing response to fulvestrant for 1 year at present

  27. Case #2: DCR • 45-year-old AA woman vocalist with stage 2 breast cancer • 1999: LMRM • T = 3.2 cm, N = 0/10, ER/PR/HER2- • AC q 3 w x 4 • 2006: difficulty hitting the high notes and DOE during dance routines

  28. Case #2: DCR • 2006: biopsy of CW mass: c/w BC (ER/PR/HER2-) • EOD: multiple pulmonary nodules and extensive hilar and subcarinal adenopathy compressing bronchi

  29. Case #2: DCR What treatment would you recommend: • Chemotherapy alone • Chemotherapy + biologic • Hospice

  30. Case #2: DCR What treatment would you recommend: • Chemotherapy alone • Chemotherapy + biologic • Hospice Recommend Approach • Would favor a regimen that would give the highest response in the quickest amount of time because she is symptomatic

  31. Case #2: DCR • Chemotherapy: single agent or combination • Chemotherapy + biologic • Paclitaxel + bevacizumab • Capecitabine + bevacizumab

  32. Treatment Issues • Single agent vs. combination? • Rapid response rate? • Any special considerations for triple negatives?

  33. Single Agent vs. Combination • Response rates higher with combination therapy • Time to progression better • Overall survival similar • Toxicity increased with combination

  34. Trials of Combination vs. Monotherapy in Advanced Breast Cancer Significant differences in bold, RR = response rate; TTP = time to progression; OS = overall survival. Sledge, JCO 2003; Bonneterre, Br J Ca 2002; O’Shaughnessy, JCO 2002; Albain, Proc Amer Soc Clin Oncology 2004

  35. Capecitabine Data • Oral 5FU prodrug* • Response Rate first-line1,2: 30-58% • Response Rate for anthracycline and taxane pretreated3,4: 14 to 29% • Median time to response: 12 weeks 1O’Shaughnessy, Ann Oncol 2001 2 Reynoso, Breast Ca Res Treat 2005 Suppl(S219) 3 Blum, JCO 1998 4Vahdat, Proc Amer Soc Clin Oncol 2007 *Good review: Seidman A, The Oncologist 2002;7(suppl 6):20-28 www.TheOncologist.com

  36. Docetaxel Data • Antimicrotubule agent* • Response Rate first-line1,2: 32 to 54% • Median time to response: 12 weeks 1Hudis C, J Clin Onc 1996; 2 Jones S J Clin Oncol 2005 *Good review: Nabholtz JM, Semin Oncol. 2002 Jun;29(3 Suppl 12):28-34

  37. Bevacizumab Data • Humanized monoclonal antibody to VEGF-A* • Improves survival when added to chemotherapy in colon and NSCLC • Single-agent activity in breast cancer1 1Cobleigh, M Semin Oncol. 2003 Oct;30(5 Suppl 16):117-24 *Good review: Traina, T et al Hematol Oncol Clin N Am (21)2007, 303-319

  38. Chemotherapy and Bevacizumab for MBC • Capecitabine: first and second-line therapy1,2 • Metronomic cyclophosphamide + mtx3 • Paclitaxel: first-line therapy4 1Sledge Proc Amer Soc Clin Oncol 2007 2Miller JCO 2005 3Burstein Breast Ca Res Treat 2005 Suppl 4Miller Proc Amer Soc Clin Oncol 2005

  39. ECOG 2100 RANDOMIZED Paclitaxel N = 350 First-line MBC Paclitaxel + Bevacizumab N = 365 Paclitaxel dose: 90 mg/m2 on day 1,8,15 Q 28 days Bevacizumab dose: 10 mg/kg on Day 1, 15 Miller, K et al. ASCO 2005

  40. ECOG 2100 Miller, K et al. ASCO 2005

  41. Phase III Trial Capecitabine ± Bevacizumab Miller, K et al. ASCO 2005

  42. Metronomic Cyclophosphamide + Methotrexate (CM) ± Bevacizumab(b): Randomized Phase II Study RR = response rate; TTP = time to progression Burstein et al, Breast Cancer Res Treat Suppl 2005

  43. Any Role in Special Populations? • Preliminary data from E2100 suggests a PFS benefit in triple negative population • ER/PR +, HR = 0.30 (CI 0.29 - 0.53) • ER+/PR -, HR = 0.86 (CI 0.52 - 1.43) • ER/PR -, HR = 0.47 (CI 0.35 - .63)

  44. Case #2: Outcome • Had more than a partial response in lungs and a CR in chest wall • Opted to come off treatment because of fatigue and neuropathy a year ago and has stable disease and no therapy since that time

  45. Case #3: RS • 52-year-old woman diagnosed with an IBC in 1/2003 • Neoadjuvant chemotherapy with AC followed by paclitaxel q 2 w (clinical partial response) • LMRM, T = 6 cm, N = 12, ER/PR+, HER2- by FISH • 11/2003: lung, liver, bone, and regional nodal metastases, ER/PR+ and HER2- • Pain from bone mets

  46. Case #3: RS What treatment would you recommend: • Hormonal therapy • Chemotherapy • Clinical trial • Hospice

  47. Case #3: RS What treatment would you recommend: • Hormonal therapy • Chemotherapy • Clinical trial • Hospice Issues to Considers • Heavily pre-treated, symptomatic, large disease burden and short disease free interval Treatment Recommendation • Clinical trial

  48. Epothilones: Ixabepilone (BMS-247550) • New antineoplastic class - the natural epothilones and their analogs • Low susceptibility to tumor resistance mechanisms • MRP-1 and P-gp efflux pumps • b (III) tubulin overexpression • b tubulin mutations • Activity in multiple tumor models • Demonstrated pre-clinical synergy with capecitabine Ixabepilone S. cellulosum Epothilone B

  49. 45 42 30 22 ORR (%) 19 18 pCR 15 12 0 Roché1 After adjuvant anthra Low2 Taxane-pretreated MBC Conte3 Taxane-resistant MBC Thomas4 Multiresistant(anthra / tax / cape) MBC Baselga5 Neoadjuvant T2-4, N0-3, M0 Ixabepilone Phase II Data in Breast Cancer 1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol 2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660. 5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.

  50. Stratification • Visceral metastases • Prior chemotherapy for MBC • Anthracycline resistance • Study site Study Design: International, Randomized, Open-label, Phase III Trial Ixabepilone (40 mg/m2 IV over 3 hr d1 q3wk) + Capecitabine (2000 mg/m2/dayPO 2 divided doses d1-d14 q3wk) N = 375 Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N=752 Capecitabine (2500 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 377

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