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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 • Integrate existing clinical data in the day-to-day management of advanced breast cancer Management of Advanced Breast Cancer: Efficacy vs. Toxicity 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 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 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 Stage IV Breast Cancer Chemotherapy • Modest differences in response rates • No real effect on overall survival • Toxicity issues important when palliation the goal Common Regimens for Stage IV Breast Cancer Agent CR (%) PR (%) ORR (%) TTP (mos) Paclitaxel 5 20 25 4.6 Docetaxel 2 30 32 7.5 Nab-paclitaxel NR NR 34 5.2 Capecitabine 2 18 20 8.1 Vinorelbine 5 20 25 3.0 Gemcitabine 6 6 12 3.0 Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005 Common Regimens Used in MBC: Grade 3/4 Hematologic Toxicity 100 90 80 % patients 70 60 Neutropenia Febrile neutropenia 50 Platelets 40 30 20 10 15 2 2 0 0 1 pa cl i ta xe l do ce ta xe na l bpa cl i ta xe ca l pe ci ta bi ne ge m ci ta bi ne vi no re lb in e 0 Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005 Common Regimens Used in MBC: Grade 3/4 Non-hematologic Toxicity 30 25 20 paclitaxel 15 docetaxel nab-paclitaxel 10 capecitabine gemcitabine 5 navelbine 0 Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005 Case Studies • Real patients • No wrong answer • Integrate goals of patients and physician into final decision 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 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 Case #1: DG What treatment would you recommend? Hormonal therapy Chemotherapy Radiation therapy Hospice 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 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 Hormonal Options • Another aromatase inhibitor – Exemestane – Letrozole • Estrogen receptor down-regulator – Fulvestrant 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 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 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 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 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 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 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 Summary of Fulvestrant or Aromatase Inhibitor After Failure of an AI N RR (%) SD ≥ 6 mos (%) CBR (%) Med. TTF (mos.) NCCTG 0032 80 14.3 20.8 35 11.4 SAKK 21/00 90 Treatment Fulvestrant after AI 30 Exemestane after AI Lonning 242 6.6 17 24.3 12.2 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) Case #1: Outcome • Patient in an ongoing response to fulvestrant for 1 year at present 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 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 Case #2: DCR What treatment would you recommend: Chemotherapy alone Chemotherapy + biologic Hospice 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 Case #2: DCR • Chemotherapy: single agent or combination • Chemotherapy + biologic – Paclitaxel + bevacizumab – Capecitabine + bevacizumab Treatment Issues • Single agent vs. combination? • Rapid response rate? • Any special considerations for triple negatives? Single Agent vs. Combination • Response rates higher with combination therapy • Time to progression better • Overall survival similar • Toxicity increased with combination Trials of Combination vs. Monotherapy in Advanced Breast Cancer N RR (%) TTP (mos.) OS (mos.) Doxorubicin 224 36 5.6 19 Paclitaxel 229 34 5.8 22 Combination 230 47 8 22 Docetaxel 86 43 6.5 NA 5FU/Vinorelbine 90 34 5.1 NA Docetaxel 256 30 4.2 11.5 Docetaxel + Capecitabine 255 42 6.1 14.5 Paclitaxel 262 26 2.9 15.8 Paclitaxel + gemcitabine 267 32 5.2 18.5 Author Sledge (E1193) Bonneterre O’Shaughnessy Albain 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 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 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 2 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 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 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 3Burstein JCO 2005 Breast Ca Res Treat 2005 Suppl 4Miller Proc Amer Soc Clin Oncol 2005 ECOG 2100 First-line MBC R A N D O M I Z E D Paclitaxel N = 350 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 ECOG 2100 Treatment Paclitaxel Paclitaxel + Bevacizumab P-value Response rate (%) 14.2 28.2 P < 0.0001 Median time to progression (months) 6.1 11 P < 0.0001 HR = 0.51 Overall survival ns ns HR = 0.84 Miller, K et al. ASCO 2005 Phase III Trial Capecitabine ± Bevacizumab Treatment Capecitabine Capecitabine + Bevacizumab P-value Response rate (%) 9.1 19.8 P = 0.001 Median time to progression (months) 4.17 4.86 HR = 0.98 Overall survival 15.1 14.5 NS Miller, K et al. ASCO 2005 Metronomic Cyclophosphamide + Methotrexate (CM) ± Bevacizumab(b): Randomized Phase II Study Treatment No. pts RR(%) TTP (mos) CM 21 10 2.2 CMB 34 29 5.5 RR = response rate; TTP = time to progression Burstein et al, Breast Cancer Res Treat Suppl 2005 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) 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 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 Case #3: RS What treatment would you recommend: Hormonal therapy Chemotherapy Clinical trial Hospice 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 Epothilones: Ixabepilone (BMS-247550) • New antineoplastic class - the natural epothilones and their analogs S. cellulosum Epothilone B Ixabepilone • 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 Phase II Data in Breast Cancer 45 42 ORR (%) 30 22 15 19 18 pCR Thomas4 Multiresistant (anthra / tax / cape) MBC Baselga5 Neoadjuvant T2-4, N0-3, M0 12 0 Roché1 After adjuvant anthra Low2 Conte3 TaxaneTaxane-resistant pretreated MBC MBC 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. Study Design: International, Randomized, Open-label, Phase III Trial Ixabepilone (40 mg/m2 IV over 3 hr d1 q3wk) + Capecitabine Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N=752 Stratification • Visceral metastases • Prior chemotherapy for MBC (2000 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 375 Capecitabine (2500 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 377 • Anthracycline resistance • Study site Response Rate % Response ORR (CR + PR) Investigator Ixabepilone Capecitabine + Capecitabine N = 377 N = 375 42 23 IRR Ixabepilone Capecitabine + Capecitabine N = 377 N = 375 35 P < 0.0001 14 P < 0.0001 Stable disease 36 38 41 46 Progressive disease 14 29 15 27 Unable to determine 8 10 9 12 Progression-free Survival by Independent Radiologic Review Proportion Progression Free 1.0 0.8 Median 95% CI Ixabepilone + Capecitabine 5.8 mos (5.5–7.0) Capecitabine 4.2 mos (3.8–4.5) 0.6 HR: 0.75 (0.64–0.88) P = 0.0003 0.4 0.2 0 0 4 8 12 16 20 Months 24 28 32 36 Grade 3/4 Non-hematologic Toxicities 80 Ixabepilone + Capecitabine (N = 369) % of Patients Capecitabine (N = 368) 60 40 23 18 17 20 9 0 0 8 3 6 0.3 9 4 2 3 2 3 2 3 0 Case #3: Outcome • Enrolled in BMS 046 and randomized to ixabepilone and capecitabine arm • Had a partial response that was clinically significant and was on study for 13 months. Taken off for progression Case #4: IHA • 55-year-old woman with newly diagnosed Stage IV breast cancer with massive adenopathy in right axilla rending limited motion in her arm • No neurologic symptoms and she ignored problem until she was unable to go to work as a operator • Biopsy c/w metastatic breast cancer, ER+/PR -, HER2- by FISH • Rest of evaluation unremarkable except for bone metastases Case #4: IHA What treatment would you recommend: Hormonal therapy Radiation therapy Chemotherapy Hospice Case #4: IHA What treatment would you recommend: Hormonal therapy Radiation therapy Chemotherapy Hospice Treatment Recommendation • Chemotherapy Treatment Issues: IHA • Many chemotherapy options. – Want to accomplish rapid disease control without significant toxicity. • Goal would be to cytoreduce to no symptoms and then place on hormonal therapy Chemotherapy Options • Anthracyclines • Taxanes: paclitaxel, docetaxel, nab-paclitaxel • Capecitabine • Gemcitabine • Vinorelbine First-line Chemotherapy For MBC Agent N RR (%) TTP (mos) Capecitabine1 61 30 4.1 Gemcitabine2 35 37 5.1 Vinorelbine3 157 41 6 Paclitaxel4 224 25 3.6 Docetaxel4 225 32 5.7 RR = response rate; TTP = time to progression 1O’Shaughnessy, Ann Oncol 2001; 2Blackstein, Oncology 2002; 3 Fumoleau, JCO 1993; 4Jones, JCO 2005 Nab-paclitaxel • Albumin-bound paclitaxel • Advantages: no premeds – Cremophor free – Shorter infusion time • Might make use of gp 160-albumin mediated receptor transport across endothelial cells Nab-paclitaxel Trial N Setting Schedule RR (%) Med TTP (wks) Ibrahim1 63 No limit 300 mg/m2 Q3w 48 27 1st line 125 mg/m2 QW (3 out of 4 wks) 57 NR 1st line 260 mg/m2 vs. 175 mg/m2 Q 3W 33 vs. 19 23 vs. 17 Mirtschung2 23 Gradishar3 nab-paclitaxel vs. paclitaxel 460 Significant differences in Bold; RR = response rate, TTP = time to progression; NR = not reported 1 Ibrahim, JCO 2005; 2 Mirtschung, Breast Ca Res Treat Suppl 2006; 3 Gradishar, JCO 2005 Case #4: Outcome • Patient had a near complete response to nabpaclitaxel and eventually came off of therapy due to toxicity (neuropathy) – This was chosen because she wanted to minimize her time in the office (Q 3 w schedule) • Doing well on letrozole Treatment of Advanced Breast Cancer Conclusions • Many varied approached to managing advanced breast cancer • Input from patient important in selecting a treatment • Many new drugs being developed