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

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Presentation on theme: "1 Approaches to Metastatic Disease in Breast Cancer Anne F. Schott, MD University of Michigan."— Presentation transcript:

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

2 The Goals Maximizing the quality of life (QoL), Prevention and palliation of symptoms Prolongation of survival 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 Prognostic Factors in Patients With Metastatic Breast Cancer Prognostic factorFavorableUnfavorable Performance statusGoodPoor Sites of diseaseBone, soft tissueViscera, CNS No. of sites of diseaseFewMultiple Hormone receptor statusPositiveNegative Her-2/neu statusNegative Positive (significance less clear in Her-2/neu inhibitors era) Disease-free interval>2 years<2 years Prior adjuvant therapyNoYes Prior therapy for MBCNoYes

4 Kaplan–Meier curves illustrating overall survival for patients with de novo stage IV versus relapsed disease. Dawood S et al. Ann Oncol 2010;21: © The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please

5 Survival differences among women with de novo stage IV and relapsed breast cancer

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7 Variable Hazard ratio Lower 95% Upper 95% P value Relapsed versus de novo < Race (black versus white) < Race (Hispanic and other versus white) Age at metastasis Year of metastatic diagnosis LVI (positive versus negative) HR (positive versus negative) < Grade (III versus I/II) < Visceral or other metastases versus bone only < Multiple or brain metastases versus bone only <0.0001

8 Influences on Treatment Choices Hormone receptor status of the primary tumor or its metastases HER-2/neu status The duration of the relapse-free interval since primary diagnosis The location and extent of metastases (visceral versus nonvisceral) Previous treatment (including its effects and tolerance) Patient symptoms Patient preferences Anticipated side-effects of treatment Availability and access to treatment

9 Patient Case #1 46 year old woman, breast cancer 6 years ago, 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

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

11 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

12 Concurrent chemotherapy and hormonal therapy No survival benefit seen in metastatic setting with combined tamoxifen with cytotoxic chemotherapy Adjuvant setting suggests worse outcome of chemotherapy concurrent with tamoxifen (SWOG 8814) Would this hold true for aromatase inhibitors?

13 Characteristics of Hormone Sensitive MBC A long disease-free interval (>2 years) No (or limited) visceral involvement Limited metastatic sites and disease- related symptoms and Slow disease progression

14 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

15 Selection of Hormonal Agents- Postmenopausal Aromatase inhibitors superior to tamoxifen first line Fulvestrant equal to anastrozole, following tamoxifen failure

16 Newer Strategies for Endocrine Responsive Breast Cancer? What is the role of combination endocrine therapy in metastatic disease? –S0226: anastrozole +/- fulvestrant –TAMRAD/Bolero2 adding everolimus What new agents can be used in hormonal combinations to overcome endocrine resistance?

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19 R Treatment A: exemestane (EXE) + everolimus (EVE) (n=485) Treatment B: exemestane + placebo (n=239) Randomized 2:1 N= 724 ER+, previously non-steroidal aromatase inhibitor treated MBC patients Primary Outcome: Progression Free Survival Baseline characteristics were well balanced; median age was 62 years; 56% had visceral involvement and 84% were sensitive to prior hormone therapy. Prior therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy for metastatic disease (25%). BOLERO-2

20 RESULTS Median follow up of 12.5 months

21 Patient case #2 53 year old diagnosed 2 years ago, Stage II ER-, PR-, Her-2 neu – Received AC-Taxol, lumpectomy and RT CXR incidentally showed lung nodule Recurrence also detected in liver and lymph nodes Biopsy confirmed same receptor profile Asymptomatic, PS 0

22 Question What would you recommend for this patient? –Single agent chemotherapy –Combination chemotherapy –Observation

23 The Goals Maximizing the quality of life (QoL), Prevention and palliation of symptoms Prolongation of survival

24 Active single agents in breast cancer Taxanes –Docetaxel, paclitaxel Anthracyclines –Doxorubicin, epirubicin, liposomal doxorubicin Alkylating agents Fluoropyrimidines –5-FU, capecitabine Vinorelbine Ixabepilone Eribulin Gemcitabine Platinums Topo I inhibitors

25 Additive Synergistic Antagonistic Concept of Additive, Synergistic, and Additive Combination Regimens +

26 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

27 Table 2 – Main characteristics of randomized controlled trials testing chemotherapy regimens reported 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 ( ) –

28 Author # patients Arm AArm BOS AOS Bp-ValueToxicity/QOL Feher, O410EpirubicinGemcitabine Toxicity similar O’Shaughnessy511 Docetaxel/ capecitabine Docetaxel Arm A more toxic but trend to less decrease in QOL. Cost effective Jassem, J267 Doxorubicin/ paclitaxel FAC Arm A neutropaenia. Arm B emesis Albain, KS529 Paclitaxel/ gemcitabine Paclitaxel Arm A more toxic Bontenbal, M216 Docetaxel/ doxorubicin FAC Arm A more FN Stockler, M325 Intermittent or continuous capecitabine CMF Capecitabine HFS. CMF FN Jones, S449DocetaxelPaclitaxel Docetaxel more toxic. QOL same Icli, F201Oral etoposide/ cisplatin Paclitaxel Toxicity similar 8/63 Trials With Survival Benefit None of these trials included a sequential crossover design

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

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

31 Cyclophosphamide (CPA) Effect on Capecitabine Metabolism CPA 31

32 S0430 RIBBON-1 ( NJ Robert, ASCO 2009) RIBBON-2 (Brufsky, SABCS 2009) Thomas et al (J Clin Oncol 25: SOLTI (Baselga, SABCS 2009) S0430 CAPE Combinator Placebo/ Bevacizumab Placebo/ Bevacizumab Control/ Ixabeplione Placebo/ Sorafenib CPA # of pts206/40947/97377/375114/11596 Prior chemos % Excluded 100% Excluded 9%/7% 49%/48% 37%/41% 6%/5% 54%/43% 45%/57% Excluded 54% 32% 14% Excluded ER or PR + ER- PR-Her2- Her 2+ Unknown NR 49%/47% 26%/24% 14%/16% 11%/13% 68%/77% 29%/17% Excluded 3%/6% 56%? 37%? 6%? 1% Response23.6%/35.4%NR14%/35%30.7%/38.3%36% PFS (months)5.7/8.64.1/6.94.2/5.84.1/6.45.9

33 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

34 Patient case #2.B 53 year old diagnosed 2 years ago, Stage II ER-, PR-, Her-2 neu – Received AC-Taxol, lumpectomy and RT Presented with right upper quadrant pain. Recurrence detected in bone, liver and lymph nodes Biopsy confirmed same receptor profile Highly symptomatic, PS 2

35 Question In addition to symptom management, what would you recommend for this patient? –Single agent chemotherapy –Combination chemotherapy –Observation

36 Selection of chemotherapy agents in metastatic disease Patient characteristics –Prior therapy exposures (anthracycline, taxane) –Residual toxicity (neuropathy) –GI function (capecitabine) Patient preferences –Alopecia –Oral versus IV –Weekly versus q 3 weeks Tumor characteristics? –Are there any identifiers for chemotherapy response?

37 ASCO Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays Recommendation Category2004 and 2011 Recommendations Use of CSRAs The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Chemotherapy treatment decisions Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Future research:evaluating CSRAs in clinical trials Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority. JCO August 20, 2011 vol. 29 no

38 Treatment Duration Fixed chemotherapy length? How long?

39 Results of search strategy. Gennari A et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

40 Overall survival. Gennari A et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology

41 Progression-free survival. Gennari A et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology

42 June 26, New(er) Agents in Metastatic Breast Cancer

43 Locally recurrent or MBC 2-5 prior chemotherapies Progression ≤6 months of last chemotherapy Neuropathy ≤grade 2 ECOG ≤2 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Treatment of Physician’s Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only † Randomization 2:1 PFS ORR Safety Overall survival Primary endpoint Secondary endpoints EMBRACE study design Stratification: –Geographical region, prior capecitabine, HER2/neu status Global, randomized, open-label Phase III trial (Study 305) Patients (N=762) −≥2 for advanced disease −Prior anthracycline and taxane * Approved for treatment of cancer †Or palliative treatment or radiotherapy administered according to local practice, if applicable ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival; HER2/neu, human epidermal growth factor receptor 2

44 EMBRACE Design Features Strengths: –Heavily pre-treated patient population (median 4 prior regimens), a setting of clear unmet need –Treatment choices reflect real-world options –Large trial with “all comers” design –Powered to look for OS with two-sided log-rank test Limitations: –Not a blinded study –Patients in TPC arm could receive treatments they have been exposed to previously –If many patients elected BSC, then it becomes a trial of “1 vs 0” additional lines of therapy –Does schema invite investigator bias in considering subsequent lines of therapy beyond progression?

45 Overall survival (months) Survival probability Overall survival Eribulin Median months TPC Median months HR* 0.81 (95% CI 0.66, 0.99) p-value † = months TPC (n=254) Eribulin (n=508)53.9% 1 year survival 43.7% ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata † p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals

46 Does 3 rd Line Chemotherapy Palliate Refractory Breast Cancer?  3rd line chemotherapy:  30% had improvement in emotional status  34% had major improvement in HRQL scores  6% had objective clinical response  Tumor response correlated with more energy, diminished distress, and functional improvement  Not all “benefit” was seen in responders, and not all “responders” benefit McLachlan SA, Pintilie M, Tannock IF. Breast Cancer Res Treatment 1999;54:213

47 Clinical Trials are Often Appropriate PARP inhibitors Stem cell targeted agents –Notch pathway –Hedgehog pathway –CXCR1/2 MEK AKT/PI3K Other anti-angiogenic

48 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

49 % Probability of Progression Free Survival % 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 < Time from Baseline (Weeks) <5 CTC (n=114) ≥5 CTC (n=49) ~7-8 mos ~5-6 WEEKS First Followup

50 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

51 The Goals of “Active Therapy” Prolonged survival Relief of symptoms primarily by decreasing disease bulk Not cure in the vast majority of patients “To cure sometimes, to relieve often, to comfort always” - Anonymous

52 Palliative Care At some point, “active treatment” goals are unrealistic Drop the goal “prolongation of survival” Focus only on “relief” and “comfort” –Pain and symptom management –Family involvement/planning –Spiritual needs –May be best served by hospice 52

53 In memory of…. You can shed tears that she is gone, or you can smile because she has lived. You can close your eyes and pray that she'll come back, or you can open your eyes and see all she's left. Your heart can be empty because you can't see her, or you can be full of the love you shared. You can turn your back on tomorrow and live yesterday, or you can be happy for tomorrow because of yesterday. You can remember her only that she is gone, or you can cherish her memory and let it live on. You can cry and close your mind, be empty and turn your back. or you can do what she'd want: smile, open your eyes, love and go on. ---David Harkins 53


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