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Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Breast Cancer Friday, November 12, 2010 6:00 AM – 7:30 AM Peabody Orlando Hotel Moderator Neil Love, MD Faculty Kimberly L Blackwell, MD Una Hopkins, MSN, FNP-BC Georgia Litsas, MSN, ANP-BC, AOCNP Ruth O’Regan, MD Copyright © 2011 Research To Practice. All rights reserved. Agenda Module 1 Treatment of HER2-Positive Breast Cancer in the Adjuvant and Metastatic Settings: Ms Litsas Module 2 Sequential Approaches for Patients with Advanced ER-Positive, HER2-Negative Disease: Ms Hopkins Module 3 Treatment Options for Patients with Triple-Negative Breast Cancer (TNBC): Ms Litsas Module 4 Evolving Clinical Research Strategies for Patients with Advanced ER-Positive, HER2-Negative Breast Cancer: Ms Hopkins Panel Discussion and Response to Audience Questions Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. National Patterns of Care Study in Breast Cancer • Launched October 2010 • 100 US-based community oncologists surveyed • Proportion of patients/office visits with breast cancer: 30% (median) • New patients with breast cancer seen per month: 15 (median) Patterns of Care in Breast Cancer, Research To Practice 2010. Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Breast Cancer Friday, November 12, 2010 6:00 AM – 7:30 AM Peabody Orlando Hotel Moderator Neil Love, MD Faculty Kimberly L Blackwell, MD Una Hopkins, MSN, FNP-BC Georgia Litsas, MSN, ANP-BC, AOCNP Ruth O’Regan, MD Copyright © 2011 Research To Practice. All rights reserved. Case 1 (Ms Litsas) A 64-year-old woman was diagnosed in 2003 with an ER-negative, HER2-positive, node-positive invasive ductal carcinoma (IDC) and received adjuvant chemotherapy. In 2006, metastases were diagnosed and since then the patient has received a series of regimens, including anti-HER2 agents and chemotherapy, both on and off protocol. Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. In addition to endocrine treatment what do you generally recommend as adjuvant therapy for a 60-year-old woman with an ER-positive, HER2-positive tumor and one positive node? TCH (docetaxel, carboplatin, trastuzumab) 55% AC-TH (anthracycline + cyclophosphamide + taxane + trastuzumab) 38% TC (docetaxel + cyclophosphamide) + trastuzumab Paclitaxel + trastuzumab 5% 2% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. In addition to endocrine treatment what do you generally recommend as adjuvant therapy for a 75-year-old woman with an ER-positive, HER2-positive tumor and one positive node? TCH (docetaxel, carboplatin, trastuzumab) 56% TC (docetaxel + cyclophosphamide) + trastuzumab 18% AC-TH (anthracycline + cyclophosphamide + taxane + trastuzumab) 9% Paclitaxel + trastuzumab 9% Other 8% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. In addition to endocrine treatment what do you generally recommend as adjuvant therapy for a 60-year-old woman with a 0.8-cm, node-negative, ER-positive, HER2-positive tumor? TCH (docetaxel + carboplatin + trastuzumab) 56% TC (docetaxel + cyclophosphamide) + trastuzumab 14% AC-TH (anthracycline + cyclophosphamide + taxane + trastuzumab) 8% 7% Trastuzumab alone Paclitaxel + trastuzumab None 4% 6% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. In general what treatment do you recommend for a 60-year-old patient with an ER-positive, HER2-positive tumor who received adjuvant chemotherapy/trastuzumab and endocrine treatment but develops disease relapse six months after finishing adjuvant trastuzumab? 36% Lapatinib + chemotherapy 21% Lapatinib + endocrine therapy 16% Trastuzumab + chemotherapy Trastuzumab + endocrine therapy 13% Lapatinib alone 5% Lapatinib + trastuzumab + chemotherapy 5% Other 4% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. In general what treatment do you recommend for a 60-year-old patient with an ER-positive, HER2-positive tumor who received adjuvant chemotherapy/trastuzumab and endocrine treatment but develops disease relapse 18 months after finishing adjuvant trastuzumab? 40% Trastuzumab + chemotherapy Trastuzumab + endocrine therapy 28% 15% Lapatinib + chemotherapy 6% Lapatinib + endocrine therapy Trastuzumab alone 3% Lapatinib alone 3% Other 5% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. Breast Cancer Subtypes (Luminal B subtype) (TNBC aka basal-like subtype) (HER2+ subtype) (Luminal A subtype) (Assumptions: ER+ 75%a; HER2+ 20%b) aLi CI et al. J Clin Oncol 2003;21:28-34. H et al. JAMA 2004;29(16):1972-77. bYaziji Copyright © 2011 Research To Practice. All rights reserved. Signal Transduction by the HER Family Promotes Proliferation, Survival and Invasiveness Receptor specific ligands HER2 HER2 HER4 HER1, HER2, HER3, or HER4 HER3 VEGF HER1 (EGFR) Plasma membrane P PI3K Tyrosine kinase domains Akt SOS P RAS MAP K Cytoplasm P P RAF MEK Cell proliferation Cell survival Cell mobility and invasiveness Nucleus Copyright © 2011 Research To Practice. All rights reserved. Transcription 20 Ongoing Adjuvant Phase III Trials for Patients with HER2-Positive Early BC Protocol ID: ALTTO; Accrual: 8,000 Trastuzumab q3wk x 52 wk R Lapatinib daily x 52 wk Trastuzumab qwk x 12 6-wk washout lapatinib daily x 34 wk Lapatinib daily + trastuzumab q3wk x 52 wk Protocol ID: BETH; Accrual: 3,500 R TCH* or (TH FEC†) H to complete 1 year TCHB* or (THB FEC†) HB to complete 1 year H = trastuzumab; L = lapatinib; T = docetaxel; C = carboplatin; F = 5-FU; E = epirubicin; C† = cyclophosphamide; B = bevacizumab * Chemotherapy used by NSABP/CIRG investigators (Cohort 1) † Chemotherapy used by independent investigators (Cohort 2) NCI Physician Data Query, November 2010; www.breastinternationalgroup.org; www.alttotrials.com. Copyright © 2011 Research To Practice. All rights reserved. Blackwell KL et al. J Clin Oncol 2010;28(7):1124-30. Copyright © 2011 Research To Practice. All rights reserved. Lapatinib (L) with or without Trastuzumab (T) for Heavily Pretreated mBC Following Disease Progression on T-Containing Therapy Parameter Median progression-free survival (PFS) Median overall survival (OS) Clinical benefit rate Clinical benefit rate L (n = 145) L+T (n = 146) Hazard Ratio p-value 8.1 wk 12.0 wk 0.73 0.008 39.0 wk 51.6 wk 0.75 0.106 12.4% 12.4% 24.7% 24.7% Blackwell KL et al. J Clin Oncol 2010;28(7):1124-30. -- — 0.01 0.01 Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential for a patient with breast cancer about to begin treatment with…. lapatinib- and/or trastuzumab-based therapy Copyright © 2011 Research To Practice. All rights reserved. Efficacy and Safety of Trastuzumab-DM1 vs Trastuzumab Plus Docetaxel in HER2Positive Metastatic Breast Cancer Patients with No Prior Chemotherapy for Metastatic Disease: Preliminary Results of a Randomized, Multicenter, OpenLabel Phase 2 Study (TDM4450G) Perez EA et al. Proc ESMO 2010;Abstract LBA3. Copyright © 2011 Research To Practice. All rights reserved. T-DM1 versus Trastuzumab (T) + Docetaxel (D) in HER2-Positive mBC with No Prior Chemotherapy for mBC T-DM1 (n = 67) T+D (n = 70) 47.8% 41.4% 37.3% 75.0% Efficacy Summary* Overall response rate (ORR) Safety Summary Grade ≥ 3 adverse event (AE)† †Most common AEs, any grade, T+D: Alopecia: 66.2%, neutropenia: 57.4%, diarrhea: 45.6% — 1.5%, 7.5% and 10.4% in pts receiving T-DM1. †Most common AEs, any grade, T-DM1: Nausea: 47.8%, fatigue: 46.3%, pyrexia: 35.8% — 39.7%, 46.2% and 20.6% in pts receiving T+D. Perez AE et al. Proc ESMO 2010;Abstract LBA3. Copyright © 2011 Research To Practice. All rights reserved. Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Breast Cancer Friday, November 12, 2010 6:00 AM – 7:30 AM Peabody Orlando Hotel Moderator Neil Love, MD Faculty Kimberly L Blackwell, MD Una Hopkins, MSN, FNP-BC Georgia Litsas, MSN, ANP-BC, AOCNP Ruth O’Regan, MD Copyright © 2011 Research To Practice. All rights reserved. Case 2 (Ms Hopkins) A 58-year-old woman was diagnosed in 1992 with an ER-positive, HER2-negative, node-positive IDC and received CMF followed by five years of adjuvant tamoxifen. In 2001 metastases were diagnosed and the patient received several endocrine agents in sequence followed by a sequence of single agents alone or with bevacizumab. Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. Do you generally obtain biopsies for patients who develop metastatic disease after receiving adjuvant chemotherapy for breast cancer? 74% Yes 56% 18% It’s optional but not necessary No 60 years 30% 75 years 8% 14% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. Breast Cancer Subtypes (Luminal B subtype) (TNBC aka basal-like subtype) (HER2+ subtype) (Luminal A subtype) (Assumptions: ER+ 75%a; HER2+ 20%b) aLi CI et al. J Clin Oncol 2003;21:28-34. H et al. JAMA 2004;29(16):1972-77. bYaziji Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. In general what endocrine treatment do you recommend for a postmenopausal woman who develops metastases? Fulvestrant 47% Exemestane Letrozole Tamoxifen 27% 14% 12% Patterns of Care Survey of US-Based Practicing Oncologists (n = 99) Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential for a patient with breast cancer about to begin treatment with…. fulvestrant Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential for a patient with breast cancer about to begin treatment with…. fulvestrant Copyright © 2011 Research To Practice. All rights reserved. Di Leo A et al. J Clin Oncol 2010;28(30):4594-600. Copyright © 2011 Research To Practice. All rights reserved. Proportion of Patients Alive Proportion of Patients Progression Free CONFIRM Trial Results Time (months) Objective Response and Clinical Benefit Time (months) Fulvestrant 500 mg (n=362) Fulvestrant 250 mg (n=374) Objective response 9.1% 10.2% Complete response 1.1% 0.3% Clinical benefit 45.6% 39.6% Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved. Di Leo A et al. J Clin Oncol 2010;28:4594-600. Copyright © 2011 Research To Practice. All rights reserved. Case 2 (Ms Hopkins) A 58-year-old woman was diagnosed in 1992 with an ER-positive, HER2-negative, node-positive IDC and received CMF followed by five years of adjuvant tamoxifen. In 2001 metastases were diagnosed and the patient received several endocrine agents in sequence followed by a sequence of single agents alone or with bevacizumab. Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential for a patient with breast cancer about to begin treatment with…. paclitaxel/bevacizumab Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. Overview of Efficacy Results from Individual Studies E2100 Median PFS (months) RIBBON-1 (Capecitabine) AVADO NonBV BV 5.8 11.3 Non-BV BV1 Non-BV 7.9 8.8 5.7 RIBBON-1 (Taxane, Anthra) BV NonBV BV 8.6 8.0 9.2 Hazard Ratio 0.48 0.62 0.69 0.64 p-value <0.0001 0.0003 0.0002 <0.0001 Anthra = Anthracycline 1 Bevacizumab 15 mg/kg data O’Shaughnessy J et al. Proc ASCO 2010. Abstract 1005. Copyright © 2011 Research To Practice. All rights reserved. O’Shaughnessy J et al. Proc ASCO 2010. Abstract 1005. Copyright © 2011 Research To Practice. All rights reserved. Meta-Analysis of Three Studies of Bevacizumab-Containing FirstLine Therapy in Breast Cancer: E2100, AVADO, RIBBON-1 Non-BV (n = 1,008) BV (n = 1,439) Hazard Ratio p-value PFS (in months) 6.7 9.2 0.64 <0.0001 OS (in months) 26.4 26.7 0.97 0.560 1-year survival 77% 82% 0.003 O’Shaughnessy J et al. Proc ASCO 2010. Abstract 1005. Copyright © 2011 Research To Practice. All rights reserved. Percent of Grade >3 Selected Adverse Events: Pooled Population from Phase III Studies Non-BV (n = 982) BV (n = 1679) Neutropenia 7.1 10.0 Sensory neuropathy 8.5 9.5 Hypertension 1.2 9.0 Febrile neutropenia 3.5 6.5 Venous thromboembolic event 3.8 2.8 0 2.3 0.3 1.6 0 <0.1 Proteinuria Arterial thromboembolic event RPLS O’Shaughnessy J et al. Proc ASCO 2010. Abstract 1005. Copyright © 2011 Research To Practice. All rights reserved. What patient education information do you consider essential for a patient with breast cancer about to begin treatment with…. capecitabine Copyright © 2011 Research To Practice. All rights reserved. Case 3 (Ms Litsas) A 73-year-old woman diagnosed in early 2010 with de novo metastatic TNBC consents to participation in the CALGB40502 clinical trial of bevacizumab with paclitaxel, nab paclitaxel or ixabepilone. Copyright © 2011 Research To Practice. All rights reserved. Estimated New Cancer Cases per Year in the US Estimated New Cases Breast Triple-negative subset1 209,060 ~31,359 Pancreas 43,140 CNS 22,020 Ovarian 21,880 Gastric 21,000 Multiple myeloma 20,180 Hodgkin lymphoma 8,490 Chronic myeloid leukemia 4,870 1 Value estimated by multiplying the number of new breast cancer cases by reported 15% incidence (Stead, Breast Cancer Res 2009) of TNBC. Jemal A et al. CA Cancer J Clin 2010;60(5):277-300. Copyright © 2011 Research To Practice. All rights reserved. Comparison of Subgroup Analyses of PFS from Three Phase III Studies of Bevacizumab in Combination with Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer O’Shaughnessy J et al. Proc SABCS 2009;Abstract 207. Copyright © 2011 Research To Practice. All rights reserved. Improvement in PFS for Patient Subgroups with Addition of Bevacizumab (B) in E2100, AVADO and RIBBON-1 Improvement in PFS (mos) E2100 (n = 722) AVADO* (n = 736) RIBBON-1† (n = 1,237) Overall 5.5 0.8, 0.9 2.9, 1.2 Triple-negative 5.3 0.8, 2.8 1.9, 0.3 Neoadjuvant/adjuvant taxane 7.3 4.2, 1.9 4.5, 2.4 Age ≥ 65 4.3 0.8, 0.8 2.9, 1.6 Patient Subgroup * B 7.5 mg/kg; 15 mg/kg. † Capecitabine/B; Taxane/anthracycline/B O’Shaughnessy J et al. Proc SABCS 2009;Abstract 207. Copyright © 2011 Research To Practice. All rights reserved. Synthetic Lethality — The Principle Chang J. TNBC 101 Research To Practice Webinar, 2010. Copyright © 2011 Research To Practice. All rights reserved. Final Efficacy and Safety Results of a Randomized Phase II Study of the PARP Inhibitor Iniparib (BSI-201) in Combination with Gemcitabine/ Carboplatin (G/C) in Metastatic Triple Negative Breast Cancer (TNBC) O’Shaughnessy J et al. Proc ESMO 2010;Abstract LBA11. Copyright © 2011 Research To Practice. All rights reserved. Final Efficacy Results of the Phase II Trial of Iniparib (BSI-201) Plus Gemcitabine/ Carboplatin for Patients with mTNBC Gem/Carbo (n = 62) Iniparib/Gem/Carbo (n = 61) p-value* Objective response rate 32.3% 52.5% 0.023 Clinical benefit rate 33.9% 55.7% 0.015 Median PFS 3.6 mos 5.9 mos 0.012 Median OS 7.7 mos 12.3 mos 0.014 Clinical Variable * Not adjusted for multiple interim analyses. O’Shaughnessy J et al. Proc ESMO 2010;Abstract LBA11. Copyright © 2011 Research To Practice. All rights reserved. Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Breast Cancer Friday, November 12, 2010 6:00 AM – 7:30 AM Peabody Orlando Hotel Moderator Neil Love, MD Faculty Kimberly L Blackwell, MD Una Hopkins, MSN, FNP-BC Georgia Litsas, MSN, ANP-BC, AOCNP Ruth O’Regan, MD Copyright © 2011 Research To Practice. All rights reserved. Case 4 (Ms Hopkins) A 61-year-old woman with de novo metastatic ER-positive, HER2-negative breast cancer participates for more than a year on the CALGB-40503 clinical trial of letrozole with or without bevacizumab. Copyright © 2011 Research To Practice. All rights reserved. CALGB-40503: Phase III Study of Endocrine Therapy with or without Bevacizumab for ER-/PR-Positive Advanced Breast Cancer Eligibility: Inoperable locally advanced or metastatic ER-positive and/or PR-postitive breast cancer; no prior anti-VEGF or VEGFR TKI therapy Tamoxifen or letrozole + bevacizumab q 21 days R Tamoxifen or letrozole + placebo q 21 days www.ClinicalTrials.gov, November 2010. Copyright © 2011 Research To Practice. All rights reserved. Case 4 (Ms Hopkins) A 61-year-old woman with de novo metastatic ER-positive, HER2-negative breast cancer participates for more than a year on the CALGB-40503 clinical trial of letrozole with or without bevacizumab. Copyright © 2011 Research To Practice. All rights reserved. Case 2 (Ms Hopkins) A 58-year-old woman was diagnosed in 1992 with an ER-positive, HER2-negative, node-positive IDC and received CMF followed by five years of adjuvant tamoxifen. In 2001 metastases were diagnosed and the patient received several endocrine agents in sequence followed by a sequence of single agents alone or with bevacizumab. Copyright © 2011 Research To Practice. All rights reserved. Case 1 (Ms Litsas) A 64-year-old woman was diagnosed in 2003 with an ER-negative, HER2-positive, node-positive invasive ductal carcinoma (IDC) and received adjuvant chemotherapy. In 2006, metastases were diagnosed and since then the patient has received a series of regimens, including anti-HER2 agents and chemotherapy, both on and off protocol. Copyright © 2011 Research To Practice. All rights reserved. Copyright © 2011 Research To Practice. All rights reserved. Meet The Professors Oncologist and Nurse Investigators Consult on Challenging Patient Cases in Breast Cancer Friday, November 12, 2010 6:00 AM – 7:30 AM Peabody Orlando Hotel Moderator Neil Love, MD Faculty Kimberly L Blackwell, MD Una Hopkins, MSN, FNP-BC Georgia Litsas, MSN, ANP-BC, AOCNP Ruth O’Regan, MD Copyright © 2011 Research To Practice. All rights reserved.