Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Oncology Grand Rounds Breast Cancer Nurse and Physician Investigators Discuss New Agents, Novel Therapies and Actual Cases from Practice Friday, April 29, 2016 6:00 AM – 7:30 AM Faculty Kimberly L Blackwell, MD Emily Olson, APRN, CNP, MSN Joyce O’Shaughnessy, MD Jennie Petruney, BSN, MSN, ANP Moderator Neil Love, MD Oncology Grand Rounds Series Oncology Grand Rounds: Themes • New agents and treatment strategies: Benefits and risks • Counseling patients about side effects – Practical implementation • End-of-life care • Psychosocial issues in patient care • Supporting the supporters • Job satisfaction and burnout in oncology professionals • The oncology professional just entering practice • The bond that heals Courtesy of Christiana Care Health System Initial Presentation of ATAC San Antonio Marriott Rivercenter, December 2001 Baum M, on behalf of the ATAC Trialists' Group. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in postmenopausal women. 24th Annual San Antonio Breast Cancer Symposium 2001;Abstract 8. Module 1: Neoadjuvant and Adjuvant Therapy for Patients with Localized HER2-Positive Breast Cancer Discussion Topics • Mechanisms of action of anti-HER2 agents • Side effects and toxicities of chemotherapy/antiHER2 agents and regimens • Neoadjuvant versus adjuvant treatment of HER2positive breast cancer • Patient education issues in the early HER2-positive setting • Ongoing and planned clinical trials incorporating novel HER2-directed therapies in the adjuvant and neoadjuvant settings Overview of Breast Cancer • Estimated number of new cases and deaths in 2016: – New cases = 249,260 – Deaths = 40,890 • Stage at diagnosis (Percent of patients who present with): – Localized disease = 60% – Regional disease = 33% – Metastatic disease = 5% – Unstaged disease = 2% • Five-year survival estimates (2006-2012) = 89.7% Cancer Facts and Figures 2016; American Cancer Society Surveillance Research 2011; SEER Stat Fact Sheet. Breast Cancer Stage Distribution at Diagnosis Metastatic 5% Regional 26% Locally Advanced 5% Local 64% DeSantis CE et al. CA Cancer J Clin 2016;66(1):31-42. Note: Distribution varies by race/ethnicity Distribution of Breast Cancer Subtypes HER2+ 14% TNBC 12% HR+/HER274% DeSantis CE et al. CA Cancer J Clin 2016;66(1):31-42. 35-Year-Old Woman with a ER/PR-Negative, HER2-Positive Breast Cancer (Ms Petruney) • Presented with a 7-cm, ER/PR-negative, HER2-positive breast mass • Enrolled in a trial of neoadjuvant trastuzumab/pertuzumab – Tumor progressed during treatment – Carboplatin/docetaxel added with excellent clinical response • Lumpectomy revealed a small focus of residual disease • Postoperative radiation therapy and adjuvant trastuzumab/pertuzumab • She has 3 young children • Experienced an episode of acute depression during the neoadjuvant therapy, which resolved Case discussion points (Ms Petruney) • What were some of the key patient education points that you addressed when the patient was started on neoadjuvant trastuzumab/pertuzumab? • What are the most common toxicity/tolerability issues with trastuzumab/pertuzumab? • How did the patient tolerate treatment with trastuzumab/pertuzumab? HER signaling: The network begins with the 4 HER receptors HER1/EGFR HER2 HER3 HER4 Rowinsky. Oncologist 2003;8(suppl 3):5-17; Yarden et al. Nat Rev Mol Cell Biol 2001;2:127-137. Pertuzumab and Trastuzumab: Mechanisms of Action Pertuzumab HER2 Trastuzumab Subdomain IV HER1/3/4 Dimerization domain Trastuzumab: • Inhibits ligand-independent HER2 signaling • Activates ADCC • Prevents HER2 ECD shedding Pertuzumab: • Inhibits ligand-dependent HER2 dimerization and signaling • Activates ADCC ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain Adapted from Harbeck N et al. Breast Care (Basel) 2013;8(1):49-55. Commonly Used Adjuvant and Neoadjuvant Regimens for HER2-Positive Breast Cancer Preferred Regimens • AC taxane-trastuzumab ± pertuzumab • TCH ± pertuzumab Other Regimens • Docetaxel-cyclophosphamide + trastuzumab • Paclitaxel + trastuzumab • FEC taxane + trastuzumab-pertuzumab • Trastuzumab-pertuzumab-taxane FEC NCCN Breast Cancer Guidelines v1.2016 Trastuzumab Emtansine (T-DM1): Mechanisms of Action Immune effector cell HER2 T-DM1 HER2 T-DM1 Inhibition of HER2 shedding Fcγ receptor Emtansine release Internalization Antibody-dependent cellular cytotoxicity (ADCC) P P P Inhibition of HER2 signaling Lysosome PI3K MAPK Nucleus Adapted from LoRusso PM et al. Clin Cancer Res 2011. Inhibition of microtubule polymerization Lapatinib: Mechanism of Action Ligands ErbB2 ErbB1/EGFR IGF-IR p95 ErbB2 Trastuzumab X X Cell proliferation Adapted from Vogel C et al. Jap J Clin Oncol 2010;40(11):999-1013. Would You Recommend Neoadjuvant Chemotherapy? (2.1-3.0 cm tumor) Love N et al. SABCS 2015;Abstract P1-14-20. Module 2: Management of Metastatic HER2-Positive Breast Cancer Discussion Topics • Common systemic regimens used in metastatic HER2-positive breast cancer: – Treatment schedules – Efficacy – Side effects and toxicities – Patient education issues • Integration of endocrine treatment into the management of “triple-positive” breast cancer Discussion Topics • Indications for rebiopsy, variations in HER2 and ER assay results • Diagnosis and management of CNS metastases in HER2-positive breast cancer • New agents and treatment strategies in metastatic HER2-positive breast cancer 75-Year-Old Woman with a ER/PR-Negative, HER2Positive Metastatic Breast Cancer (Ms Olson) • 4/2014: Diagnosed with ER/PR-negative, HER2-positive breast cancer and metastases in the lung and adrenal glands • Docetaxel/pertuzumab/trastuzumab – Hospitalized twice with colitis – Continued dual anti-HER2 therapy • 12/2015: Brain metastases, progressive lung lesions • Lives independently with a supportive husband, 2 grown children • Continues to travel countrywide Response to Docetaxel-TrastuzumabPertuzumab (THP) in the Lung Prior to THP PR after 4 cycles of THP CLEOPATRA Study • Centrally confirmed HER2+ locally recurrent, unresectable or metastatic BC (MBC) • ≤1 hormonal regimen for MBC • Prior (neo)adjuvant systemic rx, incl chemotherapy ± trastuzumab allowed if followed by DFS ≥ 12 mo • Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab N = 406 R 1:1 N = 402 Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab Trastuzumab: 8 mg/kg loading dose 6 mg/kg every 3 weeks until disease progression Docetaxel: 75 mg/m2 every 3 weeks (increased to 100 mg/m2 at investigator discretion) Pertuzumab: 840 mg loading dose 420 mg every 3 weeks until disease progression Baselga J et al. N Engl J Med 2012;366(2):109-19; Swain S et al. SABCS 2012;Abstract P5-1826. CLEOPATRA: Response and Survival Analyses Endpoint Pertuzumab + T + D Placebo + T + D Median OS 56.5 mo 40.8 mo Median PFS 18.5 mo 12.4 mo 80.2% 69.3% ORR Baselga J et al. N Engl J Med 2012;366(2):109-19; Swain SM et al. Lancet Oncol 2013;14(6):46171. Overall Survival (%) CLEOPATRA: Overall Survival Pertuzumab, 168 events Median OS Pertuzumab (n = 402) 56.5 mo Control (n = 406) 40.8 mo Hazard ratio: 0.68, p < 0.001 Months Swain SM et al. N Engl J Med 2015;372(8):724-34. Control, 221 events Progressive Pulmonary Mass CNS and Pulmonary Metastases MRI of CNS mets After completion of WBRT Phase III EMILIA Study HER2-positive LABC or MBC (N = 991) • Prior taxane and trastuzumab • Progression on metastatic treatment or within 6 months of adjuvant treatment T-DM1 PD 3.6 mg/kg q3w IV 1:1 Capecitabine 1,000 mg/m2 PO BID, days 1–14, q3w + PD Lapatinib 1,250 mg/day PO qd T-DM1 (n = 495) Cape-lapatinib (n = 496) Median OS 30.9 mo 25.1 mo Median PFS 9.6 mo 6.4 mo Verma S et al. N Engl J Med 2012;367(19):1783-91. EMILIA: Overall Survival Median No. of Months Lapatinib-capecitabine (n = 496) 25.1 T-DM1 (n = 495) 30.9 Overall Survival (%) 85.2% Stratified hazard ratio, 0.68 p < 0.001 64.7% 78.4% T-DM1 51.8% Lapatinib-capecitabine Months Verma S et al. N Engl J Med 2012;367(19):1783-91. Case discussion points (Ms Olson) • What type of end-of-life planning, if any, have you discussed with the patient? • How did you respond when she inquired about physician-assisted death? Module 3: Management of ER-Positive, HER2-Negative Breast Cancer Discussion Topics • Use of genomic assays to determine the need for chemotherapy and duration of adjuvant endocrine therapy • Delayed recurrence in this disease subtype; use of pseudoadjuvant therapy for patients with local recurrence • Mechanisms of action, efficacy and tolerability issues: – Endocrine agents – mTOR inhibitors – CDK4/6 inhibitors • Key factors in selecting first-line systemic treatment for metastatic disease: Chemotherapy versus endocrine therapy • Clinical factors affecting the sequencing of therapies in the metastatic setting 45-Year-Old Woman with a ER/PR-Positive, HER2-Negative Metastatic Breast Cancer (Ms Olson) • 2005: Diagnosed with ER/PR-positive, HER2-negative breast cancer (premenopausal) – Adjuvant tamoxifen x 5 years • 2015: Pelvic bone pain – Bone scan: Diffuse uptake suggesting metastatic disease – Biopsy: ER/PR-positive, HER2-negative recurrence • Bilateral oophorectomy • Letrozole/palbociclib/zoledronic acid – Clinical complete response within 3 months, which continues currently • Mother of 3 teenagers, continues to work and is experiencing a high level of anxiety about her life situation PET/CT of Bone Metastases Baseline PET/CT: New mets 3 months after letrozole-palbociclib Annual Hazard Rates of Recurrence for Breast Cancer by ER Status Recurrence Hazard Rate 0.3 ER-negative ER-positive 0.2 0.1 0 0 2 4 6 Years Saphner T et al. J Clin Oncol 1996;14(10):2738-46. 8 10 12 Progression-Free Survival (Investigator Assessed): Palbociclib-Fulvestrant versus Placebo-Fulvestrant Hazard ratio, 0.42 P < 0.001 Palbociclib-fulvestrant (N = 347) Median progression-free survival, 9.2 mo Placebo-fulvestrant (N = 174) Median progression-free survival, 3.8 mo Turner NC et al. Proc ASCO 2015;Abstract LBA502. NEJM 2015;373(3):209. Key Toxicities Associated with PalbociclibFulvestrant Palbociclib + Fulvestrant (n = 345) AE Any Grade Grade 3 Grade 4 Placebo + Fulvestrant (n = 172) Any Grade Grade 3 Grade 4 Neutropenia 79% 53% 9% 4% 0% <1% Leukopenia 46% 25% <1% 4% 0% <1% Turner NC et al. Proc ASCO 2015;Abstract LBA502. NEJM 2015;373(3):209-19. Abemaciclib Monotherapy in Advanced or Metastatic Breast Cancer 100 Change in tumor size at best response % Change from Baseline 80 60 40 * ORR (all): 12/47 (25.5%) ORR (HR+): 12/36 (33.3%) ORR (HR-): 0/9 (0%) * 20 * 0 * * * * † -20 * † * * † * * † -40 -60 -80 HR status Negative -100 Positive Unknown * † * * * † †† † 3 nonevaluable patients are not shown. All patients were required to have measurable disease. † Patient progressing on endocrine therapy before study entry and continued on that specific therapy * Indicates HER2+ Tolaney SM et al. SABCS 2014;Abstract 763. † Best Change in Tumor Size from Baseline with Abemaciclib Combined with Other Therapies Part A letrozole Part B anastrozole Part C tamoxifen Change from baseline (%) * Part D exemestane Part E exemestane + everolimus 20% increase 30% decrease Patients * For this patient, change in tumor size is greater than 100%. Tolaney SM et al. Proc ASCO 2015;Abstract 522. MONARCH 3: Phase III Study of First-Line Abemaciclib with a Nonsteroidal Aromatase Inhibitor (NSAI) Postmenopausal women with HR+, HER2- locoregionally recurrent or metastatic breast cancer with disease-free interval >12 mo following (neo)adjuvant ET or presenting de novo with metastatic disease (N = 450) Abemaciclib + NSAI until PD R 2:1 Placebo + NSAI until PD Primary endpoint: Progression-free survival (PFS) Stratification Factors: • Nature of disease (visceral metastases versus bone-only metastases versus other) • Prior (neo)adjuvant endocrine therapy (AI therapy versus other versus no prior endocrine therapy) Goetz MP et al. Proc ASCO 2015;Abstract TPS624. Clinicaltrials.gov; NCT02246621 72-Year-Old Woman with HR-Positive, HER2-Negative Metastatic Breast Cancer (Ms Petruney) • 1981: Mastectomy for early breast cancer • 2009: HR-positive, HER2-negative recurrence, primarily in bone – Exemestane/zoledronic acid (ZDA) x 2 years – Fulvestrant/ZDA x 15 months – Tamoxifen/everolimus/ZDA x 3+ years disease progression – Letrozole x 3 months disease progression – Nab paclitaxel every 3 weeks with very poor tolerance • PET scan showed significant improvement • Continued at 50% dose reduction — just completed 5th cycle with very good tolerance • Now able to participate fully in activities of daily living Package inserts for ipilimumab, nivolumab, pembrolizumab (4/2016) Case discussion points (Ms Olson) • In general, what are some of the key patient education points that you address when a patient with ER-positive metastatic breast cancer is starting on everolimus? • What are the most common toxicity/tolerability issues with everolimus? • In general, what is your approach to prevention and management of mucositis associated with everolimus? Crosstalk between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition EGFR HER2 E P P E RAS PI3K PTEN RAF E AKT ER MEK MAPK mTOR E E ER ER • mTOR activates ER in a ligand-independent manner • Estradiol suppresses apoptosis induced by mTOR blockade • Hyperactivation of the mTOR pathway is observed in endocrine therapy–resistant breast cancer cells • mTOR is a rational target to enhance the efficacy of hormonal therapy ER target gene transcription Adapted from: Di Cosimo S, Baselga J. Nat Rev Clin Oncol 2010;7:139-47. BOLERO-2: PFS with Exemestane-Everolimus in HR-Positive Advanced Breast Cancer Probability of Event (%) Hazard ratio, 0.36 p < 0.001 Everolimus plus exemestane median PFS, 10.6 mo Placebo plus exemestane median PFS, 4.1 mo Weeks Baselga J et al. N Engl J Med 2012;366(6):520-9. Case discussion points (Ms Petruney) • In general, what are some of the key patient education points that you address when a patient with breast cancer is starting on docetaxel or nab paclitaxel? • What are the most common toxicity/tolerability issues with these agents? • In general, how do you explain the difference between nab paclitaxel and the other taxanes? Module 4: Management of Triple-Negative Breast Cancer (TNBC) Discussion Topics • Global rationale for neoadjuvant treatment of breast cancer: Potential advantages in local tumor control • Role of platinum-based neoadjuvant treatment in TNBC • Common treatment sequences in metastatic TNBC • New approaches to TNBC: – Androgen receptor assays and antiandrogens – BRCA, BRCAness and the rationale for PARP inhibitors – Anti-PD-1/PD-L1 checkpoint inhibitors in TNBC – Genomic assays for patients who have received all approved therapies 54-Year-Old Oncology Infusion Nurse with TripleNegative Early Breast Cancer (Ms Petruney) • Presented with a large breast mass and positive axillary nodes – Biopsy: ER/PR-negative, HER2-negative infiltrating ductal carcinoma • Clinical trial: Neoadjuvant paclitaxel/carboplatin followed by AC • Mastectomy: Small focus of DCIS, no evidence of invasive cancer • Axillary node dissection and postoperative radiation therapy • Currently 3 years out and faring well • Greatly affected by her experience as an oncology nurse • Quit work and is travelling the country with her husband • Places a high value on experiencing life Novel Treatment Approaches to TNBC • Androgen receptor assays and antiandrogens • BRCA, BRCAness and the rationale for PARP inhibitors • Anti-PD-1/PD-L1 checkpoint inhibitors in TNBC • Genomic assays for patients who have received all approved therapies MDV3100-11: Clinical Benefit According to PREDICT AR PREDICT AR- PREDICT AR+ PREDICT AR- PREDICT AR+ Total, n (%) 62 (53%) 56 (47%) CBR16, % n 11% n=7 39% n = 22 CBR24, % n 6% n=4 36% n = 20 CR or PR, % n 3% n=2 9% n=5 Median PFS (ITT) 8.1 wks 16.1 wks n n = 62 n = 56 Time (weeks) 0-1 prior lines 2+ prior lines Active Confirmed CR or PR Time (weeks) CR, complete response; PR, partial response; PFS, progression-free survival; CBR, clinical benefit rate Traina TA et al. Proc ASCO 2015;Abstract 1003. OLYMPIA Study Design Tutt NJ et al. Proc ASCO 2015;Abstract TPS1109. Change form Baseline in Sum of Longest Diameter of Target Lesion, % Pembrolizumab in TNBC: ORR (N = 27) and Maximum Percentage Change from Baseline in Target Lesions (N = 23) Confirmed complete response (nodal disease) Confirmed partial response Stable disease Progressive disease ORR = 18.5% Nanda R et al. SABCS 2014;Abstract S1-09.