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Challenging Cases in Breast CancerOncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited FacultyThursday, May 1, 20146:00 AM – 7:30 AM Faculty Adam M Brufsky, MD Denise A Yardley, MD Joan M Armstrong, MSN, APRN-BC Emily Olson, RN, CNP ModeratorNeil Love, MD
Oncology 6-Part Case Series: Key Themes • Mechanisms of action of novel agents and tissue assays to predict response • Side effects and toxicities of novel agents; dose adjustments • Assessment and management of adherence • Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease • Local and systemic complications of cancer: Fatigue, pain, CNS involvement • Care of older, frail patients and those with comorbidities
Oncology 6-Part Case Series: Key Themes • Clinical trials as a means to access new treatments earlier • Management of anxiety and depression • Key determinants of patient satisfaction: What do people with cancer want and need? • Quality, value and cost: Investing resources optimally • End-of-life care and planning • Impact of the cancer experience on family and loved ones, including minor children • Impact of the oncology experience on oncology health professionals
Agenda A Patient with a Recent Myocardial Infarction and Locally Advanced ER/PR-Negative, HER2-Positive Breast Cancer • 53 yo unemployed single mother of 4 children with inflammatory breast cancer and a complicated history (Ms Olson) A Patient with Widespread Triple-Negative Metastatic Breast Cancer (mBC) and Bone Marrow Involvement • 67 yo with mBC and persistent low blood counts (Ms Olson)
Agenda Two Patients with HER2-Positive mBC • 62 yo with bone and liver metastases who subsequently develops brain metastases (Ms Armstrong) • 55 yo with bilateral pulmonary metastases (Ms Olson) Two patients with ER/PR-positive, HER2-negative mBC • 84 yo with bilateral pleural effusions requiring several thoracenteses(Ms Armstrong) • 61 yo with mBC who speaks no English (Ms Armstrong)
Case 1 (from the practice of Ms Olson) • A 53-year-old unemployed single mother of 4 children experienced a myocardial infarction 4 months before presenting with a 6.7-cm, inflammatory, ER/PR-negative, HER2-positive breast cancer • After a cardiology consultation she received TCH (docetaxel, carboplatin and trastuzumab) and experienced a complete clinical response • Mastectomy revealed a pathologic complete response in the breast, but 1 lymph node contained residual disease • She received trastuzumab to complete 1 year of treatment (February 2014) • Her history includes treatment for depression and extensive alcohol and tobacco use for which she is seeking treatment
Discussion Point Long-term outcomes for patients with inflammatory breast cancer
Discussion Point First-ever FDA approval of a neoadjuvant therapy of breast cancer (pertuzumab/trastuzumab/chemotherapy)
Pertuzumab and Trastuzumab: Mechanisms of Action Pertuzumab HER2 HER1/3/4 Trastuzumab Dimerization domain Subdomain IV • 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
FDA News ReleaseSeptember 30, 2013 • The US Food and Drug Administration today granted accelerated approval to pertuzumab as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting). Pertuzumab is the first FDA-approved drug for the neoadjuvant treatment of breast cancer. www.fda.gov/newsevents/newsroom/pressannouncements/ucm370393.htm
NeoSphere: Study Design TH (n = 107) Docetaxel + Trastuzumab SURGERY FEC q3wk x 3 Trastuzumab q3wk, cycles 5-17 Patients with operable or locally advanced/ inflammatory HER2-positive breast cancer THP (n = 107) Docetaxel + Trastuzumab +Pertuzumab FEC q3wk x 3 Trastuzumab q3wk, cycles 5-17 HP (n = 107) Trastuzumab +Pertuzumab Docetaxel q3wk x 4 → FEC q3wk x 3 Trastuzumab q3wk, cycles 5-17 Chemonaive and primary tumors >2 cm (N = 417) TP (n = 96) Docetaxel +Pertuzumab FEC q3wk x 3 Trastuzumab q3wk, cycles 5-21 Study dosing q3wk x 3 FEC = 5-fluorouracil, epirubicin and cyclophosphamideLocally advanced = T2-3, N2-3, M0 or T4a-C, any N, M0; operable = T2-3, N0-1, M0; inflammatory = T4d, any N, M0 Gianni L et al. Lancet Oncol 2012;13(1):25-32.
NeoSphere: pCR and Hormone Receptor Status pCR (% ± 95% CI) pCR = pathologic complete response; H = trastuzumab; P = pertuzumab; T = docetaxel Gianni L et al. Lancet Oncol 2012;13(1):25-32.
APHINITY: A Phase III Adjuvant Study Design R Target accrual: 4,806 Chemotherapy Trastuzumab x 1 yr Pertuzumab x 1 yr Resected HER2+ BC Node+ (except T0) Baseline LVEG ≥55% Chemotherapy Trastuzumab x 1 yr Placebo x 1 yr Primary endpoint: Invasive disease-free survival www.clinicaltrials.gov www.ibcsg.org ClinicalTrials.gov Identifer: NCT01358877
NCCN Breast Cancer Clinical Practice Guidelines – v3.2014 “A pertuzumab-containing regimen can be administered to patients with ≥T2 or ≥N1, HER2-positive, early-stage breast cancer.” “Patients who have not received a neoadjuvant pertuzumab-containing regimen can receive adjuvant pertuzumab.”
Discussion Point Adjuvant therapy for node-negative, HER2-positive disease: Clinical trial findings with trastuzumab/paclitaxel
Adjuvant Paclitaxel and Trastuzumab for Node-Negative HER2+ Breast Cancer Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo H, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP SABCS 2013;Abstract S1-04.
Phase II Study Design(APT Trial) HER2+ ER+ or ER- Node negative <3 cm Enroll P P P P P P P P P P P P T T T T T T T T T T T T PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12 Planned N = 400 T T T T T T T T T T T T T FOLLOWED BY 13 EVERY 3-WEEK DOSES OF TRASTUZUMAB (6 mg/kg)* *Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks Radiation and hormonal therapy were initiated after completion of paclitaxel Tolaney SM et al. SABCS 2013;Abstract S1-04.
APT Results (N = 406) Tolaney SM et al. SABCS 2013;Abstract S1-04.
ATEMPT Trial Schema R Trastuzumabemtansine (T-DM1)every 3 weeks for 17 weeks Stage I HER2+* ER+ or ER- PS 0-1 Adequate organ fx 3 N = 375 Paclitaxel + trastuzumab once weekly for 12 weeks trastuzumab every 3 weeks beginning from week 13 1 N = 500 N = 125 *HER2-positive defined as IHC 3+ or FISH ≥2.0; will be confirmed by central HER2 testing prior to study enrollment Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy Adjuvant radiation therapy can be administered concurrently with study treatment www.clinicaltrials.gov ClinicalTrials.gov Identifier: NCT01853748 PI: Sara Tolaney, MD, MPH
Discussion Point Impact of clinical depression and extensive alcohol and tobacco use on patients who are undergoing treatment for cancer
Case 2 (from the practice of Ms Olson) • A 67-year-old physical therapist was diagnosed in 2011 with locally advanced ER/PR/HER2-negative breast cancer • She received neoadjuvant dose-dense AC T followed by mastectomy and radiation therapy • Eleven months later she developed a biopsy-proven supraclavicular lymph node recurrence • Workup revealed liver metastases • She received capecitabine as first-line treatment and eribulin in the second line • She experienced persistent problems with low blood counts, and a bone marrow biopsy revealed tumor infiltration
Discussion Point Neoadjuvant treatment for triple-negative breast cancer (TNBC): Available data with platinum agents
CALGB-40603 Randomized Phase II Study Schema ddAC x 4 Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4 Paclitaxel 80 mg/m2 wkly x 12 Surgery&* XRT* No Adjuvant Systemic Treatment Planned* Bevacizumab 10 mg/kg q2wk x 9 2 X 2 Randomization Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4 Carboplatin AUC 6 q3wk x 4 ddAC x 4 Paclitaxel 80 mg/m2 wkly x 12 Paclitaxel 80mg/m2 weekly x 12 &Research biopsies if residual tumor *MD discretion Carboplatin AUC 6 q3wk x 4 Bevacizumab 10 mg/kg q2wk x 9 Research biopsies- frozen and fixed Sikov WM et al. SABCS 2013;Abstract S5-01.
pCR Breast (ypT0/is N any) ± Carboplatin 46% (40-53%) 60% (54-66%) Odds ratio: 1.76 p = 0.0018 N = 212 N = 221 Sikov WM et al. SABCS 2013;Abstract S5-01.
Mechanism of Action of Eribulin Eribulin, which is derived from a sea sponge, works by inhibiting microtubules – the scaffolding of cancer cells. Eribulin suppresses microtubule growth Eribulin Growing microtubule Eribulin sequesters tubulin into nonfunctionalaggregates Spindle Pole Eribulin Eribulin Shortening microtubule Eribulin doesn't affect microtubule shortening Nonfunctionaltubulin aggregate Adapted from Jordan MA et al. Mol Cancer Ther 2005;4:1086-95.
Neoadjuvant Phase II trial with carboplatin and eribulin in triple negative breast cancer patients Giordano SB, Jeruss JS, Bethke KP, Hansen NM, Khan S, Von Roenn J, Rosen S, Gradishar WL, Siziopikou KP, Meservey C, Kaklamani V. Northwestern University, Chicago, IL SABCS 2013;Abstract P3-14-14. Clinical response rate (PR + CR): 82.8%
A Phase III Study of Eribulin Mesylate versus Capecitabine in Patients with Locally Advanced or MBC Previously Treated with Anthracyclines and Taxanes Kaufman PA et al. SABCS 2012;Abstract S6-6.
Consider the last patient in your practice who died of triple-negative metastatic breast cancerHow long did the patient live? <12 months 5 12-24 months 19 >24 months 2 Median = 17 months Research To Practice Survey of Clinical Investigators (N = 26) December 2013.
Most common systemic agents administered Eribulin 21 Platinum 21 Capecitabine 19 Gemcitabine 18 Taxane 17
Discussion Point Consideration of toxicity profiles and methods of administration in the selection and sequencing of systemic therapies
Two Patients with HER2-Positive mBC • 62 yo with bone and liver metastases who subsequently develops brain metastases (Ms Armstrong) • 55 yo with bilateral pulmonary metastases (Ms Olson)
Case 3 (from the practice of Ms Armstrong) • A 62-year-old woman presented with ER/PR-negative, HER2-positive breast cancer • Workup revealed metastatic disease to liver and bone • Paclitaxel, trastuzumab and pertuzumab were administered, resulting in a partial response, but paclitaxel was stopped after 6 months because of fatigue • She continued on dual-antibody therapy until disease progression, at which time she was switched to trastuzumab emtansine (T-DM1) • After 6 months she developed brain metastases and received whole brain radiation therapy followed by capecitabine and lapatinib
Discussion Point Rationale for and available data with the addition of pertuzumab to trastuzumab/taxane
CLEOPATRA Study R • Centrally confirmed HER2+ locally recurrent, unresectable or metastatic BC (MBC) • ≤1 hormonal regimen for MBC • Prior (neo)adjuvant systemic rx, incl trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mo • Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab N = 406 Docetaxel + Trastuzumab + Placebo 1:1 Docetaxel + Trastuzumab + Pertuzumab N = 402 Baselga J et al. N Engl J Med 2012;366(2):109-19. Swain S et al. SABCS 2012;Abstract P5-18-26.
CLEOPATRA: Response and Survival Analyses Baselga J et al. N Engl J Med 2012;366(2):109-19. Swain SM et al. Lancet Oncol 2013;14(6):461-71.
CLEOPATRA Safety Analysis • Safety profile similar between groups • No increase in left ventricular systolic dysfunction with the addition of pertuzumab • Increased incidence of ≥Grade 3 AEs with pertuzumab • Diarrhea: 8% vs 5% • Febrile neutropenia: 14% vs 8% • All grade rash: 34% vs 24% Baselga J et al. N Engl J Med 2012;366(2):109-19.
Trastuzumab Emtansine (T-DM1): Mechanisms of Action Immuneeffector cell HER2 T-DM1 HER2 T-DM1 Inhibition of HER2 shedding Fcγ receptor Emtansine release Internalization Antibody-dependentcellular cytotoxicity(ADCC) Inhibition of HER2 signaling P P Inhibition of microtubule polymerization P P P P Lysosome PI3K MAPK Nucleus Adapted from LoRusso PM et al. Clin Cancer Res 2011.
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 3.6 mg/kg q3w IV PD 1:1 Capecitabine 1,000 mg/m2 PO BID, days 1–14, q3w + Lapatinib 1,250 mg/day PO qd PD Median OS: 30.9 vs 25.1 mo Median PFS: 9.6 vs 6.4 mo Verma S et al. N Engl J Med 2012;367(19):1783-91.
T-DM1-Associated Side Effects • 1st occurrence of Grade 3 or 4 thrombocytopenia typically occurs during the first 2 cycles of T-DM1 treatment • Majority able to continue treatment with dose modifications • 2% of patients discontinued T-DM1 due to thrombocytopenia • 7.2% of patients experienced ≥Grade 3 liver function abnormalities Verma S et al. N Engl J Med 2012;367(19):1783-91.
Phase III MARIANNE Study Design R Target Accrual: 1,095 (Active, not recruiting) T-DM1 • HER2+, locally recurrent or metastatic BC • No prior treatment for metastatic BC T-DM1 + pertuzumab Taxane + trastuzumab www.clinicaltrials.gov, April 2013 ClinicalTrials.gov Identifier: NCT01120184
Case 4 (from the practice of Ms Olson) • A 55-year-old secretary received treatment for breast cancer in 2000 and fared well until 2012, when a routine chest x-ray revealed multiple bilateral pulmonary nodules that on biopsy proved to be ER-positive, HER2-positive mBC • She received docetaxel/pertuzumab/trastuzumab x 6 cycles followed by pertuzumab/trastuzumab • While receiving chemotherapy, she developed peripheral neuropathy and alopecia, both of which resolved on the double-antibody treatment.
