SAN ANTONIO, TX—Results from the MANTICORE trial include prophylactic use of standard heart failure (HF) pharmacotherapy prevents trastuzumab-associated left ventricular ejection fraction (LVEF) and reduces treatment interruptions due to left ventricular (LV) dysfunction. These findings were presented at the San Antonio Breast Cancer Symposium.1
MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology REsearch, NCT01016886) is a 3-arm randomized (1:1:1), double-blind, controlled trial to evaluate HF pharmacotherapy in the prevention of trastuzumab-mediated LV dysfunction in patients with HER2-overexpressing (HER2+) early stage breast cancer. Its primary aim was to determine if angiotensin-converting enzyme (ACE) inhibitors or beta blockers prevent LV remodeling in patients with HER2+ early stage breast cancer receiving trastuzumab-based chemotherapy.
Adjuvant trastuzumab is the standard of care for patients with HER2+ early stage breast cancer; 5-year survival rates exceed 90%. However, a 5-fold increase in clinical HF are observed. Left ventricular remodeling is an established early indicator of myocardial injury, progressing to worsening cardiac function and overt HF. ACE inhibitors and beta-blockers reduce all-cause mortality and reverse LV remodeling in patients with HF or asymptomatic LV dysfunction. Cardiac magnetic resonance imaging (CMR) is the gold standard for quantifying LV remodeling and function.
With this in mind, the researchers designed the MANTICORE trial to prospectively evaluate pharmacologic strategies to prevent trastuzumab-mediated cardiac remodeling and/or dysfunction. Inclusion criteria were biopsy-proven invasive early stage breast cancer, HER2+ overexpression (CISH), and patients were scheduled to receive trastuzumab-based chemotherapy. Patients with a baseline LVEF <50%; prior chemotherapy or chest radiotherapy; current use of ACE inhibitors, beta blockers, or angiotensin receptor blockers; and contraindication or inability to tolerate MRI were excluded.
Participants were randomly selected in a 1:1:1 ratio to receive perindopril, bisoprolol, or placebo prior to initiating trastuzumab. The study drug was up-titrated as tolerated during the first 3 weeks and continued for the entire 12 months of trastuzumab therapy. Participants underwent a multiparametric CMR at baseline, and at 3, 12, and 24 months. Principle measures of interest included LV end-diastolic volume and LV ejection fraction.
Primary outcome was a change in indexed left ventricular end-diastolic volume on cardiac MRI following 17 cycles of trastuzumab. Secondary outcomes included change in LVEF on cardiac MRI and safety and tolerability of ACE inhibitors and beta blockers in patients with HER2+ early stage breast cancer. Although prophylactic use of standard HF pharmacotherapy protected against trastuzumab-associated declines in LVEF, ACE inhibitors and beta blockers did not prevent trastuzumab-associated LV remodeling. In addition, ACE inhibitors and beta blockers appear safe in patients with HER2+ early stage breast cancer receiving trastuzumab.
1. Pituskin E, Mackey JR, Koshman S, et al. MANTICORE 101: multidisciplinary approach to novel therapies in cardio-oncology research. Oral presentation at: San Antonio Breast Cancer Symposium; December 9-12, 2015; San Antonio, TX.