Abstract PD5-03: Prophylactic beta blockade preserves left ventricular ejection fraction in HER2-overexpresssing breast cancer patients receiving trastuzumab: Primary results of the MANTICORE randomized controlled trial
Authors: Pituskin E , Mackey JR , Koshman S , Jassal D , Pitz M , Haykowsky MJ , Thompson R , Oudit G , Ezekowitz J , Paterson I 
Published: May 2016

Background: Adjuvant trastuzumab (TRZ) is the standard of care in patients with HER2-overexpressing (HER2+) early stage breast cancer (EBC), with five-year survival rates exceeding 90%. However, significant cardiac toxicities are observed, with a fivefold increase in clinical heart failure (HF). Effective prevention of such negative sequelae is therefore of enormous clinical interest. Left ventricular (LV) remodeling is established as an early indicator of myocardial injury, progressing to worsening cardiac function and overt heart failure. 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. Accordingly, we designed the MANTICORE trial (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology REsearch, NCT01016886, November 18, 2009) to prospectively evaluate pharmacologic strategies to prevent TRZ mediated cardiac remodeling and/or dysfunction.

Objective: The primary objective was to determine if one year of standard HF pharmacotherapy can prevent TRZ mediated LV remodeling in patients with HER2+ EBC assessed by CMR.

Methods: In this double-blind trial, patients with HER2+ EBC were randomized in a 1:1:1 ratio to perindopril, bisoprolol or placebo prior to initiating TRZ. Study drug was up-titrated as tolerated in the first 3 weeks and continued for the entire 12 months of TRZ therapy. Participants underwent a multi-parametric CMR at baseline, 3, 12 and 24 months and principle measures of interest included LV end-diastolic volume and LV ejection fraction.

Results: From September 2010 to June 2014, 100 EBC patients were randomized at 2 centers. Study recruitment was halted by the investigators upon the recommendation of an independent Data Safety Monitoring Committee as a primary endpoint had been met in at least one of the treatment arms. All 12 month CMRs (primary outcome) will be completed by August 2015. Final unblinded results will be presented at SABCS.

Conclusions: MANTICORE is the first randomized double-blind controlled trial to evaluate HF pharmacotherapy in the prevention of TRZ-mediated LV dysfunction in HER2+ EBC patients. Our results have the potential to implement change in clinical practice with TRZ-based adjuvant therapy.

Citation Format: Pituskin E, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, Thompson R, Oudit G, Ezekowitz J, Paterson I. Prophylactic beta blockade preserves left ventricular ejection fraction in HER2-overexpresssing breast cancer patients receiving trastuzumab: Primary results of the MANTICORE randomized controlled trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-03.