PROJECT SUMMARY Trastuzumab, a monoclonal directed against the human epidermal growth factor (EGF) receptor-2 (HER-2), revolutionized HER-2-positive breast cancer treatment, albeit, with the therapy-limiting side effect of cardiotoxicity. We found that 40% of patients experience a left ventricular ejection fraction (LVEF) decline >10% during trastuzumab therapy, and 4% develop heart failure (HF). In 25-50% of these cases, the LVEF decline is not fully reversible, even with cardiovascular therapy. Genetic contributors to cardiac vulnerability and the best cardiovascular management strategy are unknown. A critical need exists for cardio-preventive approaches in patients at risk of trastuzumab-induced cardiotoxicity. The current application?s objective is to evaluate cardio-protective approaches using carvedilol in curative-intent trastuzumab for HER-2-positive breast cancer. Our central hypotheses are that a pre-emptive preventive approach (cardiovascular therapy with the beta-blocker carvedilol started before trastuzumab therapy), or a reactive preventive approach (cardiovascular therapy started in response to early subclinical signs of cardiac dysfunction/ injury, i.e. cardiac troponin elevation or abnormal global longitudinal strain (GLS)) will reduce cardiotoxicity compared with a standard ?wait-and-see? approach (carvedilol prescribed once cardiotoxicity has occured). We furthermore hypothesize that carvedilol extension beyond the active trastuzumab treatment leads to superior outcomes and that pharmacogenomics can predict cardiotoxicity non-responsive to cardiovascular therapy with carvedilol. This clinical trial will test these hypotheses, involving 450 adult breast cancer patients beginning a year of curative-intent trastuzumab therapy, randomized to either a preemptive, a reactive, or reference care approach. This study addresses three specific study aims: Aim 1: To compare the incidence of a) HF or asymptomatic decline in LVEF by >10% in those with LVEF ?50% or ?5% in those with LVEF decrease to a nadir of
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