A randomized, pharmacologic intervention study evaluating the effect of the angiotensin II-receptor blocker candesartan versus placebo to prevent trastuzumab-associated cardiotoxicity in women with early breast cancer.

Abstract

TPS108 Background: Trastuzumab-associated cardiotoxicity leads to morbidity and a potentially less optimal treatment in a part of patients (pts) adjuvantly treated for HER2+ breast cancer (BC). Interventions that reduce the chance to develop this toxicity are needed. Drugs interfering with the renin-angiotensin-aldosterone system, e.g. angiotensin II-receptor blockers (ARB), are used to treat various types of cardiac dysfunction. The aim of this study is to investigate whether ARB treatment can ameliorate or prevent trastuzumab-associated cardiotoxicity during adjuvant treatment for HER2+ BC, thereby reducing treatment-related morbidity in pts with early BC. Methods: In this multicenter, double blind study (EUDRACT 2006-001707-11), women with early HER2+ BC are randomized between treatment with ARB (candesartan 32 mg once daily) or placebo. Inclusion-criteria: age ≥ 18 yrs, adjuvant regimen with anthracycline followed by trastuzumab, Left Ventricular Ejection Fraction (LVEF) ≥ 50% prior to treatment, adequate blood pressure [(BP) systolic ≥ 100/ ≤ 180 mmHg, diastolic ≥ 60/ ≤ 100 mmHg], normal organ function. Exclusion criteria: previous anthracycline-treatment, pre-existent heart failure or myocardial infarction < 6 months prior to randomization. Study medication (ARB/placebo) starts the same day as the first trastuzumab infusion, continuing up to 26 wks after completion of 1 year trastuzumab treatment. 3-monthly assessments include physical examination, BP, LVEF and blood sampling (Natriuretic Peptides, troponins), and continue up to 3 months after completion of study medication. Primary endpoint: occurrence of a cardiac event during treatment and up to 40 wks after cessation of trastuzumab. Cardiac event is defined as decline in LVEF of > 15% or decrease to a value < 45%. In total 200 randomized pts are needed (80% power, α 0.05) to detect a significant reduction in cardiotoxicity rate from 0.30 to 0.13 (odds ratio 0.35). Currently 124 pts are registered. From a recent planned safety analysis after 10 cardiac events the IDMC found no reason for discontinuation of accrual. No significant financial relationships to disclose.