• Annelies H Boekhout, Jourik A Gietema, Milojkovic KerklaanBojanaBDivision of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands., Erik D van Werkhoven, Renske Altena, Aafke Honkoop, Maartje Los, Willem M Smit, Peter Nieboer, Carolien H Smorenburg, MandigersCaroline M P WCMDepartment of Internal Medicine, Canisius Wilhemina Hospital, Nijmegen, the Netherlands., Agnes J van der Wouw, Lonneke Kessels, Annette W G van der Velden, Petronella B Ottevanger, Tineke Smilde, Jaap de Boer, Dirk J van Veldhuisen, Ido P Kema, Elisabeth G E de Vries, and Jan H M Schellens.
• Division of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
• JAMA Oncol. 2016 Aug 1; 2 (8): 1030-7.

ImportanceThis is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects.ObjectiveTo determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%.DesignThis randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.InterventionsA total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment.Main Outcomes And MeasuresThe primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects.ResultsA total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003).Conclusions And RelevanceThe findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects.Trial Registrationclinicaltrials.gov Identifier: NCT00459771.

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