Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity

J Clin Oncol. 2017 Mar 10;35(8):870-877. doi: 10.1200/JCO.2016.68.7830. Epub 2016 Nov 28.


Purpose The primary toxicity of trastuzumab therapy for human epidermal growth factor receptor 2-overexpressing (HER2-positive) breast cancer is dose-independent cardiac dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. We hypothesized that angiotensin-converting enzyme inhibitors and β-blockers could prevent trastuzumab-related cardiotoxicity. Patients and Methods In this double-blinded, placebo-controlled trial, patients with HER2-positive early breast cancer were randomly assigned to receive treatment with perindopril, bisoprolol, or placebo (1:1:1) for the duration of trastuzumab adjuvant therapy. Patients underwent cardiac magnetic resonance imaging at baseline and post-cycle 17 for the determination of left ventricular volumes and left ventricular ejection fraction (LVEF). Cardiotoxicity was evaluated as the change in indexed left ventricular end diastolic volume and LVEF. Results Thirty-three patients received perindopril, 31 received bisoprolol, and 30 received placebo. Baseline demographic, cancer, and cardiovascular profiles were similar between groups. Study drugs were well tolerated with no serious adverse events. After 17 cycles of trastuzumab, indexed left ventricular end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36). In secondary analyses, trastuzumab-mediated decline in LVEF was attenuated in bisoprolol-treated patients (-1 ± 5%) relative to the perindopril (-3 ± 4%) and placebo (-5 ± 5%) groups ( P = .001). Perindopril and bisoprolol use were independent predictors of maintained LVEF on multivariable analysis. Conclusion Perindopril and bisoprolol were well tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy-related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling-the primary outcome-was not prevented by these pharmacotherapies.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bisoprolol / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology
  • Cardiotoxicity / diagnostic imaging
  • Cardiotoxicity / etiology*
  • Cardiotoxicity / prevention & control*
  • Double-Blind Method
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Middle Aged
  • Perindopril / therapeutic use
  • Receptor, ErbB-2
  • Stroke Volume / drug effects
  • Trastuzumab / administration & dosage
  • Trastuzumab / adverse effects*
  • Ventricular Remodeling / drug effects


  • Adrenergic beta-1 Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
  • Bisoprolol
  • Perindopril