Heart Failure Therapies for the Prevention of HER2-Monoclonal Antibody-Mediated Cardiotoxicity: A Systematic Review and Meta-Analysis of Randomized Trials

SIMPLE SUMMARY: Monoclonal antibodies targeting HER2 are used for the management of early and metastatic HER2-positive breast cancer. Approximately 10–15% of patients diagnosed with breast cancer will be HER2-positive. The incidence of heart failure in breast cancer patients is becoming increasingly problematic, owing to the ageing of the population and the growing number of cancer survivors. The aim of our review was to assess the published evidence for the use of cardio-prevention strategies in HER2-monoclonal antibody-mediated cardiotoxicity. Whilst in the assessed trials the use of heart failure therapies did not reduce the risk of trastuzumab-associated cardiotoxicity, there was a reduction in the mean change in LVEF and in the rates of interruptions to HER2 therapy in patients treated with beta-blockers. This highlights the possible applications for neurohormonal therapies to prevent cardiotoxicity and mitigate interruption to vital HER2-monoclonal antibody treatment. ABSTRACT: Monoclonal antibodies including trastuzumab, pertuzumab, and antibody-drug conjugates, form the backbone of HER2-positive breast cancer therapy. Unfortunately, an important adverse effect of these agents is cardiotoxicity, occurring in approximately 10% of patients. There is increasing published data regarding prevention strategies for cardiotoxicity, though seldom used in clinical practice. We performed a systematic review and meta-analysis of randomized-controlled trials to evaluate pharmacotherapy for the prevention of monoclonal HER2-directed antibody-induced cardiotoxicity in patients with breast cancer. Online databases were queried from their inception until October 2021. Effects were determined by calculating risk ratios (RRs) and 95% confidence intervals (CI) or mean differences (MD) using random-effects models. We identified five eligible trials. In the three trials (n = 952) reporting data on the primary outcome of cardiotoxicity, there was no clear effect for patients assigned active treatment compared to control (RR = 0.90, 95% CI 0.63 to 1.29, p = 0.57). Effects were similar for ACE-I/ARB and beta-blockers (p homogeneity = 0.50). Active treatment reduced the risk of HER2 therapy interruptions (RR = 0.57, 95% CI 0.43 to 0.77, p < 0.001) with similar findings for ACE-I/ARB and beta-blockers (p homogeneity = 0.97). Prophylactic treatment with ACE-I/ARB or beta-blocker therapy may be of value for cardio-protection in patients with breast cancer prescribed monoclonal antibodies. Further, adequately powered randomized trials are required to define the role of routine prophylactic treatment in this patient group.