Pertuzumab Cardiotoxicity in Patients with HER2 Positive Cancer: A Systematic Review and Meta-analysis

ABSTRACT Background: HER2 over-expressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The cardiotoxicity of trastuzumab, a HER2-targeting monoclonal antibody, is well established. However, the cardiotoxic effect of pertuzumab, another HER2-directed therapy, is less well documented. The objective of this systematic review and meta-analysis was to determine the risk of cardiac events in patients with HER2 positive cancer receiving pertuzumab. Methods: We performed a systematic review of phase 2 and 3 randomized controlled trials (RCTs) in which the addition of pertuzumab to other standard therapies in patients with stage I-IV HER2 positive cancer was evaluated and cardiac adverse effects reported. We searched Medline (1946-2020), Embase (1974-2020), and CENTRAL. Two independent reviewers assessed the risk of bias and extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and random-effects models. Results: Eight RCTs (8420 patients) were included: 1 gastro-esophageal; and 7 breast cancer trials. Participants’ median age ranged from 49 to 61.5 years. All participants received trastuzumab and chemotherapy in addition to pertuzumab or placebo. Compared with placebo, pertuzumab increased the risk of clinical heart failure (HF) [RR (95% CI): 1.97 (1.05-3.70); I2 = 0%]. However, pertuzumab had no demonstrable effect on asymptomatic/ minimally symptomatic left ventricular systolic dysfunction (LVSD) [RR (95% CI): 1.19 (0.89 to 1.61); I2 =19%]. Conclusions: Pertuzumab increases the risk of clinical HF, but not asymptomatic/ minimally symptomatic LVSD, in HER2 positive cancer patients. Further research into the mechanisms underlying pertuzumab-related HF is needed to understand its clinical spectrum of cardiotoxicity.