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

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.

Cancer treatment-related cardiotoxicity: a focus on sacubitril/valsartan

“…The question as to whether the prophylactic use of β-blockers, spironolactone or ACEIs/ARBs is protective against CTRCD in patients without established cardiac disease has been investigated in several small clinical trials (with contradictory results) [49][50][51][52][53][54][55][56] . Of the 473 cancer patients who were included, 114 patients who showed an elevated troponin I level greater than 0.07 ng/mL after high-dose chemotherapy were randomly assigned to ACEI or placebo groups [51] .…”

“…Furthermore, spironolactone used in female patients diagnosed with breast cancer protected against anthracycline-induced cardiotoxicity [49] . A meta-analysis of five randomized trials evaluated the prophylactic effect of β-blockers or ACEIs/ARBs on reducing the incidence of CTRCD in breast cancer patients receiving a trastuzumab regimen [53] . Prophylactic treatment with β-blockers or ACEIs/ARBs did not reduce the risk of CTRCD but did reduce the risk of HER2 therapy interruptions and reduced LVEF [53] .…”

Coronary Artery Disease and Cancer: Treatment and Prognosis Regarding Gender Differences

“…Relevant cardiotoxicity occurs in approximately 10% of patients treated with these agents. This cardiotoxicity is manifested by a decrease in LV function with or without clinical signs of heart failure [ 62 , 63 ]. However, an increase in myocardial infarction due to this antibody therapy is not observed [ 63 ].…”

Cancer treatment-related cardiotoxicity: A focus on sacubitril/valsartan

“…Whether the prophylactic use of β-blockers, spironolactone or ACEI/ARB is protective against CTRCD in patients without established cardiac disease has been investigated in some small clinical trials, with contradictory results (17)(18)(19)(20)(21)(22)(23)(24). Of the 473 cancer patients, 114 patients who showed an elevated troponin I greater than 0.07 ng/ml after high-dose chemotherapy were randomly assigned to ACEI or placebo (19).…”

“…Spironolactone used in female patients diagnosed with breast cancer protected against anthracycline-induced cardiotoxicity (17). A meta-analysis of five randomized trials evaluated the prophylactic effect of β-blockers or ACEIs/ARBs on reducing the incidence of CTRCD in breast cancer patients receiving a trastuzumab regimen (21). Prophylactic treatment with β-blockers or ACEIs/ARBs did not reduce the risk of CTRCD but did reduce the risk of HER2 therapy interruptions and reduced LVEF (21).…”