Cardiotoxicity of newer HER2-Directed therapies in breast cancer: A systematic review and meta-analysis of incidence and comparative risk

PURPOSE: This systematic review and meta-analysis aimed to estimate the incidence and comparative risk of cardiotoxicity associated with newer HER2-targeted therapies compared with conventional trastuzumab-based regimens. It also evaluates the differences across drug classes, clinical subgroups, and monitoring strategies. MATERIALS AND METHODS: PubMed, Embase, CENTRAL, and Scopus were searched (2005-2025) for randomized controlled trials (RCTs) and prospective studies reporting cardiac outcomes with HER2-directed therapies. Pooled cardiotoxicity incidence was calculated from single-arm studies and intervention arms of RCTs and risk ratios (RRs) from RCTs using random-effects models. Subgroup analyses were performed by drug class, anthracycline exposure, HER2 category, age, and cardiac monitoring frequency. Certainty of evidence was assessed using GRADE. RESULTS: Fifty-eight studies (35,984 patients) were included. Pooled cardiotoxicity incidence was 5.08% (95% CI, 3.37 to 7.58) with left ventricular ejection fraction (LVEF) decline in 4.68% patients, and other cardiac events were each reported in <1% patients. Across 32 RCTs, no significant difference in cardiotoxicity was observed between newer HER2-directed therapies and trastuzumab-based comparator regimens (including trastuzumab monotherapy or trastuzumab combined with chemotherapy, with or without pertuzumab) (RR, 0.97; 95% CI, 0.73 to 1.29). Subgroup analyses showed variability across study characteristics, with higher incidence observed in studies using more frequent cardiac monitoring (8.15%; 95% CI, 3.13 to 19.61%, P > 0.05). CONCLUSION: Newer HER2-directed therapies demonstrate low cardiotoxicity, with rare serious events and no evidence of excess risk compared with conventional trastuzumab-based regimens. These findings support cardiac safety but suggest the need for standardized monitoring and uniform cardiotoxicity definitions.