HER2-targeted therapies and multikinase inhibitors are associated with heterogeneous cardiovascular toxicities, including myocardial dysfunction, hypertension, and arrhythmias.
What are the mechanisms and clinical evidence of cardiovascular toxicity associated with novel HER2-targeted agents and multikinase inhibitors?
This review highlights the mechanisms and clinical evidence of cardiovascular toxicity from HER2-targeted agents and TKIs, emphasizing the need for individualized risk stratification and cardio-oncology monitoring.
The advent of novel Human Epidermal growth factor Receptor 2 (HER2)-targeted therapies and tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in HER2-positive malignancies, particularly breast cancer. However, these agents carry a growing burden of cardiovascular adverse events, representing a critical concern in modern oncology. This narrative review explores the evolving landscape of cardiovascular toxicity associated with these therapeutic classes, integrating mechanistic insights with real-world clinical data. HER2-targeting monoclonal antibodies and antibody–drug conjugates exert off-target effects on cardiomyocytes via HER2 pathway inhibition, leading to reversible or irreversible myocardial dysfunction. In parallel, small-molecule TKIs, especially those targeting multiple kinases, have been associated with hypertension, arrhythmia, QT prolongation, and heart failure, through mechanisms such as mitochondrial dysfunction, endothelial damage, and disruption of cardioprotective signaling. We summarize clinical evidence elucidating the molecular basis of these toxicities and critically review clinical trials and post-marketing data highlighting their incidence and management. The review emphasizes the heterogeneity of cardiotoxicity profiles across different agents, underscoring the need for individualized cardiovascular risk stratification and monitoring. Finally, we address the emerging role of cardio-oncology in bridging oncologic efficacy with cardiac safety, advocating for multidisciplinary approaches, biomarker-guided surveillance, and standardized definitions of cardiotoxicity. As precision oncology advances, a parallel refinement in cardiotoxicity prediction and prevention is imperative to optimize patient outcomes.
Suleiman et al. (2026) conducted a review in HER2-positive malignancies and cardiovascular toxicity. HER2-targeted therapies and tyrosine kinase inhibitors was evaluated. HER2-targeted therapies and multikinase inhibitors are associated with heterogeneous cardiovascular toxicities, including myocardial dysfunction, hypertension, and arrhythmias.