HER2-targeted therapies and cardiotoxicity: From major concern to manageable risk

HER2-targeted therapies have dramatically improved outcomes for patients with HER2-positive breast cancer, but their potential for cardiotoxicity remains a critical clinical concern. Early trials reported high rates of cardiac dysfunction, particularly with concomitant anthracycline use, prompting the development of intensive cardiac monitoring strategies. However, emerging evidence suggests that most cardiotoxic events are asymptomatic, reversible, and rarely require permanent treatment discontinuation, particularly with newer agents such as antibody–drug conjugates. Clinical determinants include baseline left ventricular dysfunction, age, comorbidities, and combination chemotherapy, while biomarkers and advanced imaging are promising tools for early detection. Mechanistically, HER2 inhibition disrupts cardiomyocyte survival pathways and mitochondrial function, but the relationship between these changes and clinically meaningful heart failure remains incompletely defined. Recent studies, including SAFE-HEaRt, demonstrate that HER2 therapy can often be safely continued under cardio-oncology supervision with appropriate cardioprotective interventions. Nevertheless, gaps persist in risk stratification, long-term surveillance, and the integration of biomarkers and imaging into routine practice. This article critically examines the pathophysiology, clinical risk factors, and management of HER2 therapy-induced cardiotoxicity, ultimately arguing that with proper monitoring and multidisciplinary care, cardiotoxicity should not preclude optimal oncologic treatment.