Cardiotoxicity of Antibody-Drug Conjugates in HER2-Positive Cancer: Beyond Left Ventricular Ejection Fraction Decline

Human epidermal growth factor receptor 2-targeted antibody-drug conjugates—ado-trastuzumab emtansine and trastuzumab deruxtecan—have transformed the treatment of human epidermal growth factor receptor 2-positive breast cancer. Because their antibody backbone derives from trastuzumab, which is associated with reversible left ventricular (LV) dysfunction, cardiovascular safety remains clinically relevant. In pivotal randomized trials, symptomatic heart failure was rare, and clinically significant declines in LV ejection fraction (LVEF) were uncommon: LV dysfunction occurred in roughly 0.4–1.8% of ado-trastuzumab emtansine-treated patients and approximately 2.7–4.6% of trastuzumab deruxtecan-treated patients, almost always asymptomatic and frequently reversible. However, these reassuring estimates derive from populations selected for normal baseline LVEF and limited cardiovascular comorbidity, with short follow-up and endpoints anchored to LVEF. Reliance on serial LVEF alone may underestimate cardiovascular injury, because LVEF is insensitive to early, subclinical dysfunction. Global longitudinal strain and cardiac biomarkers (troponins and natriuretic peptides) detect myocardial changes earlier and are endorsed by contemporary cardio-oncology guidelines, although prospective validation specific to antibody-drug conjugates is lacking, and strain-guided management has not improved long-term outcomes. We examine why LVEF-only surveillance is incomplete and outline a risk-stratified, multimodal monitoring framework grounded in current guidelines.