As the use of antibody-drug conjugates (ADCs) continue to expand in breast cancer, understanding the potential cardiovascular risks is increasingly important, particularly in curative settings. A recent primer published in JACC: CardioOncology reviews mechanisms of cardiovascular injury, summarizes observed toxicities, and highlights risk factors, mitigation strategies and future directions.

Heather Moore, PharmD, et al., explain how each component of an ADC – the antibody, linker and cytotoxic payload – can independently contribute to risk. Most metastatic human epidermal growth factor receptor 2 (HER2)-antibody-based therapies have been associated with cardiotoxicity, with risk varying by age and treatment population.

The authors also note that trastuzumab deruxtecan (T-DXd) differs from trastuzumab emtansine in drug-to-antibody ratio, payload, mechanism of action and linker design. These differences result in greater systemic payload exposure and may influence off-target toxicity profiles, including cardiovascular effects. The reported incidence of T-DXd–associated LVEF decline has varied across the DESTINY-Breast studies, likely reflecting differences in patient populations, treatment setting and line of therapy. Newer ADCs entering breast cancer treatment include sacituzumab govitecan and datopotamab deruxtecan.

Although evidence remains limited, emerging real-world data are helping to identify risk factors for ADC-associated cardiovascular toxicity in breast cancer. Established risk factors for HER2-directed therapies include prior exposure to anthracyclines, low or abnormal baseline LVEF, preexisting cardiac disease and hypertension. The authors state that data for HER2-directed ADCs are similar.

"Evidence guiding cardiovascular surveillance during ADC therapy remains limited and differs between HER2-directed and non–HER2-directed ADCs," write the authors. Considering the remaining knowledge gaps, they write that prospective studies, pragmatic clinical trials and real-world evidence are needed to define surveillance, cardioprotection and cardiovascular disease prevention strategies that maximize the benefits of ADCs while minimizing cardiovascular harm.