Comorbidity Burden and Cumulative Anti-HER2 Exposure Associated with Cardiac Dysfunction in Breast Cancer: A Real-World Cardio-Oncology Cohort

Background: Cancer therapy-related cardiac dysfunction (CTRCD) remains an important complication of human epidermal growth factor receptor 2 (HER2)-targeted therapy in patients with breast cancer. Although conventional cardiovascular risk factors and serial cardiac imaging are routinely incorporated into cardio-oncology surveillance, the potential contribution of global comorbidity burden and cumulative anti-HER2 treatment exposure remains incompletely characterized. We investigated the occur-rence, clinical course, and factors associated with CTRCD in a large real-world population of patients with breast cancer receiving HER2-targeted therapy. Methods: Adult patients with breast cancer exposed to HER2-targeted therapy and undergoing longitudinal cardio-oncology surveillance at a single tertiary center between January 2014 and December 2024 were included. CTRCD was defined according to contemporary European cardio-oncology criteria integrating left ventricular ejection fraction (LVEF), left ventricular global longitudinal strain (LV-GLS), and cardiac biomarkers when available. Baseline comorbidity burden was quantified using the Charlson Comorbidity Index (CCI), while cumulative anti-HER2 exposure was quantified according to the total number of treatment cycles. Factors associated with CTRCD were investigated using univariable and parsimonious multivariable logistic regression. Results: A total of 850 patients with breast cancer receiving anti-HER2 therapy were included. CTRCD occurred in 179 patients (21.1%) and was predominantly mild, whereas clinically overt heart failure occurred in 2.9%. LVEF and LV-GLS deteriorated at nadir and subsequently showed substantial recovery during follow-up. Conventional cardiovascular risk factors, previous anthracycline exposure, tumor grade, baseline LVEF, and baseline LV-GLS were not significantly associated with CTRCD. In multivariable analysis, increasing CCI (adjusted OR 1.35 per one-point increase, 95% CI 1.12–1.63; p=0.002) and cumulative anti-HER2 exposure (adjusted OR 1.41 per five additional cycles, 95% CI 1.10–1.80; p=0.006) were independently associated with CTRCD. CTRCD probability progressively increased across higher CCI categories and with increasing cumulative anti-HER2 exposure. Conclusions: In this 10-year cardio-oncology cohort of patients with breast cancer, CTRCD was relatively frequent during HER2-targeted therapy but was predominantly mild, infrequently associated with overt heart failure, and frequently reversible. Global comorbidity burden and cumulative anti-HER2 exposure were independently associated with CTRCD, suggesting that cardiotoxic risk may reflect the interplay between baseline patient vulnerability and treatment-related bur-den. If prospectively validated, these readily available variables may provide additional information for longitudinal cardiovascular risk assessment and help individualize surveillance during prolonged HER2-targeted therapy.