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 occurrence, 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 were retrospectively identified over a 10-year accrual period (January 2014–December 2024). Mean individual follow-up was approximately 2.0 years (range, 0.5–9.0 years). CTRCD was defined according to the harmonized International Cardio-Oncology Society (IC-OS) definitions incorporated into the 2022 ESC Guidelines on cardio-oncology, 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) remained associated with CTRCD after mutual adjustment. Progressively higher observed proportions of CTRCD were found across increasing CCI categories and cumulative anti-HER2 exposure levels. Conclusions: In this large real-world cohort assembled over a 10-year accrual period, CTRCD was relatively frequent but predominantly mild and reversible. Greater global comorbidity burden and cumulative anti-HER2 exposure were associated with a higher occurrence of CTRCD. However, the association with cumulative anti-HER2 exposure should be considered hypothesis-generating rather than causal because of potential time-dependent and reverse-causality bias. Prospective validation is required to determine their potential role in individualized cardiovascular surveillance.