Clinical phenotypes of cardiotoxicity in breast cancer patients undergoing contemporary oncologic therapy

Background Cardiotoxicity remains a major clinical challenge in breast cancer patients treated with contemporary oncologic therapies, particularly anthracycline-based regimens and HER2-targeted treatments. Although guideline-recommended surveillance strategies are widely implemented, substantial interindividual heterogeneity in cancer therapy–related cardiac dysfunction (CTRCD) persists, limiting the performance of conventional single-parameter risk stratification and underscoring the need for integrative, data-driven phenotyping approaches. Purpose To identify clinically interpretable cardiotoxicity phenotypes and evaluate their association with ESC-defined cardiotoxic outcomes in a real-world breast cancer cohort. Methods We conducted a retrospective analysis of 314 breast cancer patients undergoing systemic oncologic therapy with longitudinal cardiac follow-up. Clinical characteristics, cardiovascular comorbidities, oncologic treatment exposures, echocardiographic parameters, and serial biomarker measurements were assessed. The primary endpoint was ESC-defined CTRCD according to the 2022 ESC Cardio-Oncology Guidelines. Serial NT-proBNP measurements from baseline through 18-month follow-up were incorporated as markers of myocardial stress. Unsupervised clustering integrating clinical, treatment-related, echocardiographic, and biomarker variables was applied to derive distinct cardiotoxicity risk phenotypes, with cluster structure optimized using internal validity metrics. Results ESC-defined cardiotoxicity occurred in 44 of 314 patients (14.0%) over a median follow-up of 18 months. Three distinct cardiotoxicity phenotypes with heterogeneous risk profiles were identified. One phenotype demonstrated a substantially higher incidence of cardiotoxicity and was characterized by combined oncologic treatment exposures, increased cardiometabolic burden, more pronounced deterioration in cardiac function, and elevated baseline NT-proBNP levels with marked longitudinal increases during follow-up. Phenotype-based stratification suggested cardiotoxic vulnerability beyond individual clinical, treatment-related, or echocardiographic variables alone. Conclusions Distinct and clinically interpretable cardiotoxicity phenotypes can be identified among breast cancer patients receiving contemporary oncologic therapy. A high-risk phenotype defined by combined cardiotoxic exposures, adverse cardiac remodeling, and longitudinal NT-proBNP elevation is associated with a substantially increased risk of ESC-defined CTRCD. Integrating clinical, echocardiographic, and biomarker-based phenotyping may enable personalized, risk-adapted surveillance strategies and facilitate earlier, targeted cardioprotective interventions in cardio-oncology practice.