Abstract 4366595: Risk Stratification for Cancer Therapy-Related Cardiac Dysfunction: External Validation of a HER2+ Breast Cancer Nomogram

Background: Cancer therapy–related cardiac dysfunction (CTRCD) is a well-recognized adverse effect of HER2-targeted therapies, particularly trastuzumab. While current guidelines recommend serial left ventricular ejection fraction (LVEF) monitoring every 3 months during treatment, such uniform surveillance may lead to overutilization in low-risk patients. Objective: This study aimed to externally validate a nomogram from Memorial Sloan Kettering to predict CTRCD in a contemporary cohort of patients with HER2-positive breast cancer. Methods: This retrospective study included women with HER2-positive breast cancer treated with trastuzumab between 2013&2022 at a large cancer center. The primary endpoint was 1-year CTRCD-free survival, with CTRCD defined as an LVEF decline ≥10% to <53% or a ≥16% reduction from baseline. Patients were stratified into risk groups based on total nomogram points. Model performance was evaluated in the validation cohort using Kaplan-Meier estimates, calibration plots, concordance index (C-index), and area under the ROC curve (AUC). Results: The derivation and validation cohorts demonstrated notable differences in baseline characteristics. Patients in the validation cohort (n=356) had a higher mean BMI (39.6% vs. 22.9%) and greater prevalence of cardiovascular comorbidities, including hypertension (34.8% vs. 23.5%), diabetes (11.5% vs. 7.2%), and hyperlipidemia (24.7% vs. 17.1%) but with substantially lower anthracycline exposure (31.5% vs. 77.8%) compared to the derivation cohort. 9.6% of patients developed CTRCD within 395 days of trastuzumab initiation, which was defined as the 1-year CTRCD event. The 1-year CTRCD event rates across increasing quartiles of the nomogram score were 6.0%, 4.4%, 9.6%, and 19.5%, respectively, indicating effective risk stratification. Kaplan-Meier–estimated 1-year CTRCD-free survival was 90.1%, closely aligned with the nomogram-predicted probability of 87.8%. The model demonstrated excellent discriminative performance, with a C-index of 0.68 (95% CI, 0.49–0.86) and an AUC of 0.69 (95% CI, 0.58–0.78) (Figure A, B). Conclusion: The novel CTRCD nomogram demonstrated excellent discriminatory power and generalizable to an independent, real-world patient population. These findings support its utility for personalized CTRCD risk stratification and suggest its potential to guide less frequent LVEF monitoring in low-risk patients receiving HER2-targeted therapy.