Predicting the 10-year risk of cardiomyopathy in long-term survivors of childhood cancer

Abstract

Background: Considering the heightened risk of cancer treatment-related cardiomyopathy and cardiac death in long-term survivors of childhood cancer, we aimed to develop and validate a clinically applicable risk prediction model for cardiomyopathy.

Patients and methods: Childhood cancer survivors from the St. Jude Lifetime Cohort, [SJLIFE, model-development; n = 3479; median age 32.3 years, interquartile range (IQR) 24.4-40.9 years] and the Childhood Cancer Survivor Study (CCSS, model-validation; n = 6875; median age 33.2 years, IQR 27.9-38.9 years) were assessed for demographic and cardiovascular risk factors, treatment exposures, and polygenic risk scores (PRSs) for cardiomyopathy, heart failure, cardiac structure and function, and anthracycline-related cardiomyopathy risk. Multivariable Poisson regression predicted the 10-year risk of cardiomyopathy (Common Terminology Criteria for Adverse Events grade ≥3: requiring heart failure medications or heart transplantation or leading to death) following baseline visit/survey. Model performance was assessed by area under the receiver operating characteristic curve (AUC).

Results: Cardiomyopathy was clinically identified in 75 (2.2%, SJLIFE) and self-reported in 87 (1.3%, CCSS) survivors within 10 years of the baseline assessment. AUC of the clinical model with sex, age at cancer diagnosis, cumulative anthracycline, and mean heart radiation doses was 0.833 (SJLIFE) and 0.812 (CCSS). Age at baseline, hypertension, and genetic ancestry showed associations with higher cardiomyopathy rates in SJLIFE but did not increase AUC in CCSS (0.812). Adding PRSs for hypertrophic cardiomyopathy and left ventricular end-systolic volume improved AUC in CCSS (0.822; P = 0.016). Compared with existing survivorship-care guidelines, the PRS model classified fewer survivors as high-risk or moderate-risk, while identifying survivors in those categories as having 1.5-times greater risk.

Conclusions: We developed and validated models with highest-to-date performance for estimating the 10-year risk of cardiomyopathy in survivors of childhood cancer. Results could enhance identification of at-risk survivors beyond current guidelines.

Keywords: cardiomyopathy; childhood cancer survivors; genetic factors; heart failure; polygenic risk score; risk prediction.