Pharmacogenomics of cancer therapy-related cardiomyopathy in childhood cancer survivors.

Abstract

Cancer therapy-related cardiomyopathy (CTR-cardiomyopathy) is the leading noncancer late effect contributing to morbidity and mortality among adult survivors of childhood cancer. Anthracycline chemotherapy and thoracic radiotherapy are the primary treatment-related risk factors. However, substantial variability among similarly treated individuals highlights the role of germline genetic susceptibility. This review summarizes pharmacogenomic evidence for CTR-cardiomyopathy and the integration of genetic and clinical risk factors for individualized risk prediction. We searched PubMed through July 2026 for studies examining the molecular underpinnings and risk prediction in these survivors. Candidate gene studies identified associations across pathways involved in drug transport (ABCC1, ABCC2, SLC28A3), metabolism (CBR3), oxidative stress (SOD2, CYBA, NCF4), DNA damage response (RARG, XRCC5, MGMT), and inflammation (P2RX7). Genome-wide studies have identified additional loci, including HAS3, ancestry-specific signals (PHTF1/MAGI3, AGBL1), and a doxorubicin-specific locus (KCNK17). Despite progress, barriers to clinical implementation remain, including heterogeneous phenotype definitions, limited replication, especially in non-European populations, and lack of prospectively validated risk models. Integration of multi-omics approaches may improve detection of subclinical cardiac injury. Ultimately, combining polygenic and other omic risk scores with clinical factors and validating these models prospectively across diverse populations will be essential for advancing precision survivorship care.