Genetic and Molecular Determinants of Cancer Therapy-Related Cardiovascular Toxicity

Cancer therapy-related cardiovascular toxicity (CTR-CVT) is an umbrella term for myocardial, vascular, electrical, and inflammatory complications of cytotoxic, targeted, immune, and radiation-based therapies. Cancer therapy-related cardiac dysfunction (CTRCD) is used here more narrowly for treatment-related myocardial dysfunction, typically identified by changes in left ventricular ejection fraction, global longitudinal strain, and/or cardiac biomarkers. The pathophysiology of CTR-CVT is multifactorial, but the implicated pathways should not be interpreted as equally causal. The dominant initiating mechanism is therapy-specific - anthracycline injury is best supported by topoisomerase IIβ (TOP2B)-mediated DNA damage with secondary mitochondrial and redox injury; HER2-directed toxicity by disruption of NRG1-ERBB2/ERBB4 survival signalling; fluoropyrimidine toxicity by coronary vasomotor dysfunction; VEGF-pathway inhibition by endothelial dysfunction and hypertension; immune checkpoint inhibitor toxicity by loss of immune tolerance; and radiotherapy injury by endothelial and microvascular damage with progressive fibrosis. Mitochondrial dysfunction, oxidative stress, inflammation, calcium dysregulation, apoptosis, and ferroptosis frequently act as downstream or amplifying pathways, although the clinical relevance of several regulated cell-death mechanisms remains incompletely established. Genetic susceptibility may further modify risk, but the strength of evidence differs among reported loci. Replicated pharmacogenetic associations, rare variants in established cardiomyopathy genes, and preliminary candidate-gene findings should therefore be considered separately. Most available studies remain limited by small cohorts, heterogeneous phenotyping, ancestry imbalance, and incomplete external replication. This review critically evaluates the hierarchy and strength of mechanistic and genetic evidence and discusses the extent to which these findings can currently inform risk stratification, surveillance, prevention, and treatment in precision cardio-oncology.