Genetic susceptibility to early anthracycline cardiotoxicity: the role of CBR3 polymorphisms
A Rozhanskiy, I Predeus, L Grandini, B Loureiro, G Laudissi, J Tome, A Cerqueira, J V Pontes, E SantAnna MeloAbstract
Anthracyclines are widely used chemotherapeutic agents but are associated with dose-dependent cardiotoxicity, which may manifest as clinical heart failure or subclinical left ventricular dysfunction. Genetic variability has been proposed as a potential modifier of susceptibility to anthracycline-induced cardiotoxicity. Polymorphisms in the carbonyl reductase 3 (CBR3) gene may influence the formation of cardiotoxic anthracycline alcohol metabolites, potentially altering individual risk.
To evaluate whether polymorphisms in the CBR3 gene are associated with an increased risk of cardiotoxicity in cancer patients treated with anthracyclines.
A systematic review and meta-analysis were conducted according to PRISMA guidelines. PubMed, Embase, and Cochrane Library were searched from inception to 11th November 2025. Observational studies evaluating the association between CBR3 polymorphisms and anthracycline-related cardiotoxicity were included.
Cardiotoxicity was defined as clinical heart failure or subclinical left ventricular ejection fraction (LVEF) decline. Pooled effect estimates (OR/RR/HR) with 95% confidence intervals (CI) were calculated using a random-effects model. Genetic models (homozygous, heterozygous, and dominant comparisons: G/G vs A/A; G/A vs A/A; dominant model) were analyzed. Subgroup analyses were performed according to outcome type (clinical vs subclinical cardiotoxicity).
A total of 11 studies including 2051 patients were analyzed. No significant association was observed between CBR3 polymorphisms and isolated biomarker elevation (BNP or troponin) (Figures 1 and 2). However, CBR3 variants were significantly associated with subclinical left ventricular ejection fraction (LVEF) decline (pooled effect −1.20; 95% CI −1.84 to −0.56; p=0.005) (Fig. 3). No statistically significant association was found for clinically overt heart failure (Fig. 2). Heterogeneity was significant across analyses (p<0.001).
CBR3 polymorphisms are associated with subclinical anthracycline-induced ventricular dysfunction but not with overt heart failure or isolated biomarker elevation. These findings suggest a potential role for pharmacogenetic risk stratification in early cardiotoxicity detection.Figures