CBR3 V244M is associated with LVEF reduction in breast cancer patients treated with doxorubicin

Abstract

Background: The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts.

Objectives: This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment.

Methods: We recruited 155 patients with breast cancer receiving treatment with doxorubicin (DOX) at Roswell Park Comprehensive Care Center (Buffalo, NY) to a prospective single arm observational pharmacogenetic study. Patients were genotyped for the CBR3 V244M variant. 92 patients received an echocardiogram at baseline (t_{0 month}) and at 6 months (t_{6 months}) of follow up after DOX treatment. Apical two-chamber and four-chamber echocardiographic images were used to calculate volumes and left ventricular ejection fraction (LVEF) using Simpson's biplane rule by investigators blinded to all patient data. Volumetric indices were evaluated by normalizing the cardiac volumes to the body surface area (BSA).

Results: Breast cancer patients with CBR3 GG and AG genotypes both experienced a statistically significant reduction in LVEF at 6 months following initiation of DOX treatment for breast cancer compared with their pre-DOX baseline study. Patients homozygous for the CBR3 V244M G allele (CBR3 V244) exhibited a further statistically significant decrease in LVEF at 6 months following DOX therapy in comparison with patients with heterozygous AG genotype. We found no differences in age, pre-existing cardiac diseases associated with myocardial injury, cumulative DOX dose, or concurrent use of cardioprotective medication between CBR3 genotype groups.

Conclusions: CBR3 V244M genotype status is associated with changes in echocardiographic parameters suggestive of early anthracycline-related cardiomyopathy in subjects undergoing chemotherapy for breast cancer.

Keywords: Anthracycline; Breast Cancer; Carbonyl Reductase 3; Cardiotoxicity; Cardiovascular disease; Chemotherapy; Doxorubicin; Survivorship.

Fig. 1

Left ventricular systolic function in adult breast cancer patients treated with DOX by echocardiogram at baseline and 6 months. We obtained apical two-chamber and four-chamber echocardiographic images at baseline (prior to DOX treatment; t_0m) and 6 months (±2 weeks) following the initiation of DOX therapy (t_6m). These images were used to calculate LVEF using Simpson’s biplane rule by investigators blinded to all patient data. The data was graphed as a violin plot showing the median (thick dashed line), quartiles (dotted line) and overall distribution of LVEF by CBR3 V244M genotype (AA, AG, GG) at t_0m and t_6m. p < 0.0001, two-way ANOVA

Fig. 2

Comparison of ΔLVEF, SVI, EDVI and ESVI between CBR3 V244M genotypes. Baseline and 6-month echocardiographic images were used to calculate volumes and LVEF by blinded investigators. Volumetric indices were evaluated by normalizing cardiac volumes to body surface area (BSA). Baseline metrics were subtracted from 6-month values to calculate changes in a) LVEF, b) stroke volume index (SVI), c) end systolic volume index (ESVI) or d) end diastolic volume index (EDVI) between CBR3 V244M genotypes (AA, AG, GG) after DOX treatment. p = 0.040, one-way ANOVA. Data expressed as mean ± SEM

Fig. 3

Regression effect plots for the significant regression variables in the ΔLVEF model. The regression effect plot for ΔLVEF is shown for a) ARB (p = 0.019) and b) CBR3 V244M genotype (GG, p = 0.029), and c) the interaction between ARB use and CBR3 genotype