The Impact of Polymorphisms in ATP-Binding Cassette Transporter Genes on Anthracycline-Induced Early Cardiotoxicity in Patients with Breast Cancer

Abstract

Background. Cardiac side effects associated with anthracycline-based treatment may seriously compromise the prognosis of patients with breast cancer (BC). Evidence shows that genes that operate in drug metabolism can influence the risk of anthracycline-induced cardiotoxicity (AIC). ATP-binding cassette (ABC) transporters could serve as one of the potential biomarkers for AIC risk stratification. We aimed to determine the link between single-nucleotide polymorphisms (SNPs) in several ABC genes (ABCB1 rs1045642, ABCC1 rs4148350, ABCC1 rs3743527) and cardiotoxicity. Methods. The study included 71 patients with BC, who were treated with doxorubicin-based chemotherapy. Two-dimensional echocardiography and speckle-tracking echocardiography were performed. AIC was defined as a new decrease of 10 percentage points in the left ventricular ejection fraction (LVEF). SNPs in ABCB1 and ABCC1 genes were evaluated using real-time PCR. Results. After a cumulative dose of 236.70 mg/m2 of doxorubicin, 28.2% patients met the criteria of AIC. Patients who developed AIC had a larger impairment in left ventricular systolic function compared to those who did not develop AIC (LVEF: 50.20 ± 2.38% vs. 55.41 ± 1.13%, p p ABCC1 rs4148350 TG genotype was associated with higher rates of cardiotoxicity (TG vs. GG OR = 8.000, 95% CI = 1.405–45.547, p = 0.019). Conclusions. The study showed that ABCC1 rs4148350 is associated with AIC and could be a potential biomarker to assess the risk of treatment side effects in patients with BC.

Keywords

• anthracycline
• doxorubicin
• breast cancer
• cardiotoxicity
• ATP-binding cassette transporters
• polymorphism