Anthracycline-Induced Cardiotoxicity: predictors for risk assessment in women without cardiovascular diseases

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Objective. To evaluate prognostic role of molecular (endothelin-1, soluble Fas-L, NT-proBNP, interleukin-1β, TNF-α) and genetic factors (gene polymorphisms of endothelial NO synthase NOS3 (rs1799983), endothelin-1 receptor type A (EDNRA, C + 70G, rs5335), NADPH oxidase (C242T, rs4673), p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522), nitric oxide synthase (NOS3, Glu298Asp, rs1799983), Caspase 8 (CASP8, rs3834129 and rs1045485), interleukin-1β gene (Il-1β, rs1143634), TNF-α gene (rs1800629), superoxide dismutase-2 gene (SOD2, rs4880), glutathione peroxidase-1 gene (GPX1, rs1050450) in development of endothelial dysfunction and anthracycline-induced cardiotoxicity (AIC) in women without cardiovascular diseases (CVD). Methods. A total of 176 women, median age of 45.0 [42.0; 50.0] years with breast cancer and without CVD who received anthracycline antibiotics as part of chemotherapy (CT) were enrolled in the study. Two-dimensional transthoracic echocardiography was performed at baseline and at the 12 months after chemotherapy. Serum levels of molecular biomarkers were measured using an enzyme immunoassay baseline, right after chemotherapy and at 12 months after chemotherapy. Evaluation of gene polymorphisms was carried out by PCR at baseline. Results. After the 12 months of chemotherapy all patients had breast cancer remission and were divided into 2 groups: group 1 (n = 52) comprised patients with AIC, group 2 (n = 124) comprised those without it. The baseline levels of all biomarkers did not differ. After completion of chemotherapy the concentrations of endothelin-1, sFas-L statistically increased only in group 1. The levels of the NT-proBNP, TNF-α and interleukin-1β in both groups were normal before the initiation and after completion of CT. However, at 12 months after CT in the group with developed AIC, the levels of these biomarkers exceeded normal concentration for HF. Based on ROC-analysis, the levels of sFas-L ≥95.8 pg/mL (AUС=0.951; р=0.001), NT-proBNP ≥71.5 pg/mL (AUС=0.951; р=0.0001), and endothelin-1 ≥9.0 pg/mL (AUC = 0.7; p < 0.001) at the end of chemotherapy were identified as a cut-off values predicting development of AIC during 12 months after CT. The development of AIC was significantly related to the presence of Arg/Arg genotype of p53 protein gene (OR = 2.972; p = 0.001), T/T genotype of the NOS3 rs1799983 gene (OR = 3.059, p = 0.018), T/T genotype of the NADPH oxidase gene rs4673 (OR = 2.753, p = 0.008). Other gene polymorphisms did not differ between groups. Conclusion. Our data suggest that evaluation of polymorphisms gene of p53 (rs1042522), NOS3 (rs1799983) and NADPH oxidase gene (rs4673) can be recommended before chemotherapy in women with breast cancer and without cardiovascular disease for the risk assessment of AIC. The serum levels of NT-proBNP, endothelin-1, sFas-L after chemotherapy may be considered as non-invasive biomarkers for prediction of AIC development during the 12 months after chemotherapy.