Anthracycline-induced cardiotoxicity: molecular and genetic predictors for risk assessment

Abstract

Abstract Objective The objective of this study was to evaluate the role of molecular and genetic biomarkers in the development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy. Methods A total of 176 women, median age of 45,0 [42,0; 50,0] years with breast cancer without cardiovascular diseases who received anthracycline antibiotics as part of polychemotherapeutic treatment were enrolled in the study. Two-dimensional transthoracic echocardiography and 6-minute walk test were performed at baseline and at the 12 months after polychemotherapy. Serum levels of NT-proBNP, sFas-L were measured using an enzyme immunoassay after polychemotherapeutic treatment. Evaluation of gene polymorphisms of p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522) and nitric oxide synthase (NOS3, Glu298Asp, rs1799983) were carried out by polymerase chain reaction at baseline. Results After the 12 months of polychemotherapy all patients had breast cancer remission and were divided into 2 groups: group 1 (n=52) comprised patients with anthracycline-induced cardiotoxicity, group 2 (n=124) comprised those without it. After polychemotherapeutic treatment the median value of NT-proBNP in group 1 was higher (p<0,00001) by 52,4% than in group 2 (113 [101,8; 126,15] pg/mL and 53,8 [43,4; 63,0] pg/mL, respectively). The median value of sFas-L in group 1 was higher (p<0,00001) by 44,3% than in group 2 (125,3 [111,85; 133,95] pg/mL and 69,8 [59,8; 77,6] pg/mL, respectively). Based on ROC-analysis, sFas-L concentration of 95.8 pg/mL (sensitivity of 92.2%, specificity of 92.1%, and AUC=0,951; p=0,0001) and NT-proBNP concentration of 71.5 pg/mL (sensitivity of 99.9%, specificity of 91.9%, and AUC=0,951; p=0,0001) were identified as a cut-off values predicting the development of anthracycline-induced cardiotoxicity. The development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy significantly was related to the presence of T/T genotype of NOS3 gene (OR = 3,059; p=0,018) and with Arg/Arg genotype of p53 protein gene (OR = 2,972; p=0,001). While, the presence of Pro/Pro the Pro53 gene genotype of p53 protein gene was related to the absence of anthracycline-induced cardiotoxicity. Conclusion Our data suggest that evaluation of polymorphisms gene of p53 (rs1042522) and NOS3 (rs1799983) can be recommended before polychemotherapy in women with breast cancer for the risk assessment of anthracycline-induced cardiotoxicity. The serum levels of NT-proBNP and sFas-L after polychemotherapy may be considered as non-invasive biomarkers for prediction of the development of anthracycline-induced cardiotoxicity in women with breast cancer during the 12 months after polychemotherapy. Funding Acknowledgement Type of funding source: None