Polymorphism rs4673 and plasma paraoxonase 1 level for prediction and early diagnosis of anthracycline-mediated cardiotoxicity in patients with breast cancer.

Abstract

12077 Background: Anthracyclines are highly effective chemotherapeutic agents, used for a wide variety of malignancies. Despite their antitumor efficacy there is a risk of cardiotoxic manifestations that reduce the time and quality of life of patients. The purpose was to study the effectiveness of molecular genetic tests based on rs4673 CYBA genotyping (c.242C > T) and measurement of plasma paraoxonase 1 (PON1) level in patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For rs4673 genotyping, DNA was extracted from the blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). The concentration of PON1 in blood plasma was measured at baseline and after 4 course of chemotherapy with anthracyclines using ELISA kits (Cloud-Clone Corp., China/USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AMC the frequency of the minor allele rs4673 (c.214C > T CYBA) was 0.38, the frequency of genotypes C/C was 0.4, C/T - 0.43, and T/T - 0.17. The risk of AMC increased by 6.49 times in the presence of the rs4673 polymorphic allele (p = 0.002). The area under the ROC curve of the test based on rs4673 genotyping was 71.9%. The concentration of PON1 after the 4 courses of chemotherapy increased by 19.57% in the group of patients without cardiotoxic manifestations (p = 0.018) and in the group of patients with AMC by 20.23% (p = 0.007) as compared to the initial level. Besides, after 4 courses of chemotherapy the PON1 level was higher in patients with AMC by 25.08% (p = 0.026) than in patients without cardiovascular complications. The sensitivity of the test based on the measurement of the PON1 level in the blood plasma after 4 courses of chemotherapy was 100%, the specificity was 70.8% with a cut-off value of 2.9 ng/ml. Conclusions: This study has showed that genotyping of patients for the rs4673 polymorphism allows pre-stratification of the risk group white determination of the PON1 level in blood plasma after 4 courses of chemotherapy gives the opportunity to identify patients with AMC and promptly correct the chosen treatment.