Predicting the occurrence and prevention of early anthracycline cardiotoxicity of chemotherapy in patients with breast cancer

Abstract

Background: Methylenetetrahydrofolate Reductase (MTHFR) is the key enzyme of xenobiotic detoxification, involved in the metabolism of anticancer drugs. Genotyping of the polymorphism MTHFR allows to make prognosis of chemotherapy side effects in different patients, personalize pharmacotherapy. Methods: QTc interval and myocardial systolic and diastolic function of 100 patients with breast cancer stages T1‐3N0‐3M0 treated with neo/adjuvant anthracycline chemotherapy were investigated. In the main study group 50 patients received cardioprotective medications (enalapril 2.5 mg orally twice daily and carvedilol 6.25 mg orally twice daily). The polymorphisms of MTHFR gene in control group were evaluated using Real‐Time PCR. Statistica10.0 software was used to perform analysis of variance. Results: It was established that the specific manifestations of early cardiotoxicity of doxorubicin at a cumulative dose 300 mg/m2 were QTc prolongation over 460 msec in the main group in 5 (10%) patients, in the control group ‐ 13 (26%) patients, as well as diastolic dysfunction (DD) of the left ventricle type 1 in the main group in 5 (10%) patients, in the control group ‐ 15 (30%) patients. The absence of cardioprotective therapy in our study was a risk factor for these complications: QTc interval prolongation (OR=3.15, 2.05‐4.21, p=0.03) and DD (OR=3.85, 2.75‐4.96, p=0.01).A molecular genetic analysis had shown that QT prolongation and DD were detected in 36.4% of patients with T/T genotype, in 36.6% ‐ with C/T genotype and only 9.1% patients with genotype C/C. The risk of cardiotoxicity of chemotherapy in patients with breast cancer, which is the carrier of one or two mutant alleles of the gene MTHFR (genotype C/T and T/T) is 2.68 times higher (OR=2.68; 95% CI=1.24‐5.78; p<0.01) in comparison with carriers of genotype C/C. Conclusions: It is reasonable to determine the MTHFR gene polymorphism in patients with early breast cancer prior to treatment which allow to identifying a high‐risk cardiotoxicity group for timely and adequate cardioprotective therapy administration.