Pharmacogenetic markers of toxicity of FOLFOX/XELOX chemotherapy in patients with gastrointestinal tumors: a prospective observational study

Abstract

Introdiction . Systemic chemotherapy (CT) based on oxaliplatin, 5-fluorouracil, capecitabine is the standard of treatment for advanced gastric, colorectal and rectal cancer, which is characterized by frequent development of severe adverse events (AEs). The results of translational studies in the Russian patient population are limited, it is necessary to study pharmacogenetic markers. Aim. To study the frequency of carrying allelic variants of DPYD, GSTP1, MTHFR, XPC, ERCC1, TYMS genes and their association with the development of AEs during palliative treatment with FOLFOX/XELOX. Materials and methods . A total of 166 patients (67 gastric cancer, 99 colorectal cancer) were included in the prospective observational study. All patients underwent pharmacogenetic testing by hybridization analysis on biological microarrays ( DPYD (rs2297595 and rs75017182), MTHFR (rs1801133), XPC (rs2228001), TYMS (rs11280056), ERCC1 (rs3212986)) and PCR ( GSTP1 (rs1695), ERCC1 (rs11615)) before starting CT. The genotype frequency distribution was analyzed between the groups of patients with and without the development of severe AEs. Results . AEs developed in 97.7% of patients, severe AEs accounting for 54.2%. According to the results of univariate analysis, TC genotype of DPYD gene rs2297595 OR = 3.0 (95% CI 1.2–7.3, p = 0.025), GG genotype of GSTP1 gene rs1695 OR = 2.9 (95% CI 1.02–8.6, p = 0.038) were associated with the development of severe neutropenia. In multivariate analysis TT genotype rs2297595 of the DPYD gene remained the only predictor of severe neutropenia (B ± SE = -1.103 ± 0.503; DI [-2.090; -0.116]; p = 0.028). Conclusions . The results of this study allowed us to identify possible markers of toxicity of FOLFOX/XELOX chemotherapy.