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.