Genetic polymorphisms are associated with imatinib plasma levels and periorbital edema in Chinese patients with gastrointestinal stromal tumors receiving adjuvant imatinib

Abstract

Abstract Purpose Imatinib mesylate (IM) offers a significant survival benefit to patients with gastrointestinal stromal tumors (GIST). However, the clinical responses of IM vary drastically between individuals. Therefore, this study aimed to assess the role of genetic polymorphisms of metabolic enzymes, transporters and drug targets in IM plasma levels and adverse reactions in Chinese patients with GIST.Methods The dose-adjusted trough plasma levels (C0/D) of IM in 95 patients were quantified using two-dimensional liquid chromatography. Nine SNPs in six genes were detected. The relationships between C0/D, single nucleotide polymorphisms (SNPs) and adverse reactions were tested. Logistic regression was used to test the risk factors for IM-related grade ≥ 2 periorbital edema.Results A range of C0/D from 1.33 to 7.04 ng/mL·mg-1 for the 95 patients was found. G allele carriers (CG+GG) of SLC22A1 rs683369 and T allele carriers (GT+TT) of ABCG2 rs2231142 had significantly higher C0/D. For all grades of periorbital edema, an increase in incidence with age was found, while this differed from more severe periorbital edema. Grade ≥ 2 periorbital edema was related to the carriership of two C-alleles in EGFR rs2072454 with an adjusted OR of 2.85 (95% CI=1.10–7.40; P=0.032), two T-alleles in SLC22A1 rs1867351 with an adjusted OR of 3.42 (95% CI=1.32–8.88; P=0.010) and two A-alleles in CYP1A2 rs11636419 with an adjusted OR of 3.15 (95% CI=1.08–9.20; P=0.036). None of the nine SNPs was found to be related to gastrointestinal reactions.Conclusions Rs683369 and rs2231142 have an impact on the metabolism of IM; rs2072454, rs1867351, and rs11636419 are linked to grade ≥ 2 periorbital edema. These SNPs may be biomarkers for IM dose adjustment and IM-related grade ≥ 2 periorbital edema.