Associations between CYP2A6 polymorphisms and outcomes of adjuvant S-1 chemotherapy in patients with curatively resected gastric cancer

Abstract

Background: Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients. Methods: Patients received adjuvant S-1 (40 mg/m2 twice daily, days 1–28, every 6 weeks for eight cycles) after curative surgery for pathological stage II–III gastric cancer. We analyzed the wild-type allele (W) (CYP2A6*1) and four variant alleles (V) (CYP2A6*4, *7, *9, *10) that abolish or reduce this enzyme activity. Results: Patients (n = 200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57 years (range, 32–83 years); 128 men, 72 women. With a median follow-up of 46.4 months, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 83.1 % (95 % CI, 77.7–88.5 %) and 94.8 % (95 % CI, 91.6–98.0 %), respectively. Genotype distributions were as follows: W/W (n = 49, 24.5 %), W/V (n = 94, 47.0 %), and V/V (n = 57, 28.5 %). Overall toxicity did not differ according to genotype for any grade (p = 0.612) or grade ≥3 (p = 0.143). However, RFS differed significantly according to CYP2A6 genotype. The 3-year RFS rates were 95.9 % for W/W, 83.1 % for W/V, and 72.5 % for V/V (p = 0.032). Carriers of W/V and V/V genotypes had a poorer RFS with a hazard ratio of 3.41 (95 % CI, 1.01–11.52; p = 0.049) and 4.03 (95 % CI, 1.16–13.93; p = 0.028), respectively, compared with the W/W genotype. Conclusions: CYP2A6 polymorphisms are not associated with toxicity of S-1 chemotherapy, but correlate with the efficacy of S-1 in the adjuvant setting for gastric cancer.