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

Abstract

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. Patients received adjuvant S-1 (40mg/m2 twice daily, days 1-28, every 6weeks 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. Patients (n=200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57years (range, 32-83 years); 128 men, 72 women. With a median follow-up of 46.4months, 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. 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.