CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients

BACKGROUND: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. METHODS: Among MGC patients (n = 108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (* 4, * 7, * 9, * 10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). RESULTS: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4 = 66.7 vs 58.3 vs 32.3%; P = 0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P = 0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P = 0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P = 0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P = 0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P = 0.004) for response, and adjusted hazard ratios of 3.748 (P = 0.0001) for TTP and 2.961 (P = 0.006) for death. CONCLUSION: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin. British Journal of Cancer (2011) 104, 1126-1134. doi: 10.1038/bjc.2011.24 www.bjcancer.com Published online 1 March 2011 (c) 2011 Cancer Research UK