Pharmacogenetics studies in patients with advanced lungcancer: prognostic value of the thymidylate synthase 2R/3Rpolymorphism and predictivity of NER factor XPD K751Qand XRCC1 R399Q polymorphisms following platinum-basedchemotherapy

Lung cancer is one of the most frequent killers in most populations, and treatment is mainly based on platinum derivatives. Survival is limited and highly variable, probably depending both on tumor features and sensitivity to treatment. Pharmacogenetic studies can contribute to better understand both kind of variables. As candidate genes we choose TS, whose expression controls cell proliferation and the 3R allele is associated with higher expression, XPD, whose K751Q SNP affects repair activity, and the XRCC1 R399Q SNP. We enrolled 322 consecutive patients, 80% males, 86% smokers, 82% NSCLC. Among them, 244 received platinum derivatives, mainly in combination with gemcitabine. The control group was represented by 253 healthy medical students. Uni- and multivariate statistical analysis was performed with the SPlus package. On December 2004, the median follow up period was 320 days. Survival was estimated on a subgroup of 128 patients with enrollment <6 months from diagnosis and >9 months follow-up. Patients' genotype frequencies were not significantly different from controls'. Median survival was significantly increased in TS 2R homozygotes (17.3m) vs. 9.6m in 2R/3R and 8.7m in 3R/3R, independently of the treatment. The effect of platinum treatment was statistically significant in KK homozygotes, who showed a significantly longer survival (13.3m in Pt-treated vs 7.7m in nonPt-treated), while it was ineffective in QQ homozygotes. Relapses were 22.8% in KK and 43.5% in QQ. The XRCC1 SNP was not significantly associated with any of the clinical parameters. Pharmacogenetics may predict non-responsiveness and address patients to alternative non-platinum based treatments.