Pharmacogenetics studies in patients with advanced lung cancer: Prognostic value of the thymidylate synthase 2R/3R polymorphism and predictivity of NER factor XPD K751Q and XRCC1 R399Q polymorphisms following platinum-based chemotherapy

Background: Lung cancer is the commonest cause of cancer-related deaths and although chemotherapy has bean proven to increase survival it has limited efficacy. Survival data are highly dependant both on tumor features and stage of the disease. Pharmacogonetic studios can conIJ'lbute to better understand both kind of variables. In most of the cases chemotherapy is based on an association of a platinum analog and an antimetabolite. Methods: To assess genetic polymorphisms we choose as cancldate genes Thymidilate Synthase (TS), whose expression controls cell proliferation and the 3R allele is associated with higher expression, and of two different DNA repair genes: XPD, whose K751Q single nucleotide polymorphism (SNP) affects repair activity, and the XRCC1 R399Q. The TS 2-3 repeat polymorphisms (2R/3R) was characterized by agarose gel-electrophoresis of the PCR products. SNPs were characterterized using PCR-RPLP technique by digesting the amplified XPD exon 23 with Pstl and XRCC1 exon 10 with Hpall. We enrolled 322 consecutive patients referred for chemotherapy to a single center. 90% males. 96% current or previous smokers, 82% NSCLC, 62% stage IV disease. Among them, 244 received platinum derivatives, mainly in combination with gemcitabine. The control group was represented by 253 healthy medical students. Uni- and multivariate analysis was performed with the SPlus package for the following variables: objective response, relapse, adverse events and deaths. At multivariate analysis the effect of three polymorphisms was agiustedd for age and clinical stage at diagnosis, sex, smoking habit, histology and treatment. 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 Results: Patients' genotype frequencies (TS: 2R2R 24.3%. 2R3R 46.4%, 3R3R 29.3%; XPD: KK 41.3% KQ 44.4% QQ 14.3%; XRCCI: RR 12.1%, RQ 39.1%. QQ 48.8%) were not significantly different from controls. Median survival was significantly increased in TS 2R homozygotes (17.3 months vs. 9.6 months in 2R/3R and 8.7 months in 3R/3R) (adjusted OR 3R/3R versus 2R/2R =4.05, 95%CI:1.43-11.52; 2R/3R versus 2R/2R = 2.74, 95%CI: 1.06-7.11). The XPD genotype was not associated with objective response to platinum treatment and the smoking habit. The effect of platinum treatment was statistically significant in XPD KK homozygotes, who showed a significantly longer survival (13.3 months in platinum treated versus 7.7 months in non platinum-treated), while it was ineffective in KQ heterozygotas (11.4 months in platinum treated and 13 months in non Platinum treated) and QQ homozygotes (11 months in platinum-treated versus 11.7 months in non platinum-treated) At the multivariate analysis the survival advantage for KK platinum treated patients was maintained after adjustment for stage of the disease. Relapses were less frequently reported in KK than in QQ (22.8.% versus 43.5%. OR 2.33: 95% CI:1.08 - 5.05). The XRCC1 polymorphism was not significantly associated with any of the clinical parameters. Conctusions: TS genotype assessment may contribute to better define the prognosis of lung cancer as well as the assessment of XPD genotype may predict the responsiveness to chemethorapy.