Effect of germline polymorphisms of DNA repair genes on chemotherapy outcome in advanced non-small cell lung cancer (NSCLC) patients.

Abstract

e18057 Background: The identification of predictors of efficacy of chemotherapy in NSCLC could help in the selection of patients who are more likely to benefit from a particular scheme and the avoidance of undue toxicity in poor responders. We examined the role of several polymorphisms in DNA repair and DNA synthesis genes as pharmacogenetic markers in the outcome of NSCLC patients. Methods: A blood sample was collected from 117 patients with NSCLC and genomic DNA was isolated from the peripheral blood nucleated cells. Polymorphisms were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were excision repair cross-complementing-1 (ERCC1 Asn118Asn), xeroderma pigmentosum group D (XPD Lys751Gln), thymidylate synthase (TS) (VNTR/5’UTR, 2R G>C SNP, 3R G>C SNP) and Methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were eligible (14 patients with stage I-II were excluded). The median PFS was significantly longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months (m) and 10 m, respectively, as compared to 6 m for the C/C patients (p=0.034). Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) than those C/C (10.5 m; p=0.1). Subgroup analysis revealed that ERCC1 C/T or T/T genotypes were associated with increased PFS in male (p=0.005), smokers (p=0.036) and age <70 years (p=0.012). Patients with A/A or A/C genotypes in codon 751 in XPD had a trend to longer median OS than those C/C (p=0.09). No differences in median PFS were observed. No association between TS and MTHFR polymorphisms and outcome was found in overall population. Conclusions: ERCC1 C/T or T/T genotype in codon 118 might be useful for predicting the outcome of NSCLC patients treated with platinum-based chemotherapy specially in male, smokers and age <70 subgroups.