DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma

Abstract

Background: The objective of this study was to investigate whether polymorphisms in DNA repair genes affect clinical outcome of never-smokers with lung adenocarcinoma (NSLA).

Method: Common polymorphisms in the DNA repair genes ribonucleotide reductase M1 (RRM1), excision repair cross-complementation group 1 (ERCC1), and x-ray repair cross-complementing group 1 (XRCC1) were genotyped in DNA samples from 158 patients among 313 NSLA who were randomized to receive either gefitinib or gemcitabine plus cisplatin (GP) as first-line therapy. Immunohistochemistry for ERCC1 (n = 38) and direct sequencing of the epidermal growth factor gene (EGFR) (n = 42) were performed using tumor samples.

Results: Patients who had the XRCC1 arginine (Arg)/Arg polymorphism at codon 399 (399Arg/Arg) had a higher response rate to gefitinib (71% vs 36%; P = .002) and had more EGFR-mutant tumors (82% vs 29%; P = .001) than patients who had the glutamine (Gln) allele. Patients who had the ERCC1 adenine-adenine (AA) polymorphism at codon 8092 (8092AA) had a higher response to GP than patients who had the cytosine-cytosine (CC) or the CA genotype (100% vs 44%; P = .043).When gefitinib was compared with GP, significantly longer progression-free survival (PFS) was observed with gefitinib among patients who had the XRCC1 399Arg/Arg genotype (7.5 months vs 6.6 months; P = .013), the RRM1 2464 guanine-guanine (GG) genotype (11.5 months vs 6.0 months; P = .004), and the ERCC1 8092CA genotype (7.5 months vs 6.4 months; P = .024). When the 3 genotypes were analyzed jointly, significantly longer PFS was observed with gefitinib among patients who had ≥2 genotypes (8.1 months vs 6.4 months; P = .009), whereas a trend for longer PFS was observed with GP among patients without the 3 genotypes (6.3 months vs 2.0 months; P = .06). In a multivariate Cox regression model, the greater number of specific genotypes independently predicted improved overall survival (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P = .006).

Conclusions: Patients with the XRCC1 399Arg/Arg, RRM1 2464GG, and ERCC1 8092CA genotypes did benefit from gefitinib. Having more of these genotypes may predict favorable prognosis for NSLA.