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

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. Cancer 2011. © 2011 American Cancer Society.