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).


METHODS
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.
Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea. jymama@ncc.re.kr
Ji-Youn
JY
Han
Kyong-Ah
KA
Yoon
Jae Hee
JH
Park
Young Joo
YJ
Lee
Geon Kook
GK
Lee
Jong Hee
JH
Han
Sung Jin
SJ
Yoon
Tak
T
Yun
Heung Tae
HT
Kim
Jin Soo
JS
Lee
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011799:Quinazolines / Q000627:therapeutic use*; D012907:Smoking; D000076105:X-ray Repair Cross Complementing Protein 1
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011799:Quinazolines; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C071447:ERCC1 protein, human; D004720:Endonucleases; D000077156:Gefitinib