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.

• Authors: Ji-Youn Han, Kyong-Ah Yoon, Jae Hee Park, Young Joo Lee, Geon Kook Lee, Jong Hee Han, Sung Jin Yoon, Tak Yun, Heung Tae Kim, Jin Soo Lee
• Journal: Cancer (Cancer) Vol. 117 Issue 14 Pg. 3201-8 (Jul 15 2011) ISSN: 1097-0142 [Electronic] United States
• PMID: 21264830 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Cancer Society.

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• Quinazolines
• X-ray Repair Cross Complementing Protein 1
• XRCC1 protein, human
• ERCC1 protein, human
• Endonucleases
• Gefitinib

Topics

• Adenocarcinoma (drug therapy, genetics, mortality)
• Adenocarcinoma of Lung
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• DNA-Binding Proteins (genetics)
• Endonucleases (genetics)
• Female
• Gefitinib
• Genes, erbB-1
• Humans
• Lung Neoplasms (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Polymorphism, Genetic
• Quinazolines (therapeutic use)
• Smoking
• X-ray Repair Cross Complementing Protein 1