DNA Repair Gene Polymorphisms Predict Favorable Clinical Outcome in Advanced Non–Small-Cell Lung Cancer

Aristea Kalikaki; Maria Kanaki; Helen Vassalou; John Souglakos; Alexandra Voutsina; Vassilis Georgoulias; Dimitris Mavroudis

Disclosures

Clin Lung Cancer. 2009;10(2):118-123. 

In This Article

Abstract and Introduction

Abstract

Background: Genetic polymorphisms of genes involved in DNA repair and glutathione metabolic pathways may affect patients' response to platinum-based chemotherapy. We retrospectively assessed whether single nucleotide polymor-phisms (SNP) of DNA-repair genes ERCC1, XPD, XRCC1 and glutathione S-transferase genes GSTP1, GSTT1 and GSTM1 predict overall survival (OS), response and toxicity in 119 non–small-cell lung cancer (NSCLC) patients treated with platinum-based regimens as first-or second-line chemotherapy.
Patients and Methods: Patients' genotypes were determined by PCR-RFLP and sequencing approaches.
Results:  ERCC1 (Asn118Asn) genotype was significantly associated with response to treatment. Patients with either one or two C alleles (C/C, C/T) at Asn118Asn were more likely to respond to platinum-based chemotherapy compared with those without the C allele (Odds ratio, 0.10; 95% CI, 0.013-0.828; P = .033, by binary logistic regression). There was a significant association between the ERCC1 C8092A polymorphism and OS (P = .009, by log-rank test), with median survival times of 9.8 (C/C) and 14.1 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with an improved outcome. Cox's multivariate analysis suggested that the joint effect of ERCC1 polymorphic variants (C8092A and N118N) (0 vs. 2, haz-ard ratio 2.5; 95% CI, 1.26-4.96; P = .009) as well as the XRCC1 N399Q polymorphism (AA vs. GA/GG, hazard ratio 3.1; 95% CI, 1.4-6.8; P = .005) were independent prognostic factors for OS in advanced NSCLC patients treated with platinum-based chemotherapy.
Conclusion: These findings support the notion that assessment of genetic variations of ERCC1 and XRCC1 could facilitate therapeutic decisions for individualized therapy in advanced NSCLC.

Introduction

Lung cancer is a major cause of cancer mortality in Western coun-tries.[1] Non–small-cell lung cancer (NSCLC) accounts approximately for 80% of primary lung cancers, and approximately two thirds of NSCLC patients are diagnosed in advanced stages.[1] Platinum-based regimens are used as standard first-line chemotherapy in NSCLC patients with an objective response rate of about 40%, a median survival time of 8-10 months and a one-year survival rate of 30%-40%.[2,3]

Drug resistance limits the therapeutic efficacy of platinum-based regimens; thus the development of predictive markers to identify pa-tients who will derive significant benefit with minimal toxicity from chemotherapy is a continuing challenge in lung cancer research. Platinum agents are known to act through the formation of DNA adducts that inhibit DNA synthesis and transcription. Proposed mechanisms of resistance include inactivation of platinum compounds through the glutathione metabolic pathway and increased tolerance to DNA damage as a consequence of enhanced DNA-repair capacity.

Downregulation of glutathione-related enzymes may improve cisplatin sensitivity.[4,5,6] The GSTM1 and GSTT1 deletion polymor-phisms (null genotypes) have been associated with diminished GST enzyme activity whereas one nonsynonymous polymorphism occur-ring in GSTP1, the Isoleucine 105 Valine (Ile105Val) in exon 5, has been shown to result in reduced glutathione conjugating ability.[7,8,9]

Polymorphisms of the genes belonging to the base excision repair (BER) pathway, such as x-ray repair cross-complementing group 1 (XRCC1), and the nucleotide excision repair pathway, such as excision repair cross-complementing group 1 (ERCC1) and xeroderma pigmentosum group D (XPD), have been extensively studied.[10] Preclinical data suggest that the ERCC1 C8092A and Asn118Asn polymorphisms could affect the ERCC1 mRNA and protein levels, thus leading to differential cisplatin sensitivity to increased DNA repair capacity.[10,11,12,13] Two nonsynonymous polymorphisms occurring in XPD gene, the aspartic acid 312 asparagine (Asp312Asn) and the lysine 751 glutamine (Lys751Gln), have also been related to reduced DNA repair capacity and enhanced cisplatin sensitivity.[14]

Overall, these observations suggest that several single-nucleotide polymorphisms (SNP) may contribute to interindividual variability in platinum inactivation and DNA repair capacity and, therefore, could be valuable predictive factors for platinum-chemotherapy outcome. Although several studies have examined these variables, there are nu-merous discrepancies in the pattern of genotype associations between studies. We decided to investigate the predictive value of the SNPs in an independent group of Greek patients with NSCLC. In the current anal-ysis, 8 genetic polymorphisms of 6 genes (GSTP1, GSTT1, GSTM1, ERCC1, XPD, XRCC1) involved in DNA repair and metabolism of cisplatin were evaluated as possible biomarkers associated with response, toxicity, and overall survival (OS) of patients with advanced NSCLC treated with first- or second-line platinum-based chemotherapy.

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