Association between glutathione S-transferase (GST) P1 polymorphisms and survival of patients with advanced non-small cell lung cancer (NSCLC)

Abstract

7009 Background: Glutathione S-transferase (GST) P1 is a detoxification enzyme with substrate specificity for both exogenous carcinogens and therapeutic compounds. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, we reported that the exon 6 variant genotypes were associated with an increased risk of lung cancer, particularly among men, younger patients, and ever smokers. Increased cancer risk is due to reduced detoxification capacity of carcinogens. The variant genotype may also be associated with better chemotherapy response due to reduced inactivation of chemotherapy agents, and thus better survival in advanced-stage NSCLC patients, a group that is more likely to receive platinum-based chemotherapy. Methods: Stage III and IV NSCLC cases enrolled in a molecular epidemiology study at our institution were identified and genotyped for GSTP1 exons 5 and 6 by PCR-RFLP. There were 425 subjects. Results: Patients with the exon 6 variant genotype (C/T + T/T) had significantly better survival compared to patients with the wildtype genotype (CC) (P=0.037). The median survival time was 16.1 months for patients with the variant genotypes and 11.4 months for those with the wildtype. The better survival was especially apparent in patients who were younger than 55 years old (P=0.020), male (P=0.037), and ever smokers (P=0.032) but not in patients who were older than 55 years females, and never smokers. When we performed multivariate analysis using a Cox proportional hazards model, we detected a reduced hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.8 (95% CI 0.55–1.16). This protective association was statistically significant among younger patients (< 55 years) (HR 0.47, 95% CI 0.23–0.94) and among males (HR 0.65, 95% CI 0.39–1.07). Conclusions: GSTP1 exon 6 variant genotypes may be associated with improved survival among stage III and IV NSCLC patients, particularly in subsets of younger patients, males, and ever smokers. Further studies are warranted. No significant financial relationships to disclose.