Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer

Abstract

Purpose: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. Methods: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. Results: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). Conclusion: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes. © 2006 by American Society of Clinical Oncology.