Originally published as JCO Early Release 10.1200/JCO.2005.03.6640 on June 19 2006

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Genetic Variations in Radiation and Chemotherapy Drug Action Pathways Predict Clinical Outcomes in Esophageal Cancer

Xifeng Wu, Jian Gu, Tsung-Teh Wu, Stephen G. Swisher, Zhongxin Liao, Arlene M. Correa, Jun Liu, Carol J. Etzel, Christopher I. Amos, Maosheng Huang, Silvia S. Chiang, Luke Milas, Walter N. Hittelman, Jaffer A. Ajani

From the Departments of Epidemiology, Pathology, Thoracic and Cardiovascular Surgery, Radiation Oncology, Experimental Radiation Oncology, Experimental Therapeutics, GI Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Xifeng Wu, MD, PhD, Department of Epidemiology, Unit 1340, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Blvd, Houston, TX 77030; e-mail: xwu{at}mdanderson.org

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.

published online ahead of print at www.jco.org on June 19, 2006.

Supported by National Cancer Institute (National Institutes of Health) Grants No. CA74880 and CA91846, and an M.D. Anderson Cancer Center multidisciplinary research program grant for esophageal cancer.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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