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

Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patien...

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Published in:	Journal of clinical oncology Vol. 24; no. 23; pp. 3789 - 3798
Main Authors:	XIFENG WU, JIAN GU, CHIANG, Silvia S, MILAS, Luke, HITTELMAN, Walter N, AJANI, Jaffer A, WU, Tsung-Teh, SWISHER, Stephen G, ZHONGXIN LIAO, CORREA, Arlene M, JUN LIU, ETZEL, Carol J, AMOS, Christopher I, MAOSHENG HUANG
Format:	Journal Article
Language:	English
Published:	Baltimore, MD American Society of Clinical Oncology 10-08-2006 Lippincott Williams & Wilkins
Subjects:	Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - radiotherapy Adenocarcinoma - surgery Adult Aged Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Biomarkers, Tumor - genetics Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - radiotherapy Carcinoma, Squamous Cell - surgery Chemotherapy, Adjuvant Critical Pathways DNA-Binding Proteins - genetics Dose Fractionation Esophageal Neoplasms - drug therapy Esophageal Neoplasms - genetics Esophageal Neoplasms - radiotherapy Esophageal Neoplasms - surgery Esophagectomy - methods Esophagogastric Junction Esophagus Female Fluorouracil - administration & dosage Gastroenterology. Liver. Pancreas. Abdomen Genes, MDR Genotype Humans Male Medical sciences Methylenetetrahydrofolate Reductase (NADPH2) - genetics Middle Aged Neoadjuvant Therapy - methods Odds Ratio Platinum Compounds - administration & dosage Polymorphism, Single Nucleotide Predictive Value of Tests Prognosis Proportional Hazards Models Radiotherapy, Adjuvant Retrospective Studies Risk Assessment Stomach Neoplasms - drug therapy Stomach Neoplasms - genetics Stomach Neoplasms - radiotherapy Stomach Neoplasms - surgery Survival Analysis Taxoids - administration & dosage Treatment Outcome Tumors X-ray Repair Cross Complementing Protein 1 Drug Chemotherapy Cancerology Prognosis Treatment Genetic variability Esophageal disease Digestive diseases Malignant tumor Predictive factor Esophagus cancer
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Summary:	Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. 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. 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). 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2005.03.6640