A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU oxaliplatin combination chemotherapy in refractory colorectal cancer

• Published in: British journal of cancer 2004-07, Vol.91 (2), p.344-354
• Main Authors: Stoehlmacher, J, Park, D J, Zhang, W, Yang, D, Groshen, S, Zahedy, S, Lenz, H-J
• Format: Article
• Language: English
• Subjects: Acyltransferases - genetics; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Chemotherapy; Clinical outcomes; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease Progression; DNA Helicases; DNA Repair; DNA-Binding Proteins - genetics; Drug Resistance; Endonucleases - genetics; Enzymes; Epidemiology; Female; Fluorouracil - administration & dosage; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Genes; Genetics and Genomics; Genotype & phenotype; Glutathione Transferase - genetics; Humans; Male; Medical research; Medical sciences; Middle Aged; Molecular Medicine; Multivariate analysis; Oncology; Organoplatinum Compounds - administration & dosage; Oxaliplatin; Polymorphism; Polymorphism, Genetic - genetics; Predictive Value of Tests; Proteins - genetics; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Rate; Thymidylate Synthase - genetics; Time Factors; Toxicity; Transcription Factors; Treatment Outcome; Tumors; X-ray Repair Cross Complementing Protein 1; Xeroderma Pigmentosum Group A Protein; Xeroderma Pigmentosum Group D Protein
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6601975

In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S -transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3′-untranslated region (3′UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 ( P =0.037), 3.25 for GSTP1-105 ( P =0.072), 2.05 for ERCC1-118 ( P =0.037), and 1.65 for TS-3′UTR ( P =0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing ⩾2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P