Pharmacogenetic Profiling in Patients With Advanced Colorectal Cancer Treated With First-Line FOLFOX-4 Chemotherapy

• DOI: 10.1200/jco.2006.08.1844
• Publication Date: 2007-03-30T22:23:16Z
• Authors: Annamaria Ruzzo; Francesco Graziano; Fotios Loupakis; Eliana Rulli; Emanuele Canestrari; Daniele Santini; Vincenzo Catalano; Rita Ficarelli; Paolo Maltese; Renato Bisonni; Gianluca Masi; Gaia Schiavon; Paolo Giordani; Lucio Giustini; Alfredo Falcone; Giuseppe Tonini; Rosarita Silva; Rodolfo Mattioli; Irene Floriani; Mauro Magnani
• Keywords: Adult; Male; Genotype; Organoplatinum Compounds; Leucovorin; 03 medical and health sciences; 0302 clinical medicine; Antineoplastic Combined Chemotherapy Protocols; Humans; Prospective Studies; Methylenetetrahydrofolate Reductase (NADPH2); Aged; Polymorphism, Genetic; Middle Aged; Endonucleases; 3. Good health; DNA-Binding Proteins; Oxaliplatin; THYMIDYLATE-SYNTHASE GENE; GLUTATHIONE-S-TRANSFERASE; SINGLE NUCLEOTIDE POLYMORPHISM; MESSENGER-RNA LEVELS; METHYLENETETRAHYDROFOLATE REDUCTASE; EXCISION-REPAIR; FUNCTIONAL-ANALYSIS; XPD POLYMORPHISMS; TERM SURVIVAL; HUMAN-TISSUES; Pharmacogenetics; 5' Untranslated Regions; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Genotype; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Organoplatinum Compounds; Pharmacogenetics; Polymorphism, Genetic; Prospective Studies; Thymidylate Synthase; Cancer Research; Oncology; Medicine (all); Female; Fluorouracil; 5' Untranslated Regions; Colorectal Neoplasms

PurposeThe objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy.Materials and MethodsConsecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS).ResultsIn 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes.ConclusionA pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.