title: Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses.
abstract: OBJECTIVE
  The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU-folinic acid.
  
  
  METHODS
  Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively.
  
  
  RESULTS
  p53 mutations were observed in 56.7% of metastases. TS activity was significantly higher in 2R/3R tumors as compared with 2R/2R or 3R/3R. TS activity in metastasis was the only parameter linked to clinical responsiveness (responders exhibited the lower TS, P =.047). Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P =.040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P =.035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P =.018) were the only significant biologic predictors of specific survival. Stepwise analysis did not discriminate between TS activity and TS polymorphism.
  
  
  CONCLUSIONS
  Present results confirm the value of tumoral TS activity for predicting FU responsiveness, point out the importance of detailed p53 mutation analysis for predicting survival, and suggest that TS genotype in primary tumor carries a prognostic value similar to that of TS activity.
authors.affiliation: Centre Antoine Lacassagne and Centre Hospitalier Universitaire, Nice, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne
authors.forename: Maurice
authors.initials: M
authors.lastname: Chazal
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Nicolas
authors.initials: N
authors.lastname: Magné
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Formento
authors.forename: Mireille
authors.initials: M
authors.lastname: Francoual
authors.forename: Patricia
authors.initials: P
authors.lastname: Formento
authors.forename: Nicole
authors.initials: N
authors.lastname: Renée
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chamorey
authors.forename: André
authors.initials: A
authors.lastname: Bourgeon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Delpero
authors.forename: Christian
authors.initials: C
authors.lastname: Letoublon
authors.forename: Denis
authors.initials: D
authors.lastname: Pezet
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000032:analysis / Q000235:genetics*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil