title: K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.
abstract: OBJECTIVE
  K-Ras mutations predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy.
  
  
  METHODS
  This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G>C mutation), methylenetetrahydrofolate reductase polymorphism (677C>T, 1298A>C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression.
  
  
  RESULTS
  Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival.
  
  
  CONCLUSIONS
  The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.
authors.affiliation: Oncopharmacology Department, Centre Antoine Lacassagne, Université René Descartes, Paris, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Formento
authors.forename: Mireille
authors.initials: M
authors.lastname: Francoual
authors.forename: Eric
authors.initials: E
authors.lastname: François
authors.forename: Patricia
authors.initials: P
authors.lastname: Formento
authors.forename: Nicole
authors.initials: N
authors.lastname: Renée
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Maurice
authors.initials: M
authors.lastname: Chazal
authors.forename: Daniel
authors.initials: D
authors.lastname: Benchimol
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: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
chemical_list: D002955:Leucovorin; D005472:Fluorouracil