K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.
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.
Etienne-Grimaldi
Marie-Christine
MC
Oncopharmacology Department, Centre Antoine Lacassagne, Université René Descartes, Paris, France.
Formento
Jean-Louis
JL
Francoual
Mireille
M
François
Eric
E
Formento
Patricia
P
Renée
Nicole
N
Laurent-Puig
Pierre
P
Chazal
Maurice
M
Benchimol
Daniel
D
Delpero
Jean-Robert
JR
Letoublon
Christian
C
Pezet
Denis
D
Seitz
Jean-François
JF
Milano
Gérard
G
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
D002955:Leucovorin; D005472:Fluorouracil