K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.

Abstract

PURPOSE 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. EXPERIMENTAL DESIGN 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.

DOI: 10.1158/1078-0432.CCR-07-4906

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@article{EtienneGrimaldi2008KRasMA, title={K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.}, author={Marie-Christine Etienne-Grimaldi and J J Formento and Mireille Francoual and {\'E}ric François and Patricia Formento and Nicole Ren{\'e}e and Pierre Laurent-Puig and Maurice Chazal and Daniel Romeu Benchimol and J R Delpero and Christian L{\'e}toublon and Denis Pezet and J. F. Seitz and Gerard A Milano}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2008}, volume={14 15}, pages={4830-5} }