This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Etienne-Grimaldi, M.-C. Articles by Milano, G. Search for Related Content PubMed PubMed Citation Articles by Etienne-Grimaldi, M.-C. Articles by Milano, G.

K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy

Authors' Affiliations: ¹ Oncopharmacology Department, Centre Antoine Lacassagne; ² Clinique Saint George; ³ CHU de Nice, Nice, France; ⁴ UMR-S775, Université René Descartes, Paris, France; ⁵ Institut Paoli Calmettes; ⁶ CHU de Marseille, Marseille, France; ⁷ CHU de Grenoble, Grenoble, France; and ⁸ CHU de Clermont-Ferrand, Clermont-Ferrand, France

Requests for reprints: Gérard Milano, Oncopharmacology Department, Centre Antoine Lacassagne, 33, Avenue de Valombrose, 06189 Nice Cedex 2, France. Phone: 33-492-03-15-53; Fax: 33-493-81-71-31; E-mail: gerard.milano{at}nice.fnclcc.fr.

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.

This article has been cited by other articles:

				F. Loupakis, L. Pollina, I. Stasi, A. Ruzzo, M. Scartozzi, D. Santini, G. Masi, F. Graziano, C. Cremolini, E. Rulli, et al. PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer J. Clin. Oncol., June 1, 2009; 27(16): 2622 - 2629. [Abstract] [Full Text] [PDF]

				S. Staal, M. J. O'Connell, and C. J. Allegra The Marriage of Growth Factor Inhibitors and Chemotherapy: Bliss or Bust? J. Clin. Oncol., April 1, 2009; 27(10): 1545 - 1548. [Full Text] [PDF]

				A. Sartore-Bianchi, S. Artale, S. Veronese, M. Gambacorta, and S. Siena In Reply J. Clin. Oncol., January 1, 2009; 27(1): 159 - 159. [Full Text] [PDF]