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

• Published in: Clinical cancer research 2008-08, Vol.14 (15), p.4830-4835
• Main Authors: Etienne-Grimaldi, Marie-Christine, Formento, Jean-Louis, Francoual, Mireille, François, Eric, Formento, Patricia, Renée, Nicole, Laurent-Puig, Pierre, Chazal, Maurice, Benchimol, Daniel, Delpero, Jean-Robert, Letoublon, Christian, Pezet, Denis, Seitz, Jean-François, Milano, Gérard
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Female; fluoropyrimidines; Fluorouracil - administration & dosage; Genes, ras; Humans; K-Ras; Leucovorin - administration & dosage; Liver Neoplasms - pathology; Male; Middle Aged; Mutation; Neoplasm Metastasis; Polymorphism, Genetic; predictive marker; prognostic marker; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4906

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.