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Type: Journal article
Title: K-ras mutations and benefit from cetuximab in advanced colorectal cancer
Author: Karapetis, C.
Khambata-Ford, S.
Jonker, D.
O'Callaghan, C.
Tu, D.
Tebbutt, N.
Simes, R.
Chalchal, H.
Shapiro, J.
Robitaille, S.
Price, T.
Shepherd, L.
Au, H.
Langer, C.
Moore, M.
Zalcberg, J.
Citation: New England Journal of Medicine, 2008; 359(17):1757-1765
Publisher: Massachusetts Medical Soc
Issue Date: 2008
ISSN: 0028-4793
Statement of
Christos S. Karapetis, Shirin Khambata-Ford, Derek J. Jonker, Chris J. O'Callaghan, Dongsheng Tu, Niall C. Tebbutt, R. John Simes, Haji Chalchal, Jeremy D. Shapiro, Sonia Robitaille, Timothy J. Price, Lois Shepherd, Heather-Jane Au, Christiane Langer, Malcolm J. Moore and John R. Zalcberg
Abstract: Background: Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. Methods: We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. Results: Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97). Conclusions: Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone.
Keywords: Humans
Colorectal Neoplasms
Disease Progression
Antineoplastic Agents
Antibodies, Monoclonal
Palliative Care
DNA Mutational Analysis
Genes, ras
Quality of Life
Aged, 80 and over
Middle Aged
Kaplan-Meier Estimate
Antibodies, Monoclonal, Humanized
ErbB Receptors
DOI: 10.1056/NEJMoa0804385
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