K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
Christos S. Karapetis, M.D., Shirin Khambata-Ford, Ph.D., Derek J. Jonker, M.D., Chris J. O'Callaghan, Ph.D., Dongsheng Tu, Ph.D., Niall C. Tebbutt, Ph.D., R. John Simes, M.D., Haji Chalchal, M.D., Jeremy D. Shapiro, M.D., Sonia Robitaille, M.Sc., Timothy J. Price, M.D., Lois Shepherd, M.D.C.M., Heather-Jane Au, M.D., Christiane Langer, M.D., Malcolm J. Moore, M.D., and John R. Zalcberg, M.D., Ph.D.
Background Treatment with cetuximab, a monoclonal antibody directedagainst the epidermal growth factor receptor, improves overalland progression-free survival and preserves the quality of lifein patients with colorectal cancer that has not responded tochemotherapy. The mutation status of the K-ras gene in the tumormay affect the response to cetuximab and have treatment-independentprognostic value.
Methods We analyzed tumor samples, obtained from 394 of 572patients (68.9%) with colorectal cancer who were randomly assignedto receive cetuximab plus best supportive care or best supportivecare alone, to look for activating mutations in exon 2 of theK-ras gene. We assessed whether the mutation status of the K-rasgene was associated with survival in the cetuximab and supportive-caregroups.
Results Of the tumors evaluated for K-ras mutations, 42.3% hadat least one mutation in exon 2 of the gene. The effectivenessof cetuximab was significantly associated with K-ras mutationstatus (P=0.01 and P<0.001 for the interaction of K-ras mutationstatus with overall survival and progression-free survival,respectively). In patients with wild-type K-ras tumors, treatmentwith cetuximab as compared with supportive care alone significantlyimproved overall survival (median, 9.5 vs. 4.8 months; hazardratio for death, 0.55; 95% confidence interval [CI], 0.41 to0.74; P<0.001) and progression-free survival (median, 3.7months vs. 1.9 months; hazard ratio for progression or death,0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients withmutated K-ras tumors, there was no significant difference betweenthose who were treated with cetuximab and those who receivedsupportive care alone with respect to overall survival (hazardratio, 0.98; P=0.89) or progression-free survival (hazard ratio,0.99; P=0.96). In the group of patients receiving best supportivecare alone, the mutation status of the K-ras gene was not significantlyassociated with overall survival (hazard ratio for death, 1.01;P=0.97).
Conclusions Patients with a colorectal tumor bearing mutatedK-ras did not benefit from cetuximab, whereas patients witha tumor bearing wild-type K-ras did benefit from cetuximab.The mutation status of the K-ras gene had no influence on survivalamong patients treated with best supportive care alone. (ClinicalTrials.govnumber, NCT00079066
[ClinicalTrials.gov]
.)
Source Information
From Flinders Medical Centre and Flinders University, Adelaide, Australia (C.S.K.); Bristol-Myers Squibb Research and Development, Princeton, NJ (S.K.-F.); Ottawa Hospital Research Institute, University of Ottawa, Ottawa (D.J.J.); National Cancer Institute of Canada Clinical Trials Group, Kingston, ON (C.J.O., D.T., S.R., L.S.); Austin Health, Melbourne, Australia (N.C.T.); National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (R.J.S.); Allan Blair Cancer Centre, Regina, SK, Canada (H.C.); Cabrini Hospital and Alfred Hospital, Melbourne, Australia (J.D.S.); Queen Elizabeth Hospital and University of Adelaide, Adelaide, Australia (T.J.P.); Cross Cancer Institute, Edmonton, AB, Canada (H.-J.A.); Bristol-Myers Squibb, Wallingford, CT (C.L.); Princess Margaret Hospital, Toronto (M.J.M.); and Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia (J.R.Z.).
Address reprint requests to Dr. Karapetis at the Department of Medical Oncology, Flinders Medical Centre, Flinders Dr., Bedford Park, SA 5042, Australia, or at c.karapetis{at}flinders.edu.au.
K-ras Mutations and Cetuximab in Colorectal Cancer
Marchetti A., Gasparini G., Albitar M., Yeh C., Ma W., De Roock W., Lambrechts D., Tejpar S., Winder T., Scheithauer W., Lang A., Gattenlohner S., Germer C., Muller-Hermelink H.-K., Codacci-Pisanelli G., Spinelli G., Tomao S., Karapetis C., O'Callaghan C., Khambata-Ford S.
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N Engl J Med 2009;
360:833-836, Feb 19, 2009.
Correspondence
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