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Original Contribution
October 27, 2010

Association of KRAS p.G13D Mutation With Outcome in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer Treated With Cetuximab

Author Affiliations

Author Affiliations: Center for Human Genetics, University of Leuven, Leuven, Belgium (Drs De Roock and Tejpar); Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada (Dr Jonker); Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Turin, Italy (Drs Di Nicolantonio, Arena, and Bardelli and Ms Lamba); Italian Foundation for Cancer Research, Institute of Molecular Oncology (Drs Di Nicolantonio and Bardelli), and the Falck Division of Medical Oncology, Ospedale Niguarda Ca’Granda (Drs Sartore-Bianchi and Siena), Milano, Italy; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada (Drs Tu and O’Callaghan); Laboratory of Molecular Diagnostics, Institute of Pathology, Locarno, Switzerland (Dr Frattini); Cliniques Universitaires Saint-Luc, Brussels, Belgium (Dr Piessevaux); Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium (Drs Van Cutsem and Tejpar); Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Dr Khambata-Ford); Peter MacCallum Cancer Centre, University of Melbourne, and Australasian Gastrointestinal Trials Group, Melbourne, Australia (Dr Zalcberg); National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (Dr Simes); and Flinders Medical Centre and Flinders University, Adelaide, Australia (Dr Karapetis). Dr De Roock is now with the Department of General Medical Oncology, University Hospital Gasthuisberg.

JAMA. 2010;304(16):1812-1820. doi:10.1001/jama.2010.1535
Abstract

Context Patients with metastatic colorectal cancer who have KRAS codon 12– or KRAS codon 13–mutated tumors are presently excluded from treatment with the anti–epidermal growth factor receptor monoclonal antibody cetuximab.

Objective To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations.

Design, Setting, and Patients We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received off-study treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab.

Main Outcome Measures The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival.

Results In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n = 32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P = .005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P = .004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P = .003). In vitro and mouse model analysis showed that although p.G12V-mutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells.

Conclusions In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.

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