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K-ras mutations and benefit from cetuximab in advanced colorectal cancer

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dc.contributor.authorKarapetis, C.
dc.contributor.authorKhambata-Ford, S.
dc.contributor.authorJonker, D.
dc.contributor.authorO'Callaghan, C.
dc.contributor.authorTu, D.
dc.contributor.authorTebbutt, N.
dc.contributor.authorSimes, R.
dc.contributor.authorChalchal, H.
dc.contributor.authorShapiro, J.
dc.contributor.authorRobitaille, S.
dc.contributor.authorPrice, T.
dc.contributor.authorShepherd, L.
dc.contributor.authorAu, H.
dc.contributor.authorLanger, C.
dc.contributor.authorMoore, M.
dc.contributor.authorZalcberg, J.
dc.date.issued2008
dc.description.abstractBackground: 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.
dc.description.statementofresponsibilityChristos 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
dc.identifier.citationNew England Journal of Medicine, 2008; 359(17):1757-1765
dc.identifier.doi10.1056/NEJMoa0804385
dc.identifier.issn0028-4793
dc.identifier.issn1533-4406
dc.identifier.orcidPrice, T. [0000-0002-3922-2693]
dc.identifier.urihttp://hdl.handle.net/2440/52398
dc.language.isoen
dc.publisherMassachusetts Medical Soc
dc.source.urihttps://doi.org/10.1056/nejmoa0804385
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectDisease Progression
dc.subjectAntineoplastic Agents
dc.subjectAntibodies, Monoclonal
dc.subjectPalliative Care
dc.subjectDNA Mutational Analysis
dc.subjectMutation
dc.subjectGenes, ras
dc.subjectQuality of Life
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectKaplan-Meier Estimate
dc.subjectAntibodies, Monoclonal, Humanized
dc.subjectErbB Receptors
dc.subjectCetuximab
dc.titleK-ras mutations and benefit from cetuximab in advanced colorectal cancer
dc.typeJournal article
pubs.publication-statusPublished

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