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Mutations Affect Cancer Susceptibility to Cetuximab

K-ras mutations associated with lower survival in advanced colorectal cancer patients

WEDNESDAY, Oct. 22 (HealthDay News) -- Advanced colorectal cancer patients whose tumors have mutations in the K-ras gene are less likely to respond to cetuximab treatment and have lower survival, researchers report in the Oct. 23 issue of the New England Journal of Medicine.

Christos S. Karapetis, M.D., from Flinders University in Adelaide, Australia, and colleagues looked for activating mutations in exon 2 of the K-ras gene in tumor samples from 394 patients with colorectal cancer who had been randomly assigned to cetuximab plus best supportive care or best supportive care alone. Cetuximab targets the epidermal growth factor receptor (EGFR), which signals through a pathway also used by K-ras. K-ras mutations can lead to EGFR-independent activation of this pathway, the authors note.

The researchers found that 42.3 percent of tumors had at least one activating K-ras mutation, which was significantly associated with both overall and progression-free survival. Patients without mutations who were treated with cetuximab had significantly better median overall survival (9.5 versus 4.8 months, hazard ratio for death 0.55) and progression-free survival (3.7 versus 1.9 months, hazard ratio for progression or death 0.40). In patients with mutations, cetuximab provided no improvement in overall or progression-free survival over supportive care alone, and mutation status had no effect on survival in patients treated with supportive care alone.

The study and others "lead to the reasonable recommendation that all patients with advanced colorectal cancer who are being considered for anti-EGFR therapy should undergo K-ras testing, and if the cancer bears a mutated K-ras gene, they should not receive an antibody that targets EGFR," Wells A. Messersmith, M.D., and Dennis J. Ahnen, M.D., from the University of Colorado in Aurora and Denver, respectively, write in an accompanying editorial.

The study was supported in part by ImClone Systems and Bristol-Myers Squibb, and some study authors and one editorial author disclose financial ties to those and/or and other pharmaceutical companies.

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