K-ras mutations with colon cancer predict no benefit with cetuximab

NEW YORK (Reuters Health) - When K-ras mutations are present in a colorectal cancer, treatment with cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is no better than supportive care alone, according to a report in The New England Journal of Medicine for October 23.

Prior research has shown that cetuximab can improve the survival and quality of life of colorectal cancer patients who have not responded to chemotherapy. However, it is difficult to predict which patients will benefit from cetuximab therapy, which is relatively expensive.

K-ras is a G-protein that plays a key role in the EGFR signaling pathway. Therefore, mutations in K-ras could affect EGFR signaling, which in turn affects the efficacy of cetuximab.

In the present study, Dr. Christos S. Karapetis, from Flinders University in Adelaide, Australia, and colleagues looked for activating mutations in exon 2 of K-ras in tumor samples from 394 of 572 (68.9%) patients with advanced colorectal cancer who were randomized to receive best supportive care alone or with cetuximab.

Roughly 42% of tumors had K-ras mutations, the report indicates.

With wild-type K-ras tumors, cetuximab therapy increased median overall survival from 4.8 to 9.5 months and progression-free survival from 1.9 to 3.7 months (p < 0.001 for both).

By contrast, with mutated K-ras tumors, cetuximab therapy did not improve overall or progression-free survival, the authors report. The mutation status of K-ras had no bearing on survival in patients who received supportive care alone.

The authors note that the presence of mutated K-ras reliably excludes patients who will not benefit from cetuximab therapy. However, many patients with wild type K-ras tumors also will not benefit from the drug and thus there is a need for additional biomarkers, they add.

The current findings and those from other studies "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," Dr. Wells A. Messersmith, from the University of Colorado Cancer Center, Aurora, and Dr. Dennis J. Ahnen, from the University of Colorado Denver School of Medicine, write in a related editorial.

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