This variant could account for an additional 12% of nonresponsive cases.

Researchers have found that metastatic colorectal cancer patients with a BRAF mutation are less likely respond to anti-EGFR therapy. While mutations in the KRAS gene have previously explained about 30–40% of nonresponsive cases, the team now suggests that BRAF mutations may account for another 12% of resistant cases.

In the study, investigators conducted a genetic analysis of 113 tumors taken from patients with advanced colorectal cancer who had been treated with cetuximab or panitumumab. KRAS mutations were present in 30% of the patients, and a BRAF V600E mutation was detected in 11 of the remaining 79 patients who did not have KRAS mutations, which represented 10% of the total number of patients. Mutations in the two genes are mutually exclusive.

“None of the patients with tumors containing BRAF mutations had responded to the treatment, and in cases where the treatment did work, none of those patients had BRAF mutations,” reports Federica Di Nicolantonio, Ph.D., a postdoctoral research fellow at the Institute for Cancer Research and Treatment at the University of Turin School of Medicine.  “This shows that for anti-EGFR therapy to work, the BRAF gene must be the wild type and suggests that BRAF status could be a useful biomarker for selecting patients suitable for anti-EGFR treatment.”

The researchers also tested the influence of BRAF mutation on the success of anti-EGFR treatment prospectively by conducting a laboratory study that involved adding the drugs to colorectal cells altered to contain the mutated version of the BRAF gene. They found that introducing the mutated gene dramatically impaired the ability of cetuximab and panitumumab to work.

They then added the BRAF inhibitor sorafenib. That restored the sensitivity of the cells to the anti-EGFR treatment, with the combination of the cetuximab and sorafenib resulting in massive death of the cells carrying the mutated BRAF gene.
The team cautions that the research does not complete the picture of resistance to EGFR inhibitors. In spite of the predictive value of both KRAS and BRAF mutations, in the study,  52 % of nonresponsive patients did not have mutations in either gene.

The research was presented at the 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva on Thursday, October 23.


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