BRAF Mutations Predict Resistance to Treatment for Advanced Colorectal Cancer; New Gene-Expression Assay Predicts Response to Chemotherapy Combination
October 28, 2008 — Mutations in the BRAF gene limit the response to anti-epidermal growth-factor receptor (anti-EGFR) therapy in patients with metastatic colorectal cancer, researchers reported at the 20th Annual European Organization for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics, in Geneva, Switzerland. BRAF-mutation status can therefore help identify patients who are most likely to benefit from treatment with the monoclonal antibodies cetuximab (Erbitux; ImClone, Merck) and panitumumab (Vectibix, Amgen).
“Our data clearly point out BRAF mutations as another determinant of resistance to EGFR-targeted monoclonal antibodies,” said lead author Federica Di Nicolantonio, PharmD, PhD, from the Institute for Cancer Research and Treatment at the University of Turin School of Medicine, in Italy.
She pointed out that none of the patients in their study who had tumors containing BRAF mutations responded to anti-EGFR treatment. Conversely, none of the patients who responded to treatment had BRAF mutations.
Panitumumab and cetuximab are effective in an estimated 10% to 20% of chemotherapy-refractory metastatic colorectal cancer patients. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab, as previously reported by Medscape Oncology, and account for approximately 30% to 40% of resistant patients.
“None of the KRAS-mutated patients had BRAF mutations; mutations in these 2 genes are known to be mutually exclusive in colorectal cancer,” Dr. Di Nicolantonio told Medscape Oncology. “The overall frequency of BRAF-V600E mutations in our entire cohort was 10%, which is well within the published range.”
The goal of this study was to retrospectively analyze objective tumor responses, time to progression, overall survival, and the mutational status of KRAS and BRAF in 114 tumors from patients with advanced colorectal cancer who had been treated with cetuximab or panitumumab. Their secondary objective was to assess the effect of mutated BRAF on cetuximab or panitumumab response in cellular models of colorectal cancer.
In their analysis, the researchers found that KRAS mutations were present in 30% of patients and were associated with resistance to cetuximab or panitumumab. The BRAF-V600E mutation was detected in 11 of 80 patients who had wild-type KRAS. Patients with BRAF-mutated tumors also had significantly shorter progression-free and overall survival than those with wild-type BRAF tumors.
The researchers also prospectively evaluated the influence of BRAF mutations on the success of anti-EGFR treatment in a laboratory study with a cellular model of colorectal cancer. The introduction of the oncogenic BRAF-V600E allele dramatically impaired the therapeutic effect of cetuximab and panitumumab, but treatment with the BRAF inhibitor sorafenib (Nexavar, Bayer) restored sensitivity to the anti-EGFR treatment. Combining cetuximab with sorafenib produced a synergistic effect that was associated with a massive induction of caspase-mediated apoptosis in BRAF-mutated cells.
“BRAF mutations likely explain another 10% to 15% of nonresponsive cases,” said Dr. Di Nicolantonio, “But we need other groups to independently verify our findings in other cohorts of patients.”
“If BRAF mutations are confirmed to be another adverse predictive molecular marker, then oncologists and pathologists should certainly consider testing BRAF, alongside KRAS, before starting treatment with EGFR-targeted monoclonal antibodies,” she added.
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