BRAF Mutation Emerging as Prognostic in KRAS Wild-Type mCRC Patients

In metastatic colorectal cancer (mCRC), mutations in the BRAF gene are emerging as prognostic indicators of worse outcomes. The latest evidence comes from an updated analysis of the CRYSTAL study, in which patients who had wild-type (normal) KRAS gene status but mutations in BRAF had a poor prognosis in spite of treatment with cetuximab, reported Eric Van Cutsem, MD, of University Hospital Gasthuisberg, Leuven, Belgium, at the ASCO 2010 Gastrointestinal (GI) Cancers Symposium. Patients with wild-type KRAS typically respond to inhibitors of epidermal growth factor receptor (EGFR).

At the 2009 ESMO/ECCO meeting, Dr Van Cutsem presented the main results of the phase III CRYSTAL trial of 1198 patients with mCRC, in which treatment with cetuximab and FOLFIRI was associated with a 30% reduction in progression (P = .0012) and a 20% reduction in mortality (P = .0093), versus FOLFIRI alone, in the KRAS wild-type population.

At the GI Cancers Symposium, Dr Van Cutsem presented updated data on the wild-type KRAS cohort, 83% of whom had tissue samples tested for BRAF status. Of these, 6% showed mutations. The BRAF mutation was present in 9% of all patients with KRAS wild-type tumors. Overall survival in the KRAS wild-type population of 666 patients was dependent upon BRAF status, Dr Van Cutsem reported.

In the FOLFIRI plus cetuximab arm, median overall survival was 23.5 months for all KRAS wild-type patients and 25.1 months for KRAS wild-type/BRAF wild-type patients, but just 14.1 months for KRAS wild-type/BRAF mutation patients. PFS was, respectively, 9.9 months, 10.9 months, and 8.0 months.

In patients with the BRAF mutation, cetuximab had no benefit over FOLFIRI alone, as the differences between the experimental and control arms in this wild-type population were not statistically significant. “This final analysis confirms KRAS tumor mutation status

to be a predictive factor across all efficacy endpoints examined for cetuximab in combination with FOLFIRI,” Dr Van Cutsem said. “And it suggests that BRAF tumor mutations are a poor prognostic factor in first-line metastatic colorectal cancer.”