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

Colorectal cancer patients who had wild-type (normal) KRAS gene status, but mutations in the BRAF, had a poor prognosis in spite of treatment with cetuximab.

BRAF

Orlando, FL—In metastatic colorectal cancer, mutations in the

KRAS

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)

BRAF

gene status but mutations in

had a poor prognosis in spite of treatment with cetuximab, reported Eric Van Cutsem, MD, of University Hospital Gasthuisberg, Leuven, Belgium,

at the 2010 Gastrointestinal Cancers Symposium.

KRAS

Patients with wild-type

typically respond to inhibitors of epidermal growth factor receptor (EGFR).

P

At the 2009 ESMO/ECCO meeting in Berlin, Dr Van Cutsem presented the main results of the phase III CRYSTAL trial of 1198 patients with metastatic colorectal cancer, in which treatment with cetuximab and FOLFIRI was associated with a 30% reduction in progression (

P

= 0.0012) and a 20% reduction in mortality (

KRAS

= 0.0093), versus FOLFIRI alone, in the

wild-type population.

KRAS

At the GI Cancers Symposium, Dr Van Cutsem presented updated data on the wild-type

BRAF

cohort, 83% of whom had tissue samples tested for

BRAF

status. Of these, 6% showed mutations. The

KRAS

mutation was present in 9% of all patients with

wild-type tumors.

KRAS

Overall survival in the

BRAF

wild-type population of 666 patients was dependent upon

status, Dr Van Cutsem reported.

KRAS

In the FOLFIRI plus cetuximab arm, median overall survival was 23.5 months for all

KRAS

wild-type patients and 25.1 months for

BRAF

wild-type/

KRAS

wild-type patients, but just 14.1 months for

BRAF

wild-type/

mutation patients. PFS was, respectively, 9.9 months, 10.9 months, and 8.0 months.

BRAF

In patients with the

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.”