Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAFV600E mutation

Abstract

BRAF^V600E mutations are found in 10% of colorectal cancers (CRCs). The low frequency of this mutation therefore makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAF^V600E can be defined. Knowledge of the concordance between primary–metastasis pairs and the impact of BRAF^V600E on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I–IV) evenly matched for age (V600E, KRAS mutation and microsatellite instability (MSI) were determined and correlated with clinical features and patient outcomes. In multivariate analyses, increasing patient age (p = 0.04), female gender (p = 0.0005) and right‐sided tumor location (p < 0.0001) were independently associated with BRAF^V600E. The prevalence of BRAF^V600E was considerably higher in older (age > 70) females with KRAS wild‐type right‐sided colon cancers (50%) compared to the unselected cohort (10%). BRAF^V600E was associated with inferior overall survival in metastatic CRC (HR = 2.02; 95% CI 1.26–3.26), particularly evident in patients treated with chemotherapy, and is independent of MSI status. BRAF status was concordant in all primary tumors and matched metastases (79 wild‐type pairs and two mutant pairs). Clinicopathological and molecular features can identify CRC patients with a higher prevalence of BRAF^V600E. Patients with BRAF^V600E wild‐type primary tumor do not appear to acquire the mutation in their metastases, and BRAF^V600E is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAF^V600E inhibitors in CRC.