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

Jeanne Tie, Peter Gibbs, Lara Lipton, Michael Christie, Robert N. Jorissen, Antony W. Burgess, Matthew Croxford, Ian Jones, Rachel Langland, Suzanne Kosmider, Daniel McKay, Gideon Bollag, Keith Nolop, Oliver M. Sieber, Jayesh Desai

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147 Citations (Scopus)

Abstract

BRAFV600E 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 BRAFV600E can be defined. Knowledge of the concordance between primary - metastasis pairs and the impact of BRAFV600E on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I-IV) evenly matched for age (<70 and ≥70), gender and tumor location (right, left and rectum), and 81 primary - metastasis pairs. BRAFV600E, 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 BRAFV600E. The prevalence of BRAFV600E was considerably higher in older (age > 70) females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E 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 BRAFV600E. Patients with BRAF V600E wild-type primary tumor do not appear to acquire the mutation in their metastases, and BRAFV600E is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAFV600E inhibitors in CRC.

Original languageEnglish
Pages (from-to)2075-2084
JournalInternational Journal of Cancer
Volume128
Issue number9
DOIs
Publication statusPublished - 1 May 2011
Externally publishedYes

Keywords

  • BRAF
  • Colorectal cancer
  • Prognosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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