title: Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) 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 (<70 and ≥70), gender and tumor location (right, left and rectum), and 81 primary-metastasis pairs. BRAF(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.
authors.affiliation: Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Melbourne, Australia.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tie
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Michael
authors.initials: M
authors.lastname: Christie
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.forename: Matthew
authors.initials: M
authors.lastname: Croxford
authors.forename: Ian
authors.initials: I
authors.lastname: Jones
authors.forename: Rachel
authors.initials: R
authors.lastname: Langland
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kosmider
authors.forename: Daniel
authors.initials: D
authors.lastname: McKay
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Keith
authors.initials: K
authors.lastname: Nolop
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
mesh_terms: D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf