Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer

J Clin Oncol. 2017 Aug 10;35(23):2624-2630. doi: 10.1200/JCO.2016.71.4394. Epub 2017 May 9.


Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 (non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF (V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Codon*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Retrospective Studies
  • Sex Factors
  • Survival Rate


  • Codon
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf