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

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

Jeremy C Jones  1 , Lindsay A Renfro  1 , Humaid O Al-Shamsi  1 , Alexa B Schrock  1 , Andrew Rankin  1 , Ben Y Zhang  1 , Pashtoon M Kasi  1 , Jesse S Voss  1 , Alexis D Leal  1 , James Sun  1 , Jeffrey Ross  1 , Siraj M Ali  1 , Joleen M Hubbard  1 , Benjamin R Kipp  1 , Robert R McWilliams  1 , Scott Kopetz  1 , Robert A Wolff  1 , Axel Grothey  1
Affiliations
Multicenter Study

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

Jeremy C Jones et al. J Clin Oncol. .

Abstract

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.

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Figures

Fig 1.
Fig 1.
Patient flow diagram. FM, Foundation Medicine; MC, Mayo Clinic; MDACC, The University of Texas MD Anderson Cancer Center; NGS, next-generation sequencing; WT, wild type.
Fig 2.
Fig 2.
Non-V600 BRAF codon mutation distribution.
Fig 3.
Fig 3.
Kaplan-Meier estimates of overall survival (OS) according to BRAF mutation status, with simultaneous 95% CIs displayed as shaded regions, for (A) all institutions and (B) Mayo Clinic only.
See this image and copyright information in PMC

Comment in

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