^Non-V600BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer

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 ( BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of BRAF mutations in metastatic CRC. We pooled patients in whom 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 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with BRAF mutations, compared with cancers with V600E BRAF ( 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 BRAF-mutant metastatic CRC compared with those with both BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P< .001). Conclusion BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

Mutation status and surgical selection

“…According to the Cremolini et al, patients with mCRC harboring BRAF codon 594‐ and 596‐mutated tumors not only survived longer than those with BRAF V600E mutations but even surpassed patients with wild‐type mCRC (62 vs 12.6 vs 35.9 months). Jones et al corroborated those findings in a large, multi‐institutional cohort. Median OS was significantly longer in patients with non‐V600 BRAF mutations compared with those with V600E BRAF and wild‐type BRAF metastatic CRC (60.7 vs 11.4 vs 43.0 months, respectively; P < 0.001).…”

“…The resultant BRAF mutant is constitutively activated, signals independently of RAS activation, and ultimately leads to increased cellular proliferation and survival . The median survival for V600E BRAF (the most common BRAF mutation) patients with unresectable mCRC has been reported to be as low as less than 12 months . In fact, this poor prognosis seems to be unchanged despite the introduction of modern combination chemotherapies, and may be explained by the distinct pattern of metastatic spread .…”

Eastern Canadian Colorectal Cancer Consensus Conference 2017

“…Compared with their counterparts having mutant BRAF, patients with BRAF wt had a decreased risk of progression and death and better pfs (hr: 0.38; 95% ci: 0.29 to 0.51) and os (hr: 0.35; 95% ci: 0.29 to 0.42) 92 . As shown in a retrospective cohort study by Jones et al 93 , prognosis tends to be better in patients with non-V600E BRAF mutation than in those with V600E.…”

Impact of Metastasectomy in the Multimodality Approach for BRAF V600E Metastatic Colorectal Cancer: The Mayo Clinic Experience

“…Unfortunately, patients with BRAF V600E mCRC are inherently refractory to standard treatment, with a median progression‐free survival (PFS) of 4–6 months with first‐line therapies consisting of a chemotherapy doublet and biologic therapy and 2.5 months after second‐line chemotherapy . Median overall survival (OS) for BRAF V600E mCRC is 9–14 months compared with 43 months for BRAF wild‐type mCRC and up to 60.3 months for mCRC with BRAF mutations other than V600E . Therefore, a lack of exposure time to subsequent lines of therapy highlights that initial treatment decisions are paramount.…”