Population-based Screening for BRAFV600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis

Abstract

Purpose: BRAF V600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing.Experimental Design: We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAF V600E testing. Outcomes among IHC-detected BRAF V600E mCRC (BRAF IHC ) were compared with patients with next-generation sequencing (NGS)-identified BRAF V600E -mutated mCRC from two institutions (BRAF NGS ) with patients spanning from 2004 to 2018.Results: All-stage population prevalence of BRAF V600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P ¼ 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAF IHC had worse median overall survival (mOS) than BRAF NGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89-4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAF V600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96-2.27; P ¼ 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line.Conclusions: Patients with BRAF V600E -mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.

FOLFOXIRI plus Bevacizumab Versus FOLFOX plus Panitumumab for Metastatic Left-Sided RAS/BRAF Wild-Type Colorectal Cancer: Which “Side” Are You On?

“…Although there are mixed results around the use of FOLFOXIRI + bevacizumab for the first‐line treatment of BRAF V600E ‐mutated colorectal cancer in the recent meta‐analyses, it intuitively makes sense that one may want to use one's most aggressive option first, as these patients are prone to rapid deterioration and treatment attrition is high. A recent population‐based study showed that only 26% of patients with BRAF V600E ‐mutated colorectal cancer receive second‐line therapy [13].…”

The Prognostic Value of Locoregional Interventions for BRAF V600E Metastatic Colorectal Cancer: A Retrospective Cohort Analysis

“…Secondly, the number of patients with CRLM or LLM in our center was small, and thus, the results should be interpreted with caution. Thirdly, MMR or MSI status data were insufficient to analyze the mismatch repair system in patients with the BRAF V600E mutation; however, different survival outcomes were noted in advanced and mCRC with the BRAF V600E mutation [ 39 , 40 ]. Besides, in this cohort, we only identified one patient (1.1%) as dMMR, which is much lower than in western countries [ 41 ].…”

BRAF testing in metastatic colorectal carcinoma and novel, chemotherapy-free therapeutic options

“…Chu et al. investigated outcomes of immunohistochemical (IHC) and NGS testing in a cohort of almost 1900 CRC patients [ 65 ]. The rate of false-positive IHC tests was 17%; however, confirmatory re-testing by NGS was performed in only 43% of the IHC-tested patients.…”