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 = 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 = 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.