PURPOSE BRAFV600E 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. PATIENTS AND METHODS We reviewed a population-based cohort of 1898 patients with CRC that underwent reflexive immunohistochemistry (IHC) mismatch repair (MMR) & BRAFV600E testing. Outcomes among IHC detected BRAFV600E mCRC (BRAFIHC) were compared to patients with next generation sequencing identified BRAFV600E mutated mCRC from two institutions (BRAFNGS) with patients spanning from 2004-2018. RESULTS All-stage population prevalence of BRAFV600E was 12.5% (238/1898) 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. BRAFIHC had worse median overall survival (mOS) than BRAFNGS (5.5 vs 20.4 months, hazard ratio (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, BRAFV600E tumors with deficient MMR showed worse mOS compared to 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. CONCLUSION BRAFV600E mutated mCRC has 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.
Journal
Clinical Cancer Research, 2020