Clinical Implications of Cell-Free DNA in Managing BRAF V600E Mutation-Positive Colorectal Cancer

Background/Objectives: BRAFV600E-mutant colorectal cancer (CRC) is associated with poor prognosis, and despite the introduction of BEACON therapy, significant treatment challenges remain. This study investigates the clinical utility of BRAFV600E in cell-free DNA (cfDNA BRAFV600E) as a biomarker for real-time treatment monitoring in metastatic cases and for evaluating minimal residual disease (MRD) after curative resection. Methods: This single-center, prospective observational study included 37 patients with BRAFV600E-mutant CRC treated at Nippon Medical School Hospital between April 2017 and June 2024. Patients were divided into two cohorts: Cohort 1 (Stage IV cases): Evaluated cfDNA BRAFV600E for treatment monitoring. Cohort 2 (Stage I–III curatively resected cases): Assessed cfDNA BRAFV600E for recurrence risk prediction. Blood samples were collected before and during treatment and analyzed using droplet digital PCR (ddPCR) to measure cfDNA BRAFV600E levels. Results: Cohort 1 (Stage IV, n = 14): Pre-treatment cfDNA BRAFV600E was detected in 93% of cases. Patients with a decrease in cfDNA BRAFV600E variant allele frequency (VAF) after chemotherapy had significantly longer overall survival (511 vs. 189 days, p = 0.03) than those without a decrease. Cohort 2 (curatively resected, n = 23): cfDNA BRAFV600E was detected in 4/23 patients (17.4%) at 1 month post-surgery. cfDNA BRAFV600E showed better recurrence prediction compared to CEA (100% vs. 18.8%, p = 0.004). Among the seven patients who experienced recurrence, those with postoperative cfDNA BRAFV600E positivity had significantly shorter disease-free survival compared to cfDNA BRAFV600E-negative patients (179 vs. 840 days, p = 0.04). Conclusions: These findings support cfDNA BRAFV600E as a promising biomarker for monitoring treatment response and MRD detection in BRAFV600E-mutant CRC, reinforcing its role in guiding personalized treatment strategies and postoperative surveillance.