Baseline and on-treatment dynamics of <i>BRAF</i> V600E circulating tumor DNA in metastatic colorectal cancer: A systematic review and meta-analysis.

Abstract

e15570 Background: BRAF V600E–mutated metastatic colorectal cancer (mCRC) represents a biologically distinct subtype with poor prognosis and limited benefit from standard chemotherapy. Although targeted regimens have improved outcomes, reliable biomarkers to refine risk stratification and monitor treatment benefit remain lacking. We conducted a systematic review and meta-analysis to evaluate the value of circulating tumor DNA (ctDNA)–based assessment of BRAF V600E in patients with BRAF V600E–mutated mCRC. Methods: PubMed, Embase, and Cochrane were systematically searched for studies including patients with BRAF V600E–mutated mCRC treated with systemic therapy and undergoing baseline and/or prospective serial assessment of BRAF V600E ctDNA. Studies involving localized disease, BRAF wild-type mCRC, or without ctDNA evaluation were excluded. Outcomes of interest were overall survival (OS) and progression-free survival (PFS) according to baseline ctDNA variant allele frequency (VAF; low vs high) and longitudinal ctDNA changes during treatment, including clearance or VAF reduction between two timepoints. Pooled hazard ratios (HRs) were estimated using random-effects models, with heterogeneity assessed using I 2 statistics and Cochran’s Q test. Results: Among 2,365 screened records, 9 studies met inclusion criteria, encompassing 1,269 patients. Four studies (44.4%) enrolled patients treated in the first-line setting, while the remaining studies evaluated later-line therapies. Six studies (66.7%) investigated anti- BRAF –based targeted regimens. ctDNA assessment was performed using next-generation sequencing in 56.6% of studies and digital PCR in 44.4%. Low baseline BRAF V600E ctDNA VAF was associated with improved OS (HR 0.36; 95% CI 0.30-0.41; I² = 0%) and PFS (HR 0.38; 95% CI 0.27-0.54; I² = 10.4%) compared with high baseline VAF. On-treatment ctDNA clearance was associated with superior OS (HR 0.36; 95% CI 0.17-0.78; I² = 4.9%) and PFS (HR 0.24; 95% CI 0.08-0.69; I² = 52.3%). Similarly, reduction in BRAF V600E ctDNA VAF during therapy correlated with improved OS (HR 0.37; 95% CI 0.17-0.78; I² = 0%) and PFS (HR 0.34; 95% CI 0.14-0.83; I² = 0%). Conclusions: In patients with BRAF V600E–mutated mCRC, both baseline BRAF V600E ctDNA VAF and longitudinal changes in ctDNA levels are consistently associated with survival outcomes, supporting the role of ctDNA as a prognostic biomarker in this population. These findings support the clinical integration of ctDNA to refine risk stratification and to inform treatment adaptation strategies, which should be prospectively validated.