Association of Circulating Tumor DNA With Brain Metastases: A Systematic Review and Meta‐Analysis

BACKGROUND: Brain metastases are a major contributor to morbidity and mortality in patients with advanced solid tumors; however, early detection and accurate prognostic assessment remain significant clinical challenges. ctDNA is a minimally invasive biomarker that allows real-time monitoring of tumor behavior and provides information on systemic tumor burden and molecular diversity. This study aimed to systematically evaluate the diagnostic and prognostic value of ctDNA in brain metastases, with particular emphasis on the complementary roles of plasma and CSF ctDNA. METHODS: PubMed, Embase, Cochrane Library, Web of Science, and ScienceDirect were systematically searched up to January 2025. Pooled ORs, SMDs, and HRs with 95% CIs were calculated using fixed-effects or random-effects models according to heterogeneity. RESULTS: Fifteen studies (N = 1763) were included. ctDNA positivity was significantly associated with increased risk of brain metastases (OR = 1.67, 95% CI: 1.24-2.26, p = 0.001). Subgroup analysis showed that NGS had notably higher predictive performance (OR = 5.50, 95% CI: 1.92-15.76, p = 0.002). Plasma ctDNA levels were significantly higher in patients with brain metastases (SMD = 0.51, 95% CI: 0.18-0.84, p = 0.002). Notably, CSF ctDNA positivity was strongly associated with worse overall survival (HR = 2.75, 95% CI: 1.75-4.32, p < 0.001). CONCLUSION: Plasma ctDNA serves as a non-invasive biomarker for systemic metastatic risk, whereas CSF ctDNA provides superior prognostic value for intracranial disease. Using these biomarkers together in a clinical workflow could enhance risk assessment and guide treatment decisions in patients with brain metastases.