Cerebrospinal fluid ctDNA as a prognostic and disease-activity biomarker in leptomeningeal metastases: systematic review, meta-analysis, and implications for CSF-guided care.

PURPOSE: Leptomeningeal disease (LMD) is a devastating complication of advanced solid tumors with limited prognostic and response-assessment tools. Because LMD molecular evolution is frequently compartmentalized behind CNS barriers, cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) may provide CNS-specific molecular readouts of disease activity. We evaluated whether baseline CSF ctDNA profiles and longitudinal ctDNA kinetics associate with survival in LMD.

METHODS

We performed a systematic review and meta-analysis (PROSPERO CRD420251068543) of Embase, PubMed, Cochrane CENTRAL, WHO ICTRP, ClinicalTrials.gov, Europe PMC, and Web of Science from inception through June 2025. Eligible studies included adults with solid-tumor LMD undergoing anti-cancer therapy with CSF ctDNA assessed at baseline and/or serially and reported associations with overall survival (OS) and/or progression-free survival (PFS). Random-effects models pooled hazard ratios (HRs). Longitudinal studies were analyzed separately due to limited availability.

RESULTS

Fourteen studies (n = 963) evaluated baseline CSF ctDNA and two studies (n = 26) evaluated longitudinal kinetics. Adverse (non-reference) baseline ctDNA status (e.g., EGFR mutation positive vs. negative) was associated with inferior OS (pooled HR 2.40, 95% CI 1.73-3.33; I²=36.6%) and PFS (pooled HR 2.45, 95% CI 1.36-4.44; I²=15.5%). Longitudinally, increasing CSF ctDNA variant allele fraction was associated with worse OS (pooled HR 4.11, 95% CI 1.25-13.48; I²=8.5%). Across longitudinal reports, serial CSF ctDNA measurements tracked progression and response.

CONCLUSION

Baseline and serial CSF ctDNA measurements are associated with survival outcomes in LMD and may complement clinical and radiographic assessment. These findings support prospective, standardized, multi-timepoint CSF ctDNA studies in LMD and warrant CSF-access-enabled monitoring to inform therapeutic adaptation.