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ctDNA positivity linked to increased risk of brain metastases in advanced solid tumorsctDNA in blood and spinal fluid predicts brain metastases risk

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Key Takeaway
Consider ctDNA testing for risk stratification of brain metastases in advanced solid tumors, but recognize the observational nature of the evidence.

This systematic review and meta-analysis evaluated the diagnostic and prognostic value of circulating tumor DNA (ctDNA) for brain metastases in patients with advanced solid tumors, including 1763 patients across multiple studies. The analysis found that ctDNA positivity was associated with a significantly increased risk of developing brain metastases (OR=1.67, 95% CI: 1.24-2.26, p=0.001). Next-generation sequencing (NGS) showed notably higher predictive performance for brain metastases (OR=5.50, 95% CI: 1.92-15.76, p=0.002). Patients with brain metastases had significantly higher plasma ctDNA levels compared to those without (SMD=0.51, 95% CI: 0.18-0.84, p=0.002). Additionally, CSF ctDNA positivity was strongly associated with worse overall survival (HR=2.75, 95% CI: 1.75-4.32, p<0.001).

The authors note that 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 could enhance risk assessment and guide treatment decisions. However, as a meta-analysis of observational data, causal relationships cannot be established. Adverse events were not reported in the included studies, and limitations such as heterogeneity across studies were not detailed. The findings should be interpreted cautiously until confirmed in prospective trials.

A large analysis of 1,763 patients with advanced solid tumors found that the presence of circulating tumor DNA (ctDNA) in blood or cerebrospinal fluid (CSF) is linked to a higher risk of brain metastases and poorer survival. The study, a systematic review and meta-analysis, combined data from multiple studies to assess the diagnostic and prognostic value of ctDNA.

Patients with ctDNA in their blood had a 67% higher chance of having brain metastases compared to those without detectable ctDNA. Those with ctDNA in their spinal fluid had nearly three times the risk of dying during follow-up. The predictive power of next-generation sequencing (NGS) for brain metastases was also notably higher when ctDNA was present.

Importantly, the study did not report any safety concerns because it analyzed existing data rather than testing a new treatment. The findings suggest that ctDNA testing, which is non-invasive, could help doctors identify patients at higher risk for brain metastases and tailor monitoring or treatment accordingly.

However, this is a meta-analysis of observational studies, so it cannot prove cause and effect. The results should be interpreted cautiously, and more research is needed before these tests become routine. For now, the findings highlight the potential of ctDNA as a tool for risk assessment in advanced cancer.

What this means for you:
ctDNA in blood or spinal fluid may help predict brain metastases risk, but more research is needed.

Study Details

Study typeMeta analysis
EvidenceLevel 1
PublishedJun 2026
View Original Abstract ↓
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.
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