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. 2025 Mar 18;12(4):600-617.
doi: 10.1093/nop/npaf032. eCollection 2025 Aug.

Evaluating liquid biopsy biomarkers for early detection of brain metastasis: A systematic review

Jinyue Yu  1   2 , Craig Paterson  1   2 , Phillippa Davies  1   2 , Jennifer C Palmer  1   2 , Julian P T Higgins  1   2 , Kathreena M Kurian  3   1   2
Affiliations

Evaluating liquid biopsy biomarkers for early detection of brain metastasis: A systematic review

Jinyue Yu et al. Neurooncol Pract. .

Abstract

Background: Brain metastases (BMs) are the most common intracranial malignancy in adults, contributing significantly to cancer-related morbidity and mortality. Early detection is critical for optimizing treatment and improving survival. This systematic review evaluates the diagnostic potential of liquid biopsy biomarkers for detecting BM from lung, breast, and other cancers.

Methods: A comprehensive search was conducted in MEDLINE, Embase, and BIOSIS databases using keywords related to liquid biopsy, biomarkers, and BMs. Data on participant characteristics, diagnostic reference standards, types of biomarkers, primary cancer origins, and diagnostic outcomes were independently extracted. Diagnostic performance was evaluated using sensitivity, specificity, and area under the curve (AUC). Risk of bias was assessed using the QUADAS-2 tool.

Results: Thirty-one studies involving 5676 participants were included, assessing biomarkers such as cfDNA, miRNAs, proteins (eg, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], S100B), metabolomic profiles, and multi-marker models. NfL and GFAP emerged as the most promising biomarkers, demonstrating moderate to strong diagnostic performance across multiple cancer types. Multi-marker models combining NfL and GFAP achieved sensitivity and specificity exceeding 90%. S100B showed variable performance due to differences in study designs and thresholds. Emerging biomarkers like cfDNA and metabolomic profiles showed potential but require further validation.

Conclusions: Liquid biopsy biomarkers, particularly NfL and GFAP, hold promise for non-invasive BM detection. Clinical utility may be in the initial cancer workup for localized tumor to prompt brain imaging. Future research is required to validate biomarkers in larger, diverse populations across different cancer types.

Keywords: biomarkers; brain metastasis; early detection; liquid biopsy; systematic review.

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Conflict of interest statement

The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

Figures

Figure 1.
Figure 1.
PRISMA flow chart of this systematic review.
Figure 2.
Figure 2.
Forest plot of the diagnostic performance of biomarkers for lung cancer brain metastases (LCBM). Abbreviation: AUC, area under the receiver-operating characteristic curve. Studies are identified by author and year, with AUC values and 95% confidence intervals (CIs) indicating diagnostic accuracy for differentiating LCBM-positive and negative cases.
Figure 3.
Figure 3.
Forest plot of the diagnostic performance of biomarkers for breast cancer brain metastases (BCBM). Abbreviation: AUC, area under the receiver-operating characteristic curve. Studies are identified by author and year, with AUC values and 95% confidence intervals (CIs) indicating diagnostic accuracy for differentiating BCBM-positive and negative cases.
See this image and copyright information in PMC

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