Cerebral spinal fluid analyses and therapeutic implications for leptomeningeal metastatic disease

Purpose: To review applications of cerebral spinal fluid (CSF) biomarkers for the diagnosis, monitoring and treatment of leptomeningeal metastatic disease (LMD) among patients with metastatic solid tumors.

Methods: A narrative review identified original research related to CSF biomarkers among patients with metastatic solid tumors and LMD. Pre-clinical research (e.g. studies conducted in animal models) was not included. A descriptive analysis of literature was undertaken, with a focus on clinical applications related to the diagnosis, monitoring and treatment of LMD.

Results: The low cellularity of CSF in comparison to plasma is an advantage for liquid biopsy, given that circulating tumor DNA (ctDNA) is not significantly diluted by genomic DNA from non-cancer cells. This results in higher variant allelic frequencies and increased sensitivity in detecting ctDNA compared to plasma. However, the clinical significance of positive ctDNA and/or circulating tumor cells (CTCs) in the CSF, particularly in the absence of other signs of LMD (either clinical and/or radiological), remains unclear. While the use of CSF liquid biopsy to monitor treatment response is promising, this approach requires prospective validation using larger sample sizes prior to adoption in routine clinical care. Discovery efforts involving proteomics and metabolomics have potential to identify proteins involved in the regulation of energy metabolism, vasculature, and inflammation in LMD, which in turn, may offer insights into novel treatment approaches.

Conclusion: CSF liquid biopsy should be incorporated in prospective studies for patients with LMD to validate promising diagnostic and/or predictive biomarkers of treatment response, as well as new therapeutic targets.