Cerebrospinal Fluid Biomarkers of Brain Metastasis

Abstract

Abstract INTRODUCTION Cell-free mutational deoxyribonucleic acid (DNA) has been shown to be detectable in the cerebrospinal fluid (CSF) of patients with intra-axial gliomas. The same might be possible in brain metastasis (BrM). Identification of tumor-specific DNA in the CSF and correlation of these findings with CSF cytokine profiles might enable minimally invasive monitoring of treatment response and failure, which is particularly important in the era of targeted and immunotherapies where radiographic changes are becoming increasingly difficult to interpret. METHODS BrM patients were consented under an Institutional Review Board-approved protocol. Circulating tumor DNA (ctDNA) and secreted cytokines were profiled in the CSF and plasma from 31 patients. To isolate ctDNA, a novel method was developed, which applies molecular tagging and computational error-suppression techniques to next-generation DNA sequencing data. Concentrations of 42 cytokines and chemokines in the CSF and plasma were quantified by Luminex (Eve Technologies). Nineteen patients had concurrent tissue pathology. RESULTS Of the 31 patients with BrM, most had lung cancer, melanoma, and breast cancer. Preliminary analysis detected secreted cytokines in CSF and plasma in all three cancer types. As little as 5 mL and 75 μL of CSF are required for genomic and proteomic analysis, respectively. To date, cell-free DNA was found in 78% of CSF samples analyzed (N = 18), with 45% harboring mutational DNA. Notably, all patients with cytology-positive leptomeningeal disease (N = 4) also had driver mutations in their CSF. Of the 42 cytokines profiled, 31 were reliably detected in CSF and plasma across multiple primary subtypes, tumor volumes, and extent of disease. CONCLUSION ctDNA and cytokines can be detected in CSF of patients with both intraparenchymal and leptomeningeal disease. Further analysis of the biomarker differential between CSF and plasma may assist in diagnosis and understanding of the immune response to BrM.