Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications

Abstract

Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.

Keywords: CNS metastases; circulating tumor cells; clinical implications; ctDNA; liquid biopsy.

Fig. 1

Anatomic compartments in the central nervous system. (A) The CSF-containing leptomeninges comprise the pia and arachnoid and enter into perivascular spaces surrounding cortical vessels, the Virchow–Robin spaces. (B) Newly discovered lymphatic vessels along the dural sinus drain the CSF-filled leptomeninges.

Fig. 2

Liquid biopsies. (A) Cerebrospinal fluid contains both cellular and acellular material. (B) Centrifugation isolates cells for circulating tumor cell (CTC) analyses. Antibodies against cancer cell surface markers conjugated with ferromagnetic particles enable isolation of cancer cells. These cells are further detected with fluorescently conjugated antibodies as part of the CellSearch system. Alternatively, cells may be stained with fluorescently conjugated antibodies against a variety of cell surface markers and enumerated using flow cytometry. (C) Acellular material contains extracellular DNA (ctDNA). After isolation by ultracentrifugation, and library preparation, this DNA can be amplified and subjected to analysis of a single locus (PCR), or entire exomes, genes, or genomes.