ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer

Abstract

The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

“…Notably, the snapshot of a single biopsy usually does not capture the heterogeneity of glioblastomas, and several surgical biopsies and histopathological confirmation are required for a proper diagnosis. Some cases include cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity [ 173 ]. These hurdles represent a clinical challenge and an important risk for the patients leading to a lack of information about their glioblastomas.…”

“…The CSF is a source of ctDNA that can be sequenced and can reveal tumor heterogeneity providing diagnostic and prognostic information [ 173 ]. CSF-ctDNA liquid biopsies face multiple challenges including standardization of protocols, more extensive studies with more patients, and the implementation of well-designed and controlled clinical trials [ 173 ]. These hurdles need to be overcome to translate research findings into a tool for clinical practice [ 173 ].…”

Clinical Biomarkers for Early Identification of Patients with Intracranial Metastatic Disease

“…Alternatively, the data suggest that ctDNA is typically present in cerebrospinal fluid (CSF) in the setting of IMD, and that CSF ctDNA could be more representative of tumor genomic alterations and may more accurately be used to follow IMD progression compared to plasma ctDNA [ 43 , 63 , 64 ]. Our enthusiasm for this approach as a possible clinical tool is dampened by the need for lumbar puncture [ 64 ].…”

“…Alternatively, the data suggest that ctDNA is typically present in cerebrospinal fluid (CSF) in the setting of IMD, and that CSF ctDNA could be more representative of tumor genomic alterations and may more accurately be used to follow IMD progression compared to plasma ctDNA [ 43 , 63 , 64 ]. Our enthusiasm for this approach as a possible clinical tool is dampened by the need for lumbar puncture [ 64 ]. Beyond the relative contraindications to this procedure (including increased intracranial pressure and risk of cerebral herniation and coagulopathy, all of which are more likely to apply to patients with IMD), the use of ctDNA to detect IMD would require repeated lumbar punctures for continuous monitoring, increasing the risk for procedure-related complications and exposing patients to a more time-consuming and invasive form of testing [ 65 ].…”

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…Unfortunately, brain lesions may be detected only after establishment of a microenvironment supportive of tumor growth and visible proliferation using magnetic resonance imaging (MRI) or computed tomography scans; however, these technologies are not sensitive enough to detect very early metastases [11,19,25,28]. Alternative approaches that can enable early diagnoses of BM are thus being explored based on liquid biopsy of circulating tumor DNA obtained from the CSF [33]. The implications of liquid biopsies for BM are notable, as they facilitate early detection and molecular profiling of a brain lesion to initiate the most appropriate treatment.…”