Liquid biopsies in patients with diffuse glioma

Abstract

Diffuse gliomas are the most common malignant primary tumors of the central nervous system. Like other neoplasms, these gliomas release molecular information into the circulation. Tumor-derived biomarkers include proteins, nucleic acids, and tumor-derived extracellular vesicles that accumulate in plasma, serum, blood platelets, urine and/or cerebrospinal fluid. Recently, also circulating tumor cells have been identified in the blood of glioma patients. Circulating molecules, vesicles, platelets, and cells may be useful as easily accessible diagnostic, prognostic and/or predictive biomarkers to guide patient management. Thereby, this approach may help to circumvent problems related to tumor heterogeneity and sampling error at the time of diagnosis. Also, liquid biopsies may allow for serial monitoring of treatment responses and of changes in the molecular characteristics of gliomas over time. In this review, we summarize the literature on blood-based biomarkers and their potential value for improving the management of patients with a diffuse glioma. Incorporation of the study of circulating molecular biomarkers in clinical trials is essential for further assessment of the potential of liquid biopsies in this context.

Fig. 1

Overview of biomarker release, collection and assessment. In (glial) tumors, both neoplastic cells and the tumor-microenvironment release biomolecules in the circulation, either as circulating proteins (CP), circulating nucleic acids (CNA), or even complete circulating tumor cells (CTC). Blood plasma and serum are a source of circulating tumor DNA (ctDNA), circulating microRNAs (miRNAs) and circulating proteins. From whole blood, also extracellular vesicles (EVs), platelets (which internalize EVs) or complete CTCs can be isolated and used as potential biosources. These five biosources provide proteins, miRNAs, messenger RNAs (mRNA) non-coding RNAs (ncRNA) and ctDNA biomolecules (see separate lower right table). Of note, in the lower right table only biomolecules that were already identified in the particular biosources in patients with diffuse glioma are marked. These biomolecules and cells can be collected from a routinely obtained peripheral blood sample and used for further analyses in the laboratory

Fig. 2

Example of molecular biomarker assessment using liquid biopsy in patients with low- and high-grade glioma. Central black line depicts a simplified timeline of clinical events for patients with low- or high-grade glioma (LGG versus HGG). A pre-surgical working diagnosis (based on esp. clinical and radiological investigations) leads to surgery (biopsy or resection of tumor tissue). After a pathological diagnosis is made, most glioma patients receive ‘conventional chemo- and/or radiotherapy’ (CCR), but in LGG patients clinical monitoring is also (still) common practice. Especially after failure of CCR, experimental therapy (ET) can be administered. Above the timeline, imaging (available during the entire follow-up of the patient) and the most widely accepted molecular biomarkers analyzed in diffuse glioma tissue samples are depicted. Tumor tissue samples are obtained during surgery, and might again be obtained at the moment of tumor progression (dashed line box). The boxes below the timeline show promising blood-based biomarkers as deduced from this review and grouped according to their potential meaning (diagnostic, prognostic, predictive, monitoring) in different phases of the disease process. The blood-based biomarkers mentioned here are selected based on the number of studies measuring the biomarker and the number of patients included in these studies. Each character indicates for which group of diffuse glioma patients or treatment the biomarker might be suitable. ^#Predictive and monitoring markers selected for CCR regimens (temozolomide and procarbazine–lomustine–vincristine treatment). ^§Predictive and monitoring markers selected for experimental therapies (see also individual characters). Characters accompanying biomarkers: a primary GBM (pGBM) vs. healthy controls, b pGBM vs. LGG, c LGG vs. healthy control, d secondary GBM vs pGBM, e primary diffuse glioma vs. metastasis to the brain, f HGG, g LGG, h surgery, i temozolomide treatment, j chemoradiotherapy, k bevacizumab and irinotecan treatment, l cediranib treatment, m aflibercept treatment, n rindopepimut (anti-EGFRvIII) treatment, o IDH 1 mutant inhibitor AGI-5198