Circulating biomarkers in patients with glioblastoma

Abstract

Gliomas are the most common tumours of the central nervous system and the most aggressive form is glioblastoma (GBM). Despite advances in treatment, patient survival remains low. GBM diagnosis typically relies on imaging techniques and postoperative pathological diagnosis; however, both procedures have their inherent limitations. Imaging modalities cannot differentiate tumour progression from treatment-related changes that mimic progression, known as pseudoprogression, which might lead to misinterpretation of therapy response and delay clinical interventions. In addition to imaging limitations, tissue biopsies are invasive and most of the time cannot be performed over the course of treatment to evaluate 'real-time' tumour dynamics. In an attempt to address these limitations, liquid biopsies have been proposed in the field. Blood sampling is a minimally invasive procedure for a patient to endure and could provide tumoural information to guide therapy. Tumours shed tumoural content, such as circulating tumour cells, cell-free nucleic acids, proteins and extracellular vesicles, into the circulation, and these biomarkers are reported to cross the blood-brain barrier. The use of liquid biopsies is emerging in the field of GBM. In this review, we aim to summarise the current literature on circulating biomarkers, namely circulating tumour cells, circulating tumour DNA and extracellular vesicles as potential non-invasively sampled biomarkers to manage the treatment of patients with GBM.

Fig. 1

Pseudoprogression. After treatment, a brain MRI scan is performed in GBM patients. When the MRI is performed within 12 weeks of treatment, 10–30% of patients may present enhanced lesions that may improve with time, which are known as pseudoprogression. A correlation between the methylation of the MGMT gene promoter, and overexpression of p53, IRF9 and XRCC1, and the occurrence of pseudoprogression has been observed.^– Example of pseudoprogression in a male patient diagnosed with glioblastoma at 51 years of age. Initial gadolinium-enhanced T1-weighted MRI prior to any treatment (a) demonstrated a heterogeneously enhancing right temporal mass (red arrow), which was resected; histopathology was consistent with glioblastoma. Immediate postoperative imaging (b) demonstrated near-complete resection of tumour, but MRI after adjuvant radiation and chemotherapy (c) was concerned with progression due to interval development of new irregular enhancement adjacent to the cavity (green arrow). On this basis, he proceeded to further debulking surgery, the histopathology consistent with necrosis only. Five years after diagnosis, his MRI (d) remained free of evidence of recurrence, consistent with the diagnosis of pseudoprogression. Figure produced using Servier Medical Art

Fig. 2

A schematic representation of biomolecular transportation from a tumour through the BBB into the circulation. (a) In patients with GBM, a leaky BBB allows circulating biomarkers—for example, circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and microvesicles—to enter the circulatory system, from where they can be collected, via blood draw, and further analysed. (b) A breakdown of the tumoural components found in the circulatory system. Several classes of biomarkers can be accessed and measured in liquid biopsies, including CTCs, which can be shed from a primary tumour; extracellular vesicles, which can be released by tumour cells (and can carry nucleic acids and proteins inside); ctDNA, which can also be released by tumour cells. These molecules carry tumoural information (e.g., mutational status, tumoural cargo), which can be sampled non-invasively. Figure produced using Servier Medical Art

Fig. 3

A schematic representation of the two main classes of EVs. Exosomes and microvesicles differ mainly in size and origin. The diameter of exosomes is smaller (30–150 nm), and are derived from the endosomal membrane. The diameter of microvesicles ranges from (50 to 1300 nm), and are released from cell membrane budding. Figure produced using Servier Medical Art