Diffuse gliomas comprise the bulk of brain cancer in adults and the most common primitive malignant brain tumours in adults.
The 2016 WHO update combines histology with tumor genetic information; glioblastoma (GBM) can be subdivided into two types, based on the mutation in codon 132 of isocitrate dehydrogenase 1 (IDH1).
The majority of GBMs (90%) are IDH1-wildtype and arise de novo without previous low-grade tumor, whereas GBM IDH1-mutant progress from a precursor low-grade glioma. Latest WHO classification of these tumours introduced the concept of integrated diagnosis: a diagnosis based upon the integration of both morphological and molecular findings. For IDH-mutant lower-grade gliomas (grades II and III), a set of genetic parameters can distinguish astrocytomas from oligodendrogliomas. IDH-mutant astrocytomas (~80% of all astrocytomas) are defined by mutations of ATRX and TP53. IDH wild-type GBM is characterized by telomerase reverse transcriptase (TERT) promoter mutations and EGFR amplification involved in cell growth, cell cycle, proliferation, and survival.
The two groups of GBM IDH-mutant and IDH wild-type have distinct genetic and clinical profiles. Pseudoprogression, has become a major challenge in glioblastoma follow up, as only surgery or serial imaging is conclusive.
Liquid biopsy is a technique that consists of the detection of circulating tumor cells and circulating tumor DNA in peripheral fluids from cancer patients. Peripheral blood has low sensitivity in CNS neoplasms, due to hampering of the blood brain barrier (BBB) to detect CNS tumour components. It has been recently demonstrated that CSF ctDNA is more representative of brain tumour genomic alterations than plasma.
Liquid biopsy might represent a minimally invasive and repeteable procedure which provides clinically meaningful information about both diffuse glioma and pseudoprogression
The possible innovation of our study is to understand if liquid biopsy is as reliable as histological examination: positive results could lead to the use of this method in the routine clinical management of brain tumor patients in the future, saving invasive procedures complex and risk.
The liquid biopsy allows without resorting to surgical procedures to take a photograph of the molecular profile of a given tumor, and can be used for the diagnosis, the monitoring of the results of the treatments, the identification of early relapses and the identification of a pseudoprogression which not necessarely require a surgery. All these applications can be of great use in the management of patients with brain neoplasm in particular to have a genetic characterization of the disease after relapse after chemo and radiotherapy or for those tumors that, due to localization, cannot be subjected to surgery or biopsy.
Another point of our research is that the use of liquid biopsy may be linked to the early detection of relapses;it is possible to detect the presence of tumor DNA cells in the cerebrospinal fluid in advance of the time when the tumor will again be detected by MRI.
Not only non-invasive diagnosis and early detection of relapses: liquid biopsy can also be used to characterize the genetic profile of the disease in case of relapse after the administration of specific therapies (chemo and radiotherapy). This profile may indeed differ from the initial one at diagnosis, precisely because of the tumor's ability to acquire new mutations also due to cancer treatments. Finally through the liquid biopsy it will be possible to identify patients with specific genetic alterations for which targeted biological therapies have already been developed, providing them with additional therapeutic options.
The diagnosis of brain tumors today is based on histological and molecular examination carried out directly on the tumor tissue obtained by surgical removal or by diagnostic biopsy, procedures that can sometimes be complex and burdened with potential risks for the patient, and which are sometimes executable for the particular location of the tumor in the brain. The liquid biopsy consists instead in the research and analysis of genetic material of the tumor (free circulating tumor DNA) inside a biological fluid, such as peripheral blood. The main factor hampering the detection of CNS tumour components in blood is the blood brain barrier (BBB). The latter is a peculiar anatomic and functional structure aimed at regulating the traffic of molecules and cells into and outside of the CNS. Its functions rely on the synergic activity of a wide range of partners including endothelial cells, pericytes and astrocytes. The widespread presence of tight junctions allows the passage of very
small molecules only (less than a few nanometres) and this could explain the overall poor sensitivity observed by blood sampling when looking for components derived from CNS neoplasms. It has been recently demonstrated that CSF ctDNA is more representative of brain tumour genomic alterations than plasma and putative actionable gene mutations and CNA (that is, EGFR, PTEN, ESR1,IDH1, ERBB2, FGFR2) can be identified. Authors reported that CSF ctDNA has a significantly higher sensitivity than plasma for CNS genomic alterations and can be used to detect brain tumour private mutations and to monitor brain tumour progression
For all these reasons liquid biopsy is a technique that is opening previously unexpected perspectives in the management and treatment of patients with gliomas.