For patients, policy makers and other non-medical professionals
This text was prepared by ESMO for the European Alliance for Personalised Medicine in January 2015 and updated in February 2017
Glioma is a term that covers a range of tumours that arise in the brain. (Tumours secondary to other cancers that happen to have spread to the brain from other places in the body are a different problem.) Since the brain is made up of several different types of cell, the first step in personalising care for a patient with a brain tumour is to establish which cell type gave rise to the cancer. “Mixed” gliomas seem to arise from several different kinds of cell at the same time; but most can be classified as having begun with an astrocyte (astrocytomas) or oligodendrocyte (oligodendrogliomas).
Tumour types and classification
Along with trying to establish the brain cell of origin, doctors classify gliomas as I, II, III or IV according to the extent to which the malignant cells differ from their non-cancerous counterparts. Cells that show at least some of the specialised features found in a normal cell are termed low grade. Those that have lost this specialisation are high grade.
Low grade (I-II) tumours are generally slower growing than high grade tumours and are less likely to invade the healthy brain tissue that surrounds them. Grade III tumours (termed anaplastic) are more aggressive. The most aggressive (i.e. grade IV) tumours are called glioblastomas, or glioblastoma multiforme.
Initial treatment decisions depend on cell type and grade, along with the size of the tumour and its location in the brain. Size and location determine whether or not a glioma can be removed by surgery without causing unacceptable damage to brain function, but the general aim is to remove as much of the tumour as can safely be cut out. Cell type and grade also affect the likely sensitivity of the tumour to radiotherapy. Radiotherapy is generally used in addition to surgery but can be used instead of it if the tumour is inoperable or if the side effects of chemotherapy would outweigh the benefits.
For decades, the factors outlined above were the only help we had when deciding the most appropriate treatment for an individual patient. Recently, though, advances in molecular biology mean that we have important new types of information about how best to personalise treatment, especially of high grade gliomas. Molecular markers may be particularly helpful in identifying patients whose tumours are likely to respond to cytotoxic chemotherapy using drugs such as temozolomide. This alkylating agent is the current standard chemotherapy for most patients.
Some patients may be treated with another cytotoxic agent called carmustine. A wafer containing this drug can be inserted into the cavity in the brain left by removal of the tumour, where it slowly dissolves and releases the drug into the surrounding tissues.
Biomarkers
At the moment, four biomarkers are used to help predict the clinical course of glioma and, in some cases, to guide therapy.
Prognosis, and so choice of treatment, is influenced by whether or not glioma cells have specific mutations of the isocytrate dehydrogenase (IDH) gene. Presence of IDH mutations in glioblastomas is associated with longer survival.
In 2016, the World Health Organisation recognised the importance of this biomarker by introducing a new classification system which includes a distinction between tumours (both astrocytomas and glioblastomas) in which the IDH gene is normal and tumours in which it is mutated. This is the first time that brain tumour classification has taken note of molecular differences. But the purpose of this classification is partly to guide research into future therapies.
In terms of biomarkers, it is also useful to know whether or not a specific glioblastoma has reduced availability of an enzyme called MGMT (methyl guanine methyl transferase). MGMT is involved in repair of DNA, so lack of it means that tumour cells cannot repair themselves after exposure to DNA-damaging drugs such as temozolomide.
In more detail, the distinction is between tumour cells in which the structure of the MGMT gene promoter has been altered by addition of a methyl (CH3) group and cells in which this alteration has not occurred. Patients with MGMT- methylated gliomas are likely to survive longer than those whose tumour cells are non-methylated. In certain clinical settings, knowing the methylation status of the tumour may determine the choice between chemotherapy and radiotherapy.
The third biomarker is relevant to oligodendrogliomas and gliomas of mixed cellular origin. When these tumour cells show loss of genetic material from both chromosome 1p and chromosome 19q, prognosis is better than in patients whose tumour do not show this abnormality. And it appears that response to chemotherapy and radiotherapy is more likely.
Finally, mutations in the telomerase reverse transcriptase (TERT) gene have some value in predicting the risk that a glioma will develop and the duration of survival. Presence of a TERT mutation is associated with aggressive disease and suggests the need for close monitoring and, possibly, for additional chemotherapy following surgical removal of the tumour.
In several tumour types affecting organs other than the brain (perhaps most notably in lung cancers), malignant cells express an unusually large number of epidermal growth factor receptors (EGFR) or have mutations in this receptor. It is thought that such EGFR abnormalities are one factor contributing to uncontrolled growth. EGFR over-expression and mutation are also found in certain gliomas and their presence confers a poor prognosis. Drugs that specifically inhibit the EGFR are being investigated in brain tumours, but they are not used in everyday practice.
Researchers are also looking at specific inhibitors of the BRAF growth signalling pathway. We know this pathway is critically involved in melanoma and it may also play a part in the growth of brain tumours.
Compared with more common cancers such as those of the breast and colon, malignant tumours of the brain have proved particularly resistant to treatment. But, even in high grade gliomas, advances in our understanding of the molecular abnormalities underlying the disease are bringing new opportunities for pursuing personalized medicine with the aim of giving the right patient the right treatment at the optimal time for it to be effective.