Personalised Medicine at a Glance: Glioma
For patients, policy makers and other non-medical professionals
This text was prepared by ESMO for the European Alliance for Personalised Medicine – January 2015
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 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 (ie 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. 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.
At the moment, three biomarkers are used to help guide choice of therapy. Perhaps the most useful information is 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.
Prognosis, and so choice of treatment, is also 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.
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.
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. So too are specific inhibitors of the BRAF growth signalling pathway which we already know is critically involved in melanoma.
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.