Latest developments in recurrent GBM (brain tumor) treatment - MGMT methylation

GBM is a high-grade, malignant brain tumor. Based on their microscopic and molecular characteristics, high-grade brain tumors are classified as anaplastic gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma) and glioblastoma . Glioblastoma is often called GBM-4 (meaning fourth grade) and is the best-known and most extensively researched brain tumor.

Standard treatment for newly diagnosed GBM consists of brain tumor surgery to remove as much of the tumor as possible, followed by adjuvant (preventive) radiotherapy and chemotherapy. Although chemotherapy and radiotherapy prolong survival in patients with GBM, in most patients the cancer recurs after initial treatment.

Suspected GBM recurrence can be difficult to distinguish from changes caused by radiotherapy, such as edema or necrosis , and this distinction has important implications for further treatment.

Treatment decisions for patients with recurrent or aggressively progressing high-grade brain tumors should be individualized, because the treatments used in this setting are not curative. The aim is to prolong survival, improve quality of life, and provide oncological rehabilitation and supportive treatment. However, cancer does not follow the same course in every patient with recurrent GBM; some patients have a better prognosis (disease outlook). Studies have shown that patients with GBM who have MGMT methylation , an epigenetic change, respond better to chemotherapy and have better disease outcomes.

An important retrospective study involving 250 patients, on the significance of MGMT methylation in GBM, was presented at the 2018 American Academy of Neurology Meeting by Professor of Neuro-Oncology Dr. Sushma Bellamkonda.

According to this study, the presence of MGMT methylation may be a biomarker that predicts the course of the disease.

Although the World Health Organization (WHO) has revised its classification of glioblastomas, it has not included MGMT in the classification. Nevertheless, according to Dr. Bellamkonda, checking patients with glioblastoma for MGMT methylation will help select the treatment that will benefit the patient most.

In other words, some brain tumors have this MGMT methylation and others do not.

Methylation is an epigenetic change. Unlike standard mutations, epigenetic changes do not alter the main structure of DNA, but affect the expression of genetic information in DNA by activating or deactivating gene regions.

The figure below shows common epigenetic changes.

Major cancer centers in the United States have begun testing some GBM tumors for MGMT methylation. If the brain tumor tissue is positive for MGMT methylation, the patient is known to respond better to the chemotherapy drug temozolomide. In the study by Dr. Bellamkonda and colleagues, these patients were also found to respond well to a monoclonal antibody drug that inhibits new blood vessel formation , namely bevacizumab (Altuzan).

A classic feature of glioblastoma is the demonstration of new blood vessel formation (angiogenesis), which helps establish the pathological diagnosis. If a tumor has angiogenesis, it is most likely a glioblastoma. Bevacizumab suppresses new blood vessel formation, thereby reducing blood flow to the tumor.

This study provided a clearer explanation of why some patients with GBM respond very well to bevacizumab while others do not.

MGMT (MethylGuanine MethylTransferase) is an enzyme involved in the DNA repair system. Cancer cell DNA damaged by chemotherapy such as temozolamide or a targeted drug such as bevacizumab cannot repair its damage and the cell dies, because this DNA repair enzyme has been inactivated by methylation.

In other words, if the MGMT enzyme has been methylated, this means the DNA repair enzyme has been silenced. It is therefore important to test MGMT for methylation. If the patient has methylated MGMT, they derive greater benefit from temozolomide, making it easier to determine the treatment to select.

How common is MGMT methylation in brain tumors?

The rate of MGMT methylation in GBM is around 40%. However, low-grade brain tumors are known to have more MGMT methylation and IDH mutations than GBM. In other words, GBM cells have a greater capacity to repair their damaged DNA.

An IDH (isocitrate dehydrogenase) mutation is a better-characterized genetic change in brain tumors and has been integrated into the new WHO classification. When IDH is mutated, a molecule is formed that represents a critical step in glioma formation. Dr. Bellamkonda’s study found that tumors positive for an IDH mutation also tended to be more positive for MGMT methylation, and these tumors responded better to treatment.

Therefore, when MGMT methylation testing cannot be performed, an IDH mutation can be assessed.