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Classification and Prognosis of Glioblastoma

Insights From: Maciej Mrugala, MD, PhD, MPH, University of Washington Medical Center; Suriya Jeyapalan, MD, MPH, Tufts Medical Center; Daniela Bota, MD, UC Irvine Medical Center
Published: Thursday, Jan 05, 2017



Transcript:

Daniela Bota, MD:
The diagnosis of glioblastoma has changed a lot during the last years. Originally, the diagnosis was made after the tumor was resected by taking pieces of the tissue and looking at it under the microscope. And the 2 characteristics that we looked for in a tumor, that we know was a primary glial tumor, were the evidence of vascular necrosis and pseudoproliferation. And those 2 characteristics are what make a glioblastoma very aggressive. It can form its own blood supply, and the cells grow very fast to the level that they compete with each other, and they create an area of cellular death.

However, most recently—and as we will hear a lot at this meeting—we have moved from how things look on the slide to what is the molecular makeup of those tumors. So, right now in order for a glioblastoma to be classified as a glioblastoma, we are required to obtain a set of molecular markers, including the 1p/19q co-deletion. If that is present, the tumor is not a glioblastoma. It’s a different type of tumor, a little bit more rare, called anaplastic oligodendroglioma.

We are supposed to look at the expression of APRX. A mutation on the APRX signals for us that this is a non-astrocytic tumor, like a glioblastoma. And we also look at the expression of IDH1 and IDH2. The presence of mutations on those 2 genes will let us know that this is what we call a ‘secondary glioblastoma,’ a glioblastoma that is derived from a less aggressive lower grade astrocytoma, and which usually carries an excellent prognosis. In addition to that, we also test for molecular markers that give us ideas about sensitivity to treatment, such as MGMT.

Maciej Mrugala, MD, PhD, MPH: Major molecular markers that are clinically significant in glioblastoma include the MGMT gene and methylation of the promoter of the gene. Also, IDH1 mutation is important. MGMT methylation status has both prognostic and predictive values. It allows us to classify the patients into 2 categories: patients with good prognosis—these are the patients who have the methylation of the MGMT gene—and patients in a worse prognosis category that do not have the methylation of the MGMT gene. Patients that have the methylation also respond better to alkylating therapy. The primary agent that is used in this patient population is temozolomide, which is an alkylating agent, and patients who have the mutation should be receiving the drug, as they can actually have a measurable benefit in terms of survival.

So, this is the primary molecular marker that we’re using in the clinical setting. I think that most centers in the United States today are using MGMT and methylation status analysis to help make decisions about treatment of the patients with glioblastoma. It’s not a very complicated test to order and get done. Turnaround time, depending on where you are, is usually 1 week to 10 days. Many centers have developed their in-house assays, and they can do this in the facility where the patient is treated. This is a key molecular marker that we are using today. We’re also using IDH1 mutation, and this mutation molecular change can help us distinguish the primary from secondary glioblastomas. They don’t really have a predictive value, but mostly a prognostic value.

Suriya Jeyapalan, MD, MPH: The classification of gliomas has actually just undergone, this summer, a major revision. And what that means for GBMs is that these patients that used to be maybe classified as grade 2, looking under the microscope, are now being kicked up to grade 3 where they would need radiation. They would not just be treated with Temodar (temozolomide). And they don’t take into account the MGMT methylation when they’re making that, the characteristics sometimes go up to the grade 3. And so, we recently had a patient in our own medical center who, 2 years ago, would have been classified as a grade 2 based on the histology.

But, since they can no longer use the histology, they’ve actually pushed it up to, or would have pushed that person up to, a grade 3, ignoring the fact that she’s MGMT methylated, and we would have given her radiation. Because we realized that it looked more like a low-grade tumor, she was sensitive to Temodar. We just gave her the Temodar and her tumor is shrinking with the Temodar alone. So, I think this is an important caveat for people to realize that all of us are trained in the old system, but we should understand that these are guidelines and they’re classifications. We really should take a look at these tumors very closely and speak to our pathologist and say, “Look, maybe we could hold,” and speak to the radiation doctors at tumor boards and say, “Look, I know it’s classified as a grade 3 on the new classification syndrome, but these are sensitive. This person’s tumor is sensitive to Temodar, we may be able to get away with just Temodar by itself.”

Transcripts Edited for Clarity
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Transcript:

Daniela Bota, MD:
The diagnosis of glioblastoma has changed a lot during the last years. Originally, the diagnosis was made after the tumor was resected by taking pieces of the tissue and looking at it under the microscope. And the 2 characteristics that we looked for in a tumor, that we know was a primary glial tumor, were the evidence of vascular necrosis and pseudoproliferation. And those 2 characteristics are what make a glioblastoma very aggressive. It can form its own blood supply, and the cells grow very fast to the level that they compete with each other, and they create an area of cellular death.

However, most recently—and as we will hear a lot at this meeting—we have moved from how things look on the slide to what is the molecular makeup of those tumors. So, right now in order for a glioblastoma to be classified as a glioblastoma, we are required to obtain a set of molecular markers, including the 1p/19q co-deletion. If that is present, the tumor is not a glioblastoma. It’s a different type of tumor, a little bit more rare, called anaplastic oligodendroglioma.

We are supposed to look at the expression of APRX. A mutation on the APRX signals for us that this is a non-astrocytic tumor, like a glioblastoma. And we also look at the expression of IDH1 and IDH2. The presence of mutations on those 2 genes will let us know that this is what we call a ‘secondary glioblastoma,’ a glioblastoma that is derived from a less aggressive lower grade astrocytoma, and which usually carries an excellent prognosis. In addition to that, we also test for molecular markers that give us ideas about sensitivity to treatment, such as MGMT.

Maciej Mrugala, MD, PhD, MPH: Major molecular markers that are clinically significant in glioblastoma include the MGMT gene and methylation of the promoter of the gene. Also, IDH1 mutation is important. MGMT methylation status has both prognostic and predictive values. It allows us to classify the patients into 2 categories: patients with good prognosis—these are the patients who have the methylation of the MGMT gene—and patients in a worse prognosis category that do not have the methylation of the MGMT gene. Patients that have the methylation also respond better to alkylating therapy. The primary agent that is used in this patient population is temozolomide, which is an alkylating agent, and patients who have the mutation should be receiving the drug, as they can actually have a measurable benefit in terms of survival.

So, this is the primary molecular marker that we’re using in the clinical setting. I think that most centers in the United States today are using MGMT and methylation status analysis to help make decisions about treatment of the patients with glioblastoma. It’s not a very complicated test to order and get done. Turnaround time, depending on where you are, is usually 1 week to 10 days. Many centers have developed their in-house assays, and they can do this in the facility where the patient is treated. This is a key molecular marker that we are using today. We’re also using IDH1 mutation, and this mutation molecular change can help us distinguish the primary from secondary glioblastomas. They don’t really have a predictive value, but mostly a prognostic value.

Suriya Jeyapalan, MD, MPH: The classification of gliomas has actually just undergone, this summer, a major revision. And what that means for GBMs is that these patients that used to be maybe classified as grade 2, looking under the microscope, are now being kicked up to grade 3 where they would need radiation. They would not just be treated with Temodar (temozolomide). And they don’t take into account the MGMT methylation when they’re making that, the characteristics sometimes go up to the grade 3. And so, we recently had a patient in our own medical center who, 2 years ago, would have been classified as a grade 2 based on the histology.

But, since they can no longer use the histology, they’ve actually pushed it up to, or would have pushed that person up to, a grade 3, ignoring the fact that she’s MGMT methylated, and we would have given her radiation. Because we realized that it looked more like a low-grade tumor, she was sensitive to Temodar. We just gave her the Temodar and her tumor is shrinking with the Temodar alone. So, I think this is an important caveat for people to realize that all of us are trained in the old system, but we should understand that these are guidelines and they’re classifications. We really should take a look at these tumors very closely and speak to our pathologist and say, “Look, maybe we could hold,” and speak to the radiation doctors at tumor boards and say, “Look, I know it’s classified as a grade 3 on the new classification syndrome, but these are sensitive. This person’s tumor is sensitive to Temodar, we may be able to get away with just Temodar by itself.”

Transcripts Edited for Clarity
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