Brain tumor

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Unlocking the Power of Gene Expression: Molecular classification of brain tumors

Joon H. Uhm, M.D., Neurology, Mayo Clinic: Molecular testing or DNA testing on tumors -- now, in the 21st century -- needs to be considered for the great majority, if not all, brain tumor patients.

Robert B. Jenkins, M.D., Ph.D., Laboratory Medicine and Pathology, Mayo Clinic: We need to use molecular genetic tools to help improve the classification of gliomas, to determine a patient's prognosis, and to determine the kind of therapy that they should receive.

Daniel Honore Lachance, M.D., Neurology, Mayo Clinic: Brain tumors actually occur as a result of a large number of genetic alterations.

Dr. Uhm: What the researchers here at Mayo Clinic and across other institutions have found is that looking at the DNA, you can classify brain tumors far more precisely than simply by looking how pink they are, how the cells are dividing.

Dr. Jenkins: We can use, though, that genetic information to more solidly place these tumors into specific types that might respond to specific kinds of therapy.

Ian F. Parney, M.D., Ph.D., Neurologic Surgery, Mayo Clinic: Patients with certain molecular classifications that do really well with one treatment but not with another. And as we now have this established as a way that we can look at this information, we're really going to be able to tailor our treatments much better and find new treatments better for patients that may be underserved by what we had before.

Dr. Jenkins: We discovered that the short arms of chromosome one and the long arm of chromosome 19 were co-deleted in a particular kind of glioma.

Dr. Uhm: What we call 1p/19q deletion. This is when two pieces of DNA in the human chromosomes, basically, disappear. And we don't really know why that's a good thing for the patient, but when those two pieces of DNA are missing, that patient's brain tumor is actually forecasted to grow a bit more slowly but very importantly, be more sensitive to radiation and to certain categories of chemotherapy.

Dr. Jenkins: Some brain tumors have 1p/19q co-deletion. Some brain tumors have IDH mutation. Some brain tumors have TERT promoter mutation. Some tumors have all three of those. Some tumors have none of those. Some tumors have one or two of those. So we thought, well if we can test the tumors for those three alterations, we could put them into molecular genetic groups.

Dr. Lachance: By just using three key genetic mutations, gliomas could be classified into five groups that have in common certain important characteristics such as the age of presentation.

Dr. Jenkins: Those five molecular groups can predict the patient's prognosis, meaning how long they can expect to live, and at least two of the groups determine what kind of therapy the patient will get. So for example, a person that has what we called a triple-positive glioma -- meaning they have 1p/19q co-deletion, IDH mutation, and TERT promoter mutation -- those patients should be getting chemotherapy and radiation therapy regimen specifically designed for that tumor and that tumor type only.

Dr. Uhm: If a person's tumor is missing 1p19q, there's no doubt that we should give that patient chemotherapy, either with or after the radiation, and that actually doubles the life expectancy with radiation alone from about eight years to about 15, 16 years, or more.

Dr. Lachance: The patient that has the combination, say of all three mutations -- the co-deletion, IDH mutation, and the TERT promoter mutation -- we know that those patients have, in oncology speak, median survivals of greater than 15 years and with some patients that are truly long-term survivors. If we treated those patients too aggressively at the onset, when they live 15 to 20 years, they may suffer the long-term consequences of our therapies and be neurologically impaired because of the treatments. When, if perhaps, we could come up with a different approach for those patients that we know are going to do well, they might end up having a better longer term quality of life.

Dr. Uhm: IDH mutation and telomerase mutation and they also have a very good prognosis. The next one down is IDH mutation only and then you have what's called triple negative. And when you have none of these three good genetic characteristics, that patient -- it's not a guarantee that he or she would do poorly -- but it doesn't look well.

Dr. Jenkins: If they have one of the mutations, meaning if they have a TERT promoter mutation, that group of tumors is what we used to call primary glioblastoma. The most common brain tumor and the tumor of the worst prognosis. If a tumor falls into that group, they get a different chemotherapy and a different radiation therapy.

Dr. Parney: We're able to use the molecular findings to help augment the information that we get from the MRI scans to get the best surgical approach for an individual patient. If that particular tumor has an IDH mutation, then there is a very strong association with improved survival and outcome if we take out all of the area that we can safely take out. So what we always want to do in any brain tumor surgery is that we want to take out the most tumor that we can safely take out to get the best outcome and survival.

Dr. Lachance: Each person's tumor is different and therefore, in the end, each person needs an individualized approach to treating their tumor. And it's only by having this kind of detailed information available that we can begin to understand the different patterns of patients' different tumor types.

Dr. Uhm: We now have five molecular categories of glioma. We're absolutely certain it goes far beyond five. It'll be 50, 500, who knows. There are thus far 40,000 known human genes. 40,000. And we now five types of human brain tumors based upon genetics. So really, I think the sky's the limit.

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Brain & Central Nervous System Cancers: Personalized care for each patient

Jan C. Buckner, M.D., Medical Oncology, Mayo Clinic: Central nervous system tumors are rare in the overall scheme of things. They involve both the brain and spinal cord.

Fredric B. Meyer, M.D., Neurosurgery, Mayo Clinic: There are 120 brain tumors that adults and children can suffer from. We have perhaps the largest neurosurgical practice in North America, which means we have great expertise and depth in managing the most complex tumors.

Dr. Buckner: And although they may be rare, at Mayo Clinic, they're not rare. Our specialized teams are comfortable seeing these rare types of tumors day in and day out.

Dr. Meyer: We have a team of neuroradiologists who have developed leading MRI technology and programming to help us diagnose brain tumors. There's a whole host of range of technologies that have been developed here that are unique and leading the way nationally. Some of those technologies would include MR spectroscopy, MR profusion, MR diffusion -- very multi-dimensional approaches to looking at a patient's problem.

Sameer R. Keole, M.D., Radiation Oncology, Mayo Clinic: PET imaging is an incredibly useful tool in cancer care. Different isotopes give different value, but if they have a short half life, the only way you can inject them into a patient is if you have a cyclotron onsite. We have a cyclotron onsite.

Dr. Buckner: One of the problems with imaging and brain tumors is interpretation of the imaging. At Mayo Clinic, we have a more comprehensive way of obtaining the images, getting all of the information we can possibly get from the image in order to know if this is truly recurrent tumor, progressive tumor, or on the other side, is it an artifact of apparent reduced tumor size when it's just the effect of therapies?

Dr. Meyer: One of the techniques which we have developed here is using awake brain surgery and very complex mapping of the brain surface in the descending white matter tracks to try to preserve neurological function. It's important to remember that the closer a tumor or an epileptic focus comes to functioning brain tissue, the higher the risk. So when that risk is close, when those anatomies are close, we use awake mapping to try to prevent harm to a patient.

Alfredo Quinones-Hinojosa, M.D., Neurosurgery, Mayo Clinic: The image guidance, to a minimally invasive brain surgery, is crucial to be able to not only understand the anatomy of the brain, but to be able to navigate and getting into all those difficult little places where function is extraordinarily important. And a lot of these new software modalities like functional MRI allow us to have a preconceived idea of the dangerous parts of the brain. So when you go in and you want to take a tumor out, for instance, you have an idea as to which areas you should and should not touch. Those that should not be touched, most likely they need to be left behind so that patients have a much better outcome in the long term.

Dr. Meyer: In certain types of brain tumors, especially at the base of the skull, there's anatomy that needs to be protected, like nerves that are responsible for vision, for talking, and so forth. Using a Gamma Knife, for example, allows one to radiate that tumor mass but protect the surrounding brain tissue.

Dr. Keole: The key is what's surrounding that target? That's where proton beam excels. The proton beam can spare normal, healthy tissues, including those in the brain, by anywhere from 70% to 99% versus our best X-ray techniques.

Dr. Buckner: One of the most exciting developments recently has been improved molecular diagnostics for brain tumor. Mayo Clinic scientists were instrumental in developing a new classification system for gliomas.

Dr. Quinones-Hinojosa: We can take the tumors out. We can send them through the laboratory, understand the different molecular pathology and molecular biology of these cancers, but when it comes down to it, what we're trying to do is trying to enhance how we personalize medicine and how is precision medicine better utilized for the care of the patient? Every patient has a different molecular subtype. Our understanding in the lab is allowing us to understand how we can treat every patient individually. New molecular biology tools have allowed us to nowadays understand how cancer cells migrate, not only in the brain, but in other parts of the body.

Dr. Buckner: Not only is each individual tumor unique to that patient but it continues to evolve. It can evolve down different pathways and it is possible to build a mutational tree so that we understand in which direction the tumor is mutating and develop therapies appropriately.

Dr. Quinones-Hinojosa: And these molecular agents are extraordinarily important to understand, so that way we can put the brakes on those cancers. In our laboratory with our team, we have patented multiple technologies. Multiple drugs can actually play a role in blocking and stopping the cell migration.

Dr. Meyer: We have a broad range of clinical trials to treat patients with brain tumors across Mayo Clinic. Some of them are chemotherapy, some are radiation, but some of them are also viral therapies and immunotherapies.

Dr. Quinones-Hinojosa: The Mayo Clinic is at the forefront of utilizing stem cells that we get from either fat from our own body or from our own bone marrow. You can use the stem cells, especially with the way we have used them in our laboratory, as a Trojan horse. We can actually load treatments into these stem cells that we get from our own fat, and we have proven that these are stem cells like little Trojan horses, goes in there, into parts of the brain, localizes a bad cancer cell, and delivers a cargo.

Dr. Keole: I think as we move into new therapies, including immunotherapies or vaccine therapies, then that really allows us to leverage the body's immune system to help us fight the tumor. And so the goal is really going to be to try to treat the tumors, but really leave the patient in even better shape after their fight with the cancer is done.

Dr. Quinones-Hinojosa: So not only are we talking about personalized medicine, but more importantly, we're talking about precision medicine because at the end of the day, your body is the best tool that can heal your own body.

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