Join NBTS’s campaign to raise awareness about the importance of biomarker testing and clinical trials for patients with brain tumors.
READ MOREPublished on October 7, 2024 in ResearchEOY, Educational Resources
The team at the National Brain Tumor Society interviewed Keith Ligon, MD, PhD, in part one of our series to help explain pathology and biomarker testing as part of NBTS’s MyTumorID campaign. NBTS launched the MyTumorID campaign this year to educate and empower patients and care partners to make informed decisions about biomarker testing and clinical trials.
Part two of our conversation with Dr. Ligon, who is the Chief of Neuropathology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute (DFCI) and serves as the Director of the Center for Patient Derived Models at DFCI, continues below.
A: It’s made it more exciting to help patients because we have much more accurate and helpful data to provide them. We’re data-oriented physicians, and patients should think about us as their personal data consultant and generator of data. The amount of [information] we’re adding as pathologists is very high now compared to what it was even 20 years ago. That complexity is challenging but also exciting because biomarker testing is there to help us get better answers and help patients navigate their diagnosis better. It has made it challenging in that the information is more complicated and the time it takes to give patients answers now has increased, but that’s because we’re able to give them much more information.
Our diagnoses were already very accurate and reliable before. But as diagnoses get more complex and more based on quantitative biomarker tests, the data we generate is more reliable across different pathologists and hospitals. We’re able to generate information that is the same, regardless of whether it’s generated on one side of the country or in another country. That’s helping to improve value for patients as well. There is still a lot of expertise of the pathologist involved, but we are getting better at speaking the same testing “language” and understanding.
Precision medicine is important for patients with brain tumors. So much of precision medicine is about personalizing cancer care and making sure that the data we’re giving patients applies to their situation. For example, previously, patients were told that you’re taking this drug because half of the patients in a clinical trial who got the drug for this diagnosis statistically survived longer or seemed to respond. That’s good, but not very satisfying or personalized because you’re not a statistic. You’re a single patient. You want to know if it’s going to work for you, so that’s where some of these new tests and biomarkers are starting to help. They increase your odds of a closer match to the patients who were the ones that responded and take out some of the guesswork. Most precision medicine currently is done by comparing genes and mutations to treatment responses.
A new area of excitement for precision medicine is what we call “functional precision medicine.” This involves aiding treatment planning by biomarker or drug testing on the patient’s own live cells outside their body. This can be done on a cluster of tumor cells called organoids or other types of cells that continue to grow. These tests, now with new technologies, are able to very quickly give results for patients that are derived from their cells and their tumor. It’s not just based on population statistics from a clinical trial as much as before. It’s very personalized.
One way to think about it is if you’re going to get a treatment, you would want to know if your tumor cells die when they see that treatment like they are supposed to at least as a first step. We now have capabilities that are starting to emerge. Companies, as well as academics, are doing things where we do these tests on cells directly for patients. Such tests are still not standard, but that’s the kind of personalization that’s coming in the future, which, for most of us, feels like science fiction coming true.
A: The most common [malignant] brain tumors that come from brain tissue cells are gliomas. For adults or children, there are certain gene mutations and genes that people look for. They’re different for each age group and each tumor type.
For adults, the most important ones people will hear about are the IDH mutations. These are mutations in the genes IDH1 or IDH2, and their presence or absence is the first branch in the decision tree for a glioma. Perhaps the most important gene in kids is the BRAF gene, which is altered to make it overactive and drives cells to grow. Most commonly, it’s scrambled or rearranged and has a fusion of two genes together, one of them being BRAF, which turns the BRAF gene on and that causes the tumor to grow. In pediatric gliomas, you’re often trying to inhibit that altered gene or its downstream effects.
Many brain tumors have their own genes that are changed or mutated. The diversity of that is important because if you just check a few genes with a test, you’re not maybe checking enough in today’s age where we have so many different mutations known to drive tumors of the brain. We’ve gotten better at sequencing multiple genes with a single test and getting information about those genes from many different angles to try and determine what each individual tumor has.
The other test that people commonly utilize is MGMT, which is a DNA-based test to see whether the MGMT gene, which repairs DNA, is turned off by methylation. When it’s turned off by methylation, the cell is vulnerable to the damage done by therapy like chemotherapy, which works by damaging the DNA. If it can’t repair, it slows the cell from growing, or the cell dies. When it turns off that gene, it doesn’t repair anymore, so it can be susceptible to the damaging drug. It actually kills the tumor cells because they’re no longer able to repair those lesions, and they stop growing in that instance.
MMR genes are a biomarker that patients with brain tumors may have recently heard about. If you have an MGMT turned off and MMR is also turned off, that double gene combo can lead to a more aggressive tumor that doesn’t respond to treatment. This happens when tumors evade treatment. These are the things that the more data we have, the more we learn about these combinations of biomarkers and what they mean for when to expect treatments to be effective or not. We try to use new tools like algorithms and computers to make that complexity more manageable.
A: Many of the trials are actually evaluating drugs designed to specifically attack certain vulnerabilities, mutations, or molecular alterations and biomarkers in the tumor. Because of this, the drugs may only work if you have the right mutation. The trial will, therefore, be written to include only those patients.
It’s important to remember that most clinical trials for brain tumors are actually testing experimental agents, so we don’t always know precisely how the drug works or who, if anyone, will benefit. It’s also important because they want to make sure to give the drug, the trial, and the patient the best chance possible for it to work. You can give the drug to a lot of people without using a biomarker and see if it happened to work by luck. But given the science of what we know about most of the drugs, there are usually some patients it’s expected to work better in, and some patients it’s not as expected to work well in based on tumor biomarkers. We try to make sure that patients going on the trial have the best chance by making sure the patients on the trial have the right biomarkers for the drug.
The other reason is they want to make sure that the people going on the trial have the same type of tumor diagnosis [on a molecular level]. And then the next time, if it works, sometimes the drug might be expanded in its indication and be applied to other tumor types with different molecular definitions.
Patients often ask for good reason, “Why am I excluded?” Trials are undergoing an experiment, and we want to know that the risks that patients are taking are minimized and that patients have a chance of maximum benefit and not just taking on risks with no hope of the agent being potentially effective in them because we didn’t select for biomarkers.
A: The difficulties in advanced testing are sometimes not even related to the size of the medical center, but smaller centers have more challenges to run tests if they don’t see enough patients with brain tumors. The pathologist’s job is to try and coordinate biomarker testing for the patient and get the testing done, whether in their own hospital or outside. However, each hospital pathology department is different, and the tests they have available are different. If the test is not available at your pathology department, you can ask your pathologist or the department what’s available. Often, that tissue can be sent out to another pathology department with the test.
We’re your doctor and consultant, and we’re a mediator for helping get access to things that you might need. We’re very adept at sending out tissue and helping you to decide which tests are important. Sometimes, patients are approached for tests that might be a good idea for other patients but may not be a good idea for you specifically because it will be a waste of your tissue and money. The pathologist can determine how much tissue is available, what the priorities might be for you with your treatment team, and what’s most useful. Sometimes, that’s complex, so it is important to reach out to the pathologist.
If you have questions or want to know about your tumor and your report, patients or caregivers can call the pathology department and ask to speak with the pathologist whose name is on their report. With the increasing complexity of information, it’s been really exciting to help patients understand their information and data, and they’ve been excited to learn about those things as well and see exactly what it is that they’re trying to navigate and combat. So I think it’s important for patients to reach out directly to their pathologist, who’s their data and information physician, with any questions or concerns they have.
A: They’re immensely helpful. We’ve had amazing appreciation from patients and their families and understanding of how important it is to try and combat the disease through autopsy research. It’s important for some families to just understand what their loved one’s brain and their tumor looked like at the end, particularly if there were questions as to what was happening at the end of their life.
Patients and their families are also very aware that to make progress, we want to study as much as possible and learn from patients’ donations as much as possible about how to stop the tumors from growing.
Autopsy is important because the brain is not an organ that you can remove when patients are alive, like your intestine or appendix. Often, the amount of surgery and tissue removed is small to help keep a patient able to enjoy their life and function well. Ideally, people would not have any tissue removed, and then we can treat their tumor without having to do surgery at all, but that’s not possible right now for most patients. If that initial biopsy or tissue is small, it can be very limiting as far as doing research and discovery. With an autopsy, we’re not limited anymore, so that donation allows us to have an amount of tissue that really is enabling for many, many researchers to all share that tissue and find cures.
Pathologists are key to helping with that and making sure that those donations go the furthest they can to help as many people and teams as possible trying to combat and find a cure.
It’s also an opportunity to look and see how the tumor was actually interacting with the brain and its environment, and that’s not very possible with surgery because surgeons obviously don’t want to remove portions of people’s brains that are not involved with the tumor. At an autopsy, we can look at how the tumor is interacting with the brain in many different ways that are not possible while the patient’s alive, so that’s an important aspect of the donation, too.
A: The data that we deal with and work to help analyze for the patient comes from the tissue, so we’re the team members that are actually examining the cells and tissue that comes out from a surgery, for instance, or from their blood or cerebrospinal fluid (CSF). We’re the main and unique member of the tumor board team responsible for making the diagnosis and then discussing with the teams how it can be integrated with data from imaging of the tumor by MRI and other methods. This gives a complete picture of what is the best approach for treatment decisions.
With the launch of MyTumorID, the National Brain Tumor Society commits to educating patients and their care partners about the value of biomarker testing and clinical trials, empowering patients to ID their tumor, know their options, and make informed decisions about their treatment.
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