Updates to NCCN Guidelines for CNS Cancers Pinpoint the Importance of Testing

In an interview with Targeted Oncology, Craig Horbinski, MD, PhD, discussed recent recommendations and NCCN guidelines regarding the molecular profiling of gliomas and other central nervous system cancers.

Updated guidelines from the National Comprehensive Cancer Network (NCCN) underscore the importance of molecular and genetic testing for patients with central nervous system (CNS) cancers. This testing provides diagnostic and prognostic information that allows oncologists to administered individualized treatment.1

These updates focus on the management of the numerous CNS cancers, including glioma, intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors.

“To a greater extent than ever, we are incorporating molecular features specific molecular features as part of the diagnostic criteria for a lot of tumors, a lot of tumor subtypes. It's gotten to the point where pretty detailed molecular workup is essential, and it's indispensable for routine neurosurgical practice and neuropathology practice,” Craig Horbinski, MD, PhD, told Targeted OncologyTM, in an interview.

The updated guidelines also show that integrated histopathologic and molecular characterization of gliomas, as per WHO classification, should be an essential part of practice.

In the interview, Horbinski, director of neuropathology in the Department of Pathology, professor of pathology, neurological surgery, and neuropathology, Feinberg School of Medicine at Northwestern University, discussed recent recommendations and NCCN guidelines regarding the molecular profiling of gliomas.

TARGETED ONCOLOGY: Can you discuss the updated classification of gliomas based on histology and molecular features?

Horbinski: The molecular revolution in pathology and neural pathology, as it concerns brain tumors has been going on for now, better part of 2 decades. It culminated more recently with the fifth edition of the World Health Organization that was published in 2021. To the greatest extent, we are incorporating molecular features specific molecular features as part of the diagnostic criteria for a lot of tumors, a lot of tumor subtypes. It's gotten to the point where pretty detailed molecular workup is essential, and it's indispensable for routine neurosurgical practice and neuropathology practice.

What are some ways you are incorporating these molecular features into practice?

We do it on a routine basis, specifically for all our gliomas or anything we suspect to be a glioma. We run next-generation sequencing, whole genome copy number profiling, methylation profiling, genomic DNA methylation profiling, and integrate those results in with histopathology. If the histopathology says 1 thing or is a little broad in terms of what the differential could ultimately be, we add in the molecular data and then produce an integrated diagnosis.

What is the importance of molecular and genetic testing for gliomas?

A lot of these different tumors can look virtually identical, both radiologically and under the microscope, but have very different clinical outcomes, different responses to therapy, different rates of recurrence, and you can only accurately stratify those differences from patient to patient from tumor to tumor. By doing detailed molecular testing, it provides us another dimension, or several dimensions and data, that standard routine histopathology that the light microscope just can't do.

Human brain digital illustration. Electrical activity, flashes and lightning on a blue background. Image Credit: © Siarhei - stock.adobe.com

Image Credit: © Siarhei - stock.adobe.com

Can you discuss some of the NCCN molecular testing recommendations for gliomas?

For the most common adult-type diffuse gliomas, the required workup includes IDH mutation screening. For oligodendrogliomas, you have to prove 1p/19q-codeletion. It also helps to see a mutation in most cases. Other markers we screen for on a routine basis, and that should be screened for, are p53 mutations, ATRX mutations, and specifically, in the most common setting, we get glioblastomas that don't necessarily show all the histopathologic features of a glioblastoma, like necrosis of microvascular proliferation. Those are often missing in a glioblastoma, but by molecular testing, we find mutations, EGFR amplification, gain of chromosome 7, loss of chromosome 10. If one has that constellation of alterations or 1 or more of those things, the new guidelines, based on studies and outcome data, recommend that you still call it a glioblastoma. And that's just for adult type diffuse gliomas.

The pediatric glioma has undergone substantial revisions, there's new entities out there, and new types of subtypes of tumors that are defined in large part on the molecular alteration they have. Same thing for ependymomas, medulloblastomas, and all the different major types of tumors. You have to prove certain mutations and tumors in order to accurately call it that.

What are some recommendations a community oncologist should keep in mind moving forward when treating these types of cancers?

For first steps, just diagnosing them. For the community pathologist or community oncologists, the threshold for having a case sent to a tertiary or quaternary academic center that has this kind of molecular armamentarium available, the threshold should be kind of low, because we're finding that the more screening we perform, the more interesting things we catch, some of which are actually targetable. Something that might radically change the prognosis substantially, like glioblastoma or something that was thought to be glioblastoma by methylation profiling might be a pleomorphic xanthoastrocytoma. That radically changes the patient's prognosis and management. That's the first thing, just to send it so the patient doesn't have to go to a big center unnecessarily, but the tissue is easy to put in the mail and just ship. Or any other center that offers this kind of testing. Then once the testing is done, integrate it with the histopathology, producing a unifying diagnosis. Based on that, there is a lot of information in the NCCN guidelines as it concerns specific recommendations, according to what type of tumor [a patient has].

What unmet needs still exist in the space?

For one thing, a cure. That would be the first thing that comes to mind. I think the molecular, the diagnosing, the prognostication, that's all quite a few years ahead of meaningful therapeutics that are directed towards a lot of these tumor subtypes. It's not too surprising that that would be the case. It is a lot easier to develop a prognostic biomarker than it is to come up with a therapeutic that targets that specific type of tumor that you've just described.

I think in the longer term though, hopefully we're going to see more advances in therapies, immunotherapy, maybe some targeted therapies in certain circumstances. That's the biggest unmet need. As far as the next wave of diagnostics goes, it's hard to say. We started with the sequencing, the DNA assessments, and now we're in the epigenomic phase of things with methylation profiling. It'll be interesting to see if at some point, of course, that's driven by technology and its availability and cost, if either single cell sequencing becomes more feasible on a routine basis, or possibly proteomics to subtype tumors according to what they're they're expressing, either within the cell or on the cell surface, or even maybe histone modifications.

Right now, we're studying DNA modifications. DNA methylation by histone methylation and acetylation might yield even more data on tumor types. But we're talking years and years of research before we can tell what's going to pan out.


1. Horbinski C, Nabors LB, Portnow J, et al. NCCN guidelines® insights: central nervous system cancers, Version 2.2022. J Natl Compr Canc Netw. 2023;21(1):12-20. doi:10.6004/jnccn.2023.0002

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