NCCN Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-001-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until January 10, 2024. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/92887; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: January 10, 2023; Expiration date: January 10, 2024
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Central Nervous System Cancers
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Central Nervous System Cancers
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Craig Horbinski, MD, PhD, Panel Member
Donald M. Cannon, MD, Panel Member
Mary Anne Bergman, Guidelines Coordinator, NCCN
Susan Darlow, PhD, Manager, Guidelines Information Standardization, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Louis Burt Nabors, MD, Panel Chair, has disclosed serving as a scientific advisor for Chimerix Inc.
Jane Portnow, MD, Panel Vice Chair, has disclosed receiving grant/research support from Agios, Inc., Bayer HealthCare, Celularity, Incyte Corporation, and Novocure; and serving as a scientific advisor for IN8bio, Inc.
Milan G. Chheda, MD, Panel Member, has disclosed receiving grant/research support from Incyte Corporation, Merck & Co., Inc., NeoImmuneTech, and Orbus Therapeutics Inc.
Matthias Holdhoff, MD, PhD, Panel Member, has disclosed serving on a data safety monitoring board for Advarra, Inc. and PAREXEL International Corporation; and receiving an honorarium from Pfizer Inc.
Seema Nagpal, MD, Panel Member, has disclosed receiving grant/research support from Agios, Inc., Berg Health, Inovio, INSIGHTEC Ltd., Novocure, and PharmAbcine; serving as a scientific advisor for KIYATEC, Inc. and Mirati Therapeutics Inc.; serving on a trial steering committee for Biocept and Novocure; and serving as a consultant for EnClear Therapies, Inc.
Vinay Puduvalli, MD, Panel Member, has disclosed receiving grant/research support from Bexion Pharmaceuticals, Inc., Karyopharm Therapeutics, Merck & Co., Inc., Radiomedix, Inc., and Samus Therapeutics, Inc.; serving as a scientific advisor for INSIGHTEC Ltd., NewBio Therapeutics, Inc., Novocure, Orbus Therapeutics Inc., and Servier Laboratories; serving as a consultant for INSIGHTEC Ltd., Novocure, Orbus Therapeutics Inc., and Servier Laboratories; and having equity interest/stock options in Amarin Pharma Inc. and Gilead Sciences, Inc.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.
Overview
Integrated histopathologic and molecular characterization of gliomas, as per WHO classification,1 should be an essential part of practice. Molecular/genetic characterization complements standard histologic analysis, improves diagnostic accuracy, provides prognostic information, and aids in treatment selection and clinical trial enrollment. Histopathologic and molecular analysis of central nervous system (CNS) tumors is limited by interobserver discrepancies and surgical sampling that do not always capture all relevant diagnostic features in morphologically heterogeneous tumors. It is important to note, however, that most of the studies describing molecular patterns and outcomes were based on large retrospective cohorts, and many of the seminal brain tumor clinical trials were not based on those molecular patterns. Without full incorporation of molecular profiling, precision medicine for brain tumors will not be fully realized.
Updated Classification of Gliomas Based on Histology and Molecular Features
In 2016, the WHO classification for grade 2–3 gliomas was revised as follows: (1) oligodendrogliomas were gliomas that had whole-arm 1p/19q codeletion and IDH1 or IDH2 (together referred to as “IDH”) mutation (unless molecular data were not available and could not be obtained, in which case designation was based on histology with appropriate caveats); (2) anaplastic gliomas were further subdivided according to IDH mutation status; (3) oligoastrocytoma was no longer a valid designation unless molecular data (1p/19q codeletion and IDH mutation status) were not available and could not be obtained.2 Such tumors were described as “oligoastrocytoma, not otherwise specified” to indicate that the characterization of the tumor was incomplete. Very rare cases of concurrent, spatially distinct oligodendroglioma (1p/19q codeleted) and astrocytoma (1p/19q intact) components in the same tumor could also be labeled oligoastrocytoma.2 Correlations between the molecularly defined 2016 WHO categories and the histology-based 2007 WHO categories were limited and varied across studies.3–6 Thus, the change from 2007 WHO to 2016 WHO reclassified a large proportion of gliomas.
The fifth edition of the WHO classification of CNS tumors was published in 2021.1,7 In this newest classification, “adult-type diffuse gliomas” are subsumed within a supercategory of gliomas and glioneuronal tumors, and are split into 3 subtypes: (1) IDH-mutant astrocytoma; (2) oligodendroglioma, 1p/19q-codeleted and IDH-mutant; (3) glioblastoma, IDH-wild-type. WHO grades are now further specified for select CNS tumors, including diffuse gliomas. Specifically, IDH-mutant astrocytoma can be grade 2, 3, or 4. Oligodendroglioma, 1p/19q-codeleted and IDH-mutant, can be grade 2 or 3. Glioblastoma, IDH-wild-type, can only be grade 4. This updated classification further emphasizes the importance of molecular data for accurately diagnosing CNS tumors (see GLIO-1, GLIO-2, GLIO-3, and GLIO-5, pages 14–17).1
Multiple independent studies on gliomas have conducted genome-wide analyses evaluating an array of molecular features, including DNA copy number, DNA methylation, and mutations, in large populations of patients with grade 2–4 tumors.5,8,9 Unsupervised clustering analyses, an unbiased method for binning molecularly similar tumors, have been used to identify subgroups of gliomas with distinct molecular profiles.5,8,9 Further studies have shown that these molecular subgroups can be distinguished based on only a handful of molecular features, including IDH mutation and 1p/19q codeletion, biomarkers independently verified by numerous studies as hallmarks for distinguishing molecular subgroups in grade 2–3 gliomas.3–6,9–15 The unsupervised clustering analysis published by The Cancer Genome Atlas Research Network supports the idea that the majority of grade 2–3 tumors can be divided into 3 molecular subtypes: (1) mutation of IDH with 1p/19q codeletion; (2) IDH-mutant with no 1p/19q codeletion; and (3) no mutation of IDH (ie, IDH-wild-type).5 Multiple studies have shown that 1p/19q codeletion is strongly associated with IDH mutations, such that true whole-arm 1p/19q codeletion in IDH-wild-type tumors is extremely rare.3,4,12,16,17 In a tissue biopsy that is equivocal for glioma, the presence of an IDH mutation indicates at least a grade 2 diffusely infiltrative glioma.18 Some IDH-mutant diffusely infiltrative astrocytomas develop the traditional grade 4 histologic features of necrosis and/or microvascular proliferation, which suggest more aggressive behavior and worse prognosis, but are still not as severe as IDH-wild-type glioblastoma. Such tumors are now referred to as astrocytoma, IDH-mutant, WHO grade 4, to distinguish them from IDH-wild-type glioblastoma.19,20 Grade 1 noninfiltrative gliomas do not have IDH mutations.18
Other mutations commonly detected in gliomas can have diagnostic and prognostic value, such as those involving the histone chaperone protein, ATRX, which is most often found in grade 2–3 gliomas and secondary glioblastomas.21,22 ATRX mutation is robustly associated with IDH mutations, and this combination, along with TP53 mutations, is diagnostic of astrocytoma.23 In contrast, ATRX mutation is nearly always mutually exclusive with 1p/19q codeletion, and is uncommon in IDH-wild-type glioblastoma. Because loss of normal nuclear ATRX immunostaining is a fairly reliable indicator of an ATRX mutation, an IDH-mutant glioma that has loss of normal nuclear ATRX immunostaining is much more likely to be an astrocytoma than an oligodendroglioma.
Mutations in the promoter region of the telomerase reverse transcription (TERT) gene occur frequently in IDH-wild-type glioblastomas and IDH-mutant, 1p/19q codeleted oligodendrogliomas.24,25 Absence of TERT promoter mutation, coupled with IDH mutation and lack of 1p/19q codeletion, is indicative of astrocytoma. Some IDH–wild-type diffusely infiltrative astrocytomas lack the histologic features of glioblastoma (necrosis and/or microvascular proliferation) but have ≥1 molecular hallmarks of glioblastoma, including the following: EGFR amplification; gain of chromosome 7 and loss of chromosome 10; and TERT promoter mutation. In such cases, the tumor can still be diagnosed as glioblastoma, IDH-wild-type, WHO grade 4. These tumors have similar clinical outcomes as typical histologic grade 4 IDH-wild-type glioblastomas, so they may be managed accordingly.18,20 The 2021 updated WHO classification of CNS tumors also now includes CDKN2A/B homozygous deletion as evidence of grade 4 status in IDH-mutant astrocytomas, even if such astrocytomas lack necrosis and/or microvascular proliferation.1,19,26–29
H3K27M mutations in the histone-encoding H3-3A gene are mostly found in diffuse midline gliomas in both children and adults.30 Patients with these H3K27M-mutated gliomas tend to have a very poor prognosis regardless of histologic appearance, so they are classified as WHO grade 4; however, some patients seem to fare better than a grade 4 diagnosis would imply, so there remains some controversy regarding this issue.30–32 Another variant in H3-3A, resulting in a G34V (or R) mutation in histone 3.3, is characteristic of some diffusely infiltrative gliomas arising not in the midline, but in the cerebral hemispheres. These gliomas tend to occur in children and younger adults and are IDH-wild-type, but still have mutations in ATRX and TP53. Thus, the fifth edition of the WHO classification calls these tumors “diffuse hemispheric glioma, H3.3 G34-mutant, WHO grade 4.”1 H3K27M immunopositivity is associated with loss of histone trimethylation immunostaining in diffuse midline gliomas.33–37 The presence of a histone mutation can be considered solid evidence of an infiltrative glioma, which is often helpful in small biopsies of midline lesions that may not be fully diagnostic with light microscopy and/or do not clearly look like infiltrative gliomas.30,38 Both kinds of H3-3A–mutant gliomas are now subsumed by the 2021 WHO classification under “pediatric-type diffuse high grade gliomas,” even if such tumors arise in adults.1,7 None of the histone-driven gliomas are called glioblastomas anymore, because that term is now reserved exclusively for IDH-wild-type gliomas meeting the criteria discussed earlier.
Prognostic Relevance of Molecular Subgroups in Glioma
Numerous large studies of patients with brain tumors have determined that, among WHO grade 2–3 gliomas, 1p/19q codeletion correlates with greatly improved progression-free survival (PFS) and overall survival (OS).4,9,10,39–41 Likewise, the presence of an IDH mutation is a strong favorable prognostic marker for OS in grade 2–3 gliomas.5,12 Analyses within single-treatment arms showed that the IDH status is prognostic for outcome across a variety of postoperative adjuvant options. For example, in the NOA-04 phase III randomized trial, IDH mutation was associated with improved PFS, longer time to treatment failure, and extended OS in each of the 3 treatment arms: standard radiotherapy (RT; n=160); combination therapy with procarbazine/lomustine/vincristine (RT upon progression; n=78); and temozolomide (RT upon progression; n=80).40
Multiple independent studies, covering multiple grades and histology-based subtypes of gliomas,5,9,39 as well as smaller studies limited to 1 to 2 grades or histologic subtypes,4,42–44 have consistently supported the subdivision of gliomas by molecular subtype (eg, by IDH and 1p/19q status) as recommended by the WHO 2021 CNS tumor classification, because this yields greater prognostic separation than subdivision by histology alone. Multiple studies have shown that, among patients with grade 2–3 gliomas, the IDH-mutant plus 1p/19q-codeletion group (ie, oligodendroglioma) has the best prognosis, followed by IDH-mutant without 1p/19q codeletion (ie, astrocytoma), and the IDH-wild-type group (ie, glioblastoma) has the worst prognosis.4–6,39–41 Analyses within single-treatment arms have confirmed this trend in prognosis across a variety of postoperative adjuvant treatment options.4,40,41,44 TERT promoter mutations in patients with high-grade IDH-wild-type glioma are associated with shorter OS, compared with IDH-wild-type tumors without a TERT promoter mutation.6,25,45 However, a multivariable analysis of data from 291 patients with IDH-mutant, 1p/19q-codeleted oligodendrogliomas showed that absence of a TERT promoter mutation was associated with worse OS, compared with those with TERT promoter–mutant oligodendrogliomas (hazard ratio, 2.72; 95% CI, 1.05–7.04; P=.04).46 An analysis of an older database, which included 271 patients with WHO grade 2 gliomas that were diagnosed according to the 2007 WHO classification, showed that IDH-mutant gliomas were associated with increased OS and better response to temozolomide than IDH-wild-type gliomas.4
MGMT (O-6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that can confer resistance to DNA-alkylating drugs.47 Gene suppression via MGMT promoter methylation is associated with better survival outcomes in patients with high-grade glioma, and is a predictive factor for response to treatment with alkylating chemotherapy, such as temozolomide or lomustine,31,48–50 even in older adults.51,52 IDH mutations are commonly associated with MGMT promoter methylation.6 Tumors with H3K27M mutations are far less likely to be MGMT promoter methylated.30 and are associated with even worse prognosis than IDH-wild-type glioblastomas.38,53 Patients whose hemispheric high-grade gliomas contain H3-3A G34 mutations, however, have relatively higher rates of MGMT promoter methylation than H3K27M diffuse midline gliomas, and do not have a worse prognosis than patients with other IDH-wild-type glioblastomas.38,54
BRAF fusion and/or mutation testing are clinically indicated in patients with low-grade glioma. Most WHO grade 1 pilocytic astrocytomas in pediatric patients contain BRAF fusions or, less commonly, BRAF V600E mutations, especially those arising in the posterior fossa; such tumors are rarely high-grade.55 BRAF fusion is associated with better prognosis in pediatric low-grade astrocytoma.55–57 The likelihood of a BRAF fusion in a pilocytic astrocytoma decreases with age.55 BRAF V600E is present in 60% to 80% of pleomorphic xanthoastrocytomas, though it has also been found in many other low-grade gliomas, such as gangliogliomas and dysembryoplastic neuroepithelial tumors,31,55,58 as well as <5% of glioblastomas (especially epithelioid glioblastoma).59 Pediatric low-grade gliomas with BRAF fusions tend to be indolent with occasional recurrence, but only rarely do they progress to cause death.56,57,60 Retrospective studies have shown that BRAF V600E may be associated with increased risk of progression in pediatric low-grade gliomas,61 but one study found that this association did not meet the threshold for statistical significance (n=198; P=.07).57 Some studies have shown that tumors with a BRAF V600E mutation may respond to BRAF inhibitors such as vemurafenib,62–64 but ongoing trials will further clarify targeted treatment options in the presence of a BRAF fusion or V600E mutation (eg, ClinicalTrials.gov identifiers: NCT03224767, NCT03430947).
NCCN Molecular Testing Recommendations for Glioma
Recommendations for molecular testing of glioma tumors are provided in “Principles of Brain Tumor Pathology” (see BRAIN-F 6 of 10, above). Based on studies showing that IDH status is associated with better prognosis in patients with grade 2–3 glioma,16,39,40,65 the panel recommends IDH mutation testing in patients with glioma. Immunohistochemistry can detect the most common (canonical) IDH mutation, IDH1 R132H. However, sequencing must be performed to detect noncanonical IDH1 mutations (eg, IDH1 R132C) and IDH2 mutations. Because ATRX and IDH mutations frequently co-occur, a lack of ATRX immunostaining, coupled with negative R132H immunostaining for IDH1 in a glioma, should trigger screening for such noncanonical IDH mutations.23 Loss of nuclear ATRX via immunostaining should trigger reflex sequencing to confirm an ATRX mutation. Sequencing is also recommended in patients aged <55 years with negative immunohistochemistry for IDH1 R132H, regardless of ATRX immunostaining.
Testing for 1p/19q codeletion is essential for the diagnosis of oligodendroglioma. A very common method to do this is by fluorescence in situ hybridization (FISH), but FISH only targets regions near the telomeric ends of 1p and 19q. Thus, FISH is vulnerable to misinterpreting short segmental deletions as whole-arm codeletion.66–68 When possible, whole genomic copy number scanning, either by genomic copy number variation assay or DNA methylation profiling, is preferred for assessing 1p/19q status. Furthermore, because true whole-arm 1p/19q codeletion is essentially nonexistent in the absence of an IDH mutation,16,17,69 1p/19q testing is not necessary in tumors that are definitely IDH-wild-type, and tumors without an IDH mutation should not be regarded as truly 1p/19q-codeleted, even when results suggest otherwise. Mutation testing for ATRX and TERT promoter are also recommended, given the diagnostic value of these mutations.21,23–25 IDH-mutated gliomas that do not show loss of nuclear ATRX immunostaining should be strongly considered for 1p/19q testing, even if not clearly oligodendroglial by histology. H3A and HIST1H3B sequencing and BRAF fusion and/or mutation testing may be performed as clinically indicated. A K27M histone-specific antibody is available, but it can be difficult to interpret.70
Grade 3–4 gliomas should undergo testing for MGMT promoter methylation, because MGMT promoter methylated tumors typically respond better to alkylating chemotherapy compared with unmethylated tumors.48,51,52,71 There are several accepted methods for testing MGMT promoter methylation. Methylation-specific PCR has had the most validation in clinical trials,72 but a 2012 study including 100 patients with glioblastoma treated with temozolomide suggested that pyrosequencing may be the best prognostic stratifier.73 Molecular testing of glioblastomas is encouraged by the panel, because patients with a detected driver mutation (eg, BRAF V600E mutation or NTRK fusion) may be treated with a targeted therapy, and these tests improve diagnostic accuracy and prognostic stratification. Detection of genetic or epigenetic alterations could also expand clinical trial options for a patient with a CNS tumor.
In summary, in order for patients to receive appropriate care and prognostic information, molecular and genetic testing of gliomas is warranted.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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