Improved Understanding of Glioma Tumor Biology

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Mark R. Gilbert, MD

IDH wild-type lower-grade glioma should be considered as a biologically aggressive glioma, with clinical properties similar to those of glioblastoma.

—Mark R. Gilbert, MD

The management of patients with lower-grade gliomas is evolving. As evidenced by two recent publications in The New England Journal of Medicine,1,2 reviewed in this issue of The ASCO Post, there has been a substantial increase in our knowledge of the molecular characteristics of these neoplasms. This clearer understanding allows us to better subclassify these diseases, leading to a marked improvement in the prediction of biologic behavior and prognosis.

The importance of these molecular findings and the ability to accurately classify these subtypes of what have been classically deemed “lower-grade gliomas” cannot be overemphasized. Prior to these findings, intense discussions regarding the nuances of cellular morphology ensued to provide more accurate and reproducible classification of the lower-grade glioma subtypes: oligodendroglioma, oligoastrocytoma, and astrocytoma. However, despite these efforts, there was variable concordance among even the most established neuropathologists, especially with regard to the designation of oligoastrocytoma.

Pivotal Discoveries

Fortunately, there have been several pivotal discoveries over the past 20 years. First, there was the recognition that a subset of lower-grade gliomas, histologically classified as oligodendroglioma (either grade 2 or 3 by the World Health Organization [WHO] criteria) had both a better prognosis and a much higher rate of response to either chemotherapy or radiation treatment than their astrocytoma counterparts.3 Molecular analyses of these oligodendroglial tumors revealed unique chromosomal findings: the allelic loss of the short arm of chromosome 1(1p loss of heterozygosity) and the long arm of chromosome 19 (19q loss of heterozygosity).4 This molecular designation proved to be highly prognostic when evaluated in both retrospective and prospective series.

When patients on two randomized trials of anaplastic gliomas (WHO grade 3) were subclassified as “co-deleted” or “not co-deleted,” these two trials demonstrated that the combination of radiation and chemotherapy nearly doubled the overall survival duration of the patient population classified as co-deleted compared with radiation alone.5,6 Conversely, a survival benefit was not found in the patient population without the co-deletion. Therefore, these analyses definitively demonstrated the predictive value of the 1p 19q co-deletion, as it helps to determine optimal patient treatment based on its presence or absence.

The next seminal finding, published in 2008, was the discovery of mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 genes in a high percentage of lower-grade gliomas.7 The initial publications and subsequent retrospective studies of large patient cohorts confirmed that the finding of either an IDH1 or IDH2 mutation confers a much better prognosis within the WHO grade.8

Furthermore, IDH mutations confer an alteration in tumor cell metabolism that results in accumulation of an abnormal metabolite, 2-hydroxyglutarate (2-HG), which causes epigenetic changes that lead to a hypermethylated state.9 These findings are linked to improved response and patient prognosis (relative to IDH wild-type gliomas of similar histology); the potential for an imaging biomarker, as 2-HG can be detected by magnetic resonance spectroscopy; and, most important, a possible selective target for specific inhibitors or IDH-mutant targeted immunotherapy.10

Given these important findings, it was critically important that they be codified into a molecular classification system that would allow accurate classification of individual tumors. With such a classification, an accurate prognosis could be determined and clinical trials could either stratify patients accurately or be designed to study new treatments in a more homogeneous patient population.

The Importance of IDH Mutations

The studies reported by The Cancer Genome Atlas Research Network and Eckel-Passow et al1,2 have clearly accomplished this mission. Both have determined that IDH mutation status is of primary importance and, not coincidentally, that IDH mutation is probably a very early event, given the uniform finding in tumor cells when present.

What is also clear from both studies, but particularly highlighted in the work by The Cancer Genome Atlas Research Network, is that IDH wild-type lower-grade glioma should be considered as a biologically aggressive glioma, with clinical properties similar to those of glioblastoma. In this context, many in neuro-oncology are treating these patients with the same regimens as are used for patients with histologically classified glioblastoma.

From the perspective of clinical trials, failure either to stratify (balance) or exclude IDH wild-type tumors in a randomized trial may lead to misinformation, given the profound difference in prognosis with IDH-mutated tumors. Obviously, clinical trials evaluating treatments targeting the IDH mutation or its metabolic effects should exclude the IDH wild-type tumors. It is not yet clear whether future studies of glioblastoma should include the grade 3 IDH wild-type or conversely exclude the IDH-mutated glioblastoma, as these patients have an overall far better prognosis.

Beyond IDH Mutations

These studies go beyond the importance of IDH mutations, further classifying tumors by evaluating the 1p 19q status, mutations in the TERT promoter, mutations in ATRX, and mutations in p53. Eckel-Passow and colleagues combined the IDH, 1p 19q, and TERT status into a classification system akin to that popularized in breast cancer. They have proposed that tumors could range from “triple negative” to “triple positive” and that the prognosis could be predicted on this basis.

Interestingly, however, the finding of a TERT mutation alone was associated with a prognosis that was even worse than triple-negative tumors, whereas TERT mutation in the presence of IDH or IDH and 1p19q loss was associated with the best prognosis. Investigation of the underlying biology for the paradoxical effect of TERT mutation will likely provide important insights.

Clinical Implications

These collective findings have tremendous implications in the clinical care of patients with gliomas. The lower-grade tumors (WHO grade 2 or 3) can now be much more accurately classified. In the setting of IDH mutation, 1p 19q loss indicates an oligodendroglioma, whereas ATRX and/or p53 mutation signifies an astrocytic neoplasm. This would suggest that the designation of oligoastrocytoma should be considered only rarely and ideally be eliminated when biomarker data are available to resolve classification of the tumor.

Given that tumor biology is likely quite different between the astrocytic and oligodendroglial tumors, specific treatments and clinical trials will likely be needed to exploit tumor-specific biology. As described here, this is clearly the case for the IDH wild-type tumors, where the tumor cells lack the characteristic metabolic changes, molecular changes (ie, hypermethylation), or prognosis associated with the mutation.

The future is promising, as these investigations and others have resulted in a marked improvement in our understanding of glioma tumor biology. However, these findings will change the clinical research landscape, as now a previously uncommon tumor type will need to be further subclassified for trials targeting the unique biology of these cancers. This approach will mandate that large collaborative and cooperative efforts are undertaken and that the investigator and patient communities work together to speed implementation and accrual to these pivotal trials. In this way, critical laboratory findings will not only be translated into improved classification, but also into marked improvements in individualized patient treatments. ■

Disclosure: Dr. Gilbert reported no potential conflicts of interest.


1. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al: Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481-2498, 2015.

2. Eckel-Passow JE, Lachance DH, Molinaro AM, et al: Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499-2508, 2015.

3. Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12:2013-2021, 1994.

4. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473-1479, 1998.

5. Cairncross G, Wang M, Shaw E, et al: Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: Long-term results of RTOG 9402. J Clin Oncol 31:337-343, 2013.

6. van den Bent MJ, Brandes AA, Taphoorn MJ, et al: Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: Long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31:344-350, 2013.

7. Parsons DW, Jones S, Zhang X, et al: An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807-1812, 2008.

8. Weller M, Felsberg J, Hartmann C, et al: Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: A prospective translational study of the German Glioma Network. J Clin Oncol 27:5743-5750, 2009.

9. Lu C, Ward PS, Kapoor GS, et al: IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474-478, 2012.

10. Choi C, Ganji SK, DeBerardinis RJ, et al: 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18:624-629, 2012.

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