“Molecular pathology in the context of classification of malignant gliomas has been an increasingly interesting, yet somewhat confusing, topic for many years,” said Matthias Holdhoff, MD, PhD, Associate Professor of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, and panel member of the NCCN Guidelines for Central Nervous System (CNS) Cancers, in the introduction to his summary of molecular tests that have been implemented for primary brain cancers. “The recently updated 2016 WHO Classification of Tumors of the CNS provided much needed clarification that has greatly improved our understanding of these cancers and has already impacted clinical care,” he explained.
At the NCCN 23rd Annual Conference, Dr. Holdhoff presented the historic context of our understanding of gliomas, using a simplified graphic of the previous WHO Classification of gliomas, which divided them into 2 major histopathologic types: oligodendrogliomas and astrocytomas. A third type, oligoastrocytomas, were historically considered “mixed” gliomas. Further, he explained that tumors were defined based on their growth activity as either low-grade (grade II) or high-grade (grade III and IV) tumors. In 2016, for the first time, the WHO integrated molecular criteria in their classification of gliomas.1 There is now a significantly improved understanding of the fundamental biological difference between oligodendrogliomas and astrocytomas, which are now merely separated based on presence or absence of biomarkers that have direct impact on clinical practice.
He further provided a historical synopsis (2005 to present) illustrating the emerging importance of the 3 most widely used molecular biomarkers in gliomas1–13: 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation (confers improved outcome in glioblastoma [GBM] and overall better response to temozolomide), codeletion of 1p and 19q (confers improved prognosis in anaplastic oligodendroglioma; patients derive significant benefit from chemotherapy with the PCV regimen [procarbazine, lomustine, and vincristine]), and most recently, IDH1 and IDH2 mutations (associated with lower grade tumors, younger age, and improved outcomes) (Figure 1). “These 3 markers are currently the most clinically relevant markers in managing gliomas,” he emphasized.
Louis DN, Perry A, Reifenberger G et al.. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016;131:803–820.
Stupp R, Mason WP, van den Bent MJ et al.. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996.
Hegi ME, Diserens AC, Gorlia T et al.. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003.
Cairncross G, Berkey B, Shaw E et al.. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group trial 9402. J Clin Oncol 2006;24:2707–2714.
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 2013;31:337–343.
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 2013;31:344–350.
van den Bent MJ, Carpentier AF, Brandes AA et al.. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 2006;24:2715–2722.
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. van den Bent MJ Carpentier AF Brandes AA Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 2006; 24: 2715– 2722.
Parsons DW, Jones S, Zhang X et al.. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321:1807–1812.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways [published correction appears in Nature 2013;494:506]. Nature 2008;455:1061–1068.
Jiao Y, Killela PJ, Reitman ZJ et al.. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012;3:709–722.
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 2015;372:2499–2508.
Cancer Genome Atlas Research Network Brat DJ, Verhaak RG et al.. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015;372:2481–2498.
Bettegowda C, Agrawal N, Jiao Y et al.. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 2011;333:1453–1455.
van den Bent M, Baumert B, Erridge S et al.. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 2017;390:1645–1653.
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. van den Bent M Baumert B Erridge S Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 2017; 390: 1645– 1653.
Perry JR, Laperriere N, O'Callaghan CJ et al.. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 2017;376:1027–1037.