Dorothee Gramatzki1, Jörg Felsberg2, Bettina Hentschel3, Marietta Wolter2, Gabriele Schackert4, Manfred Westphal5, Luca Regli6, Niklas Thon7, Marcos Tatagiba8, Wolfgang Wick9, Uwe Schlegel10, Dietmar Krex4, Jakob Matschke11, Patrick Roth12, Marian P Suresh13, Marcel A Kamp13, Elisabeth J Rushing14, Torsten Pietsch15, Andreas von Deimling16, Michael Sabel13, Markus Loeffler3, Michael Weller12, Guido Reifenberger17. 1. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: dorothee.gramatzki@usz.ch. 2. Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany. 3. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 4. Department of Neurosurgery, University of Dresden, Dresden, Germany. 5. Department of Neurosurgery, University of Hamburg, Hamburg, Germany. 6. Department of Neurosurgery, University Hospital and University of Zurich, Zurich, Switzerland. 7. Department of Neurosurgery, Ludwig-Maximilians-University Munich, Munich, Germany. 8. Department of Neurosurgery / Interdisciplinary Division of Neuro-Oncology, University of Tübingen, Tübingen, Germany. 9. Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neurooncology German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ), Heidelberg, Germany. 10. Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany. 11. Institute of Neuropathology, University of Hamburg, Hamburg, Germany. 12. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. 13. Department of Neurosurgery, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany. 14. Department of Neuropathology, University Hospital and University of Zurich, Zurich, Switzerland. 15. Department of Neuropathology, DGNN Brain Tumor Reference Center, University Hospital Bonn, Bonn, Germany. 16. Department of Neuropathology, University Hospital Heidelberg, And CCU Neuropathology, and DKTK, German Cancer Center (DKFZ), Heidelberg, Germany. 17. Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany; German Cancer Consortium, Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: reifenberger@med.uni-duesseldorf.de.
Abstract
AIM OF THE STUDY: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma. METHODS: MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302). RESULTS: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes. CONCLUSIONS: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.
AIM OF THE STUDY: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma. METHODS:MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302). RESULTS: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes. CONCLUSIONS: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.