Richard Drexler1, Ulrich Schüller2,3,4, Alicia Eckhardt3,5,4, Katharina Filipski6,7,8, Tabea I Hartung6, Patrick N Harter6,7,8, Iris Divé9, Marie-Therese Forster10, Marcus Czabanka10, Claudius Jelgersma11, Julia Onken11, Peter Vajkoczy11, David Capper12,13, Christin Siewert12,13, Thomas Sauvigny1, Katrin Lamszus1, Manfred Westphal1, Lasse Dührsen1, Franz L Ricklefs1. 1. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Department of Pediatric Hematology and Oncology, Research Institute Children's Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. 5. Department of Radiation Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. Neurological Institute (Edinger Institute), University Hospital, Frankfurt am Main, Germany. 7. German Cancer Consortium (DKTK), Heidelberg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany. 8. Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany. 9. Dr. Senckenberg Institute of Neurooncology, University Hospital, Frankfurt am Main, Germany. 10. Department of Neurosurgery, University Hospital, Frankfurt am Main, Germany. 11. Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany. 12. Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, Berlin, Germany. 13. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract
BACKGROUND: DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. METHODS: Multicentric cohort study including 430 patients with newly diagnosed glioblastoma subjected to global DNA methylation profiling. Outcome measures included overall survival (OS), progression-free survival (PFS), prognostic relevance of EOR and MGMT promoter methylation status as well as surgical benefit for recurrent glioblastoma. RESULTS: 345 patients (80.2%) fulfilled the inclusion criteria. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (p = 0.06). 305 Patients receiving combined adjuvant therapy (RTK I: Ref.; RTK II: HR 0.9 [95% CI, 0.64-1.28]; p = 0.56; MES: 0.69 [0.47-1.02]; p = 0.06). RTK I (GTR/near GTR: Ref.; PR: HR 2.87 [95% CI, 1.36-6.08]; p < 0.01) or RTK II (GTR/near GTR: Ref.; PR: HR 5.09 [95% CI, 2.80-9.26]; p < 0.01) tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients. The MES subclass showed no survival benefit for a maximized EOR (GTR/near GTR: Ref.; PR: HR 1.45 [95% CI, 0.68-3.09]; p = 0.33). Therapy response-predictive value of MGMT promoter methylation was evident for RTK I (HR 0.37 [95% CI, 0.19-0.71]; p < 0.01) and RTK II (HR 0.56 [95% CI, 0.34-0.91]; p = 0.02) but not the MES subclass (HR 0.52 [95% CI, 0.27-1.02]; p = 0.06). For local recurrence (n=112), re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in RTK I (p = 0.03) and RTK II (p < 0.01) tumors, but not in MES tumors (p = 0.33). CONCLUSION: We demonstrate a survival benefit from maximized EOR for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II but not the MES subclass. Hence, it needs to be debated whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.
BACKGROUND: DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. METHODS: Multicentric cohort study including 430 patients with newly diagnosed glioblastoma subjected to global DNA methylation profiling. Outcome measures included overall survival (OS), progression-free survival (PFS), prognostic relevance of EOR and MGMT promoter methylation status as well as surgical benefit for recurrent glioblastoma. RESULTS: 345 patients (80.2%) fulfilled the inclusion criteria. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (p = 0.06). 305 Patients receiving combined adjuvant therapy (RTK I: Ref.; RTK II: HR 0.9 [95% CI, 0.64-1.28]; p = 0.56; MES: 0.69 [0.47-1.02]; p = 0.06). RTK I (GTR/near GTR: Ref.; PR: HR 2.87 [95% CI, 1.36-6.08]; p < 0.01) or RTK II (GTR/near GTR: Ref.; PR: HR 5.09 [95% CI, 2.80-9.26]; p < 0.01) tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients. The MES subclass showed no survival benefit for a maximized EOR (GTR/near GTR: Ref.; PR: HR 1.45 [95% CI, 0.68-3.09]; p = 0.33). Therapy response-predictive value of MGMT promoter methylation was evident for RTK I (HR 0.37 [95% CI, 0.19-0.71]; p < 0.01) and RTK II (HR 0.56 [95% CI, 0.34-0.91]; p = 0.02) but not the MES subclass (HR 0.52 [95% CI, 0.27-1.02]; p = 0.06). For local recurrence (n=112), re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in RTK I (p = 0.03) and RTK II (p < 0.01) tumors, but not in MES tumors (p = 0.33). CONCLUSION: We demonstrate a survival benefit from maximized EOR for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II but not the MES subclass. Hence, it needs to be debated whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.