DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients
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DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients. / Drexler, Richard; Schüller, Ulrich; Eckhardt, Alicia; Filipski, Katharina; Hartung, Tabea I; Harter, Patrick N; Divé, Iris; Forster, Marie-Therese; Czabanka, Marcus; Jelgersma, Claudius; Onken, Julia; Vajkoczy, Peter; Capper, David; Siewert, Christin; Sauvigny, Thomas; Lamszus, Katrin; Westphal, Manfred; Dührsen, Lasse; Ricklefs, Franz L.
In: NEURO-ONCOLOGY, Vol. 25, No. 2, 14.02.2023, p. 315-325.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients
AU - Drexler, Richard
AU - Schüller, Ulrich
AU - Eckhardt, Alicia
AU - Filipski, Katharina
AU - Hartung, Tabea I
AU - Harter, Patrick N
AU - Divé, Iris
AU - Forster, Marie-Therese
AU - Czabanka, Marcus
AU - Jelgersma, Claudius
AU - Onken, Julia
AU - Vajkoczy, Peter
AU - Capper, David
AU - Siewert, Christin
AU - Sauvigny, Thomas
AU - Lamszus, Katrin
AU - Westphal, Manfred
AU - Dührsen, Lasse
AU - Ricklefs, Franz L
N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2023/2/14
Y1 - 2023/2/14
N2 - 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 a surgical benefit for recurrent glioblastoma.RESULTS: 345 patients (80.2%) fulfilled the inclusion criteria and 305 patients received combined adjuvant therapy. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (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). Patients with 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.
AB - 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 a surgical benefit for recurrent glioblastoma.RESULTS: 345 patients (80.2%) fulfilled the inclusion criteria and 305 patients received combined adjuvant therapy. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (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). Patients with 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.
U2 - 10.1093/neuonc/noac177
DO - 10.1093/neuonc/noac177
M3 - SCORING: Journal article
C2 - 35868257
VL - 25
SP - 315
EP - 325
JO - NEURO-ONCOLOGY
JF - NEURO-ONCOLOGY
SN - 1522-8517
IS - 2
ER -
