TERT promotor status does not add prognostic information in IDH-wildtype glioblastomas fulfilling other diagnostic WHO criteria: A report of the RANO resect group


 In IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria.

In IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria.
The WHO 2021 classification restricts the diagnosis of "glioblastoma WHO grade 4" to IDH-wildtype astrocytic gliomas either with (1) classical histopathological hallmarks or (2) qualifying molecular features. 1 The latter include EGFR amplification, +7/−10 genotype, and TERT promotor mutation which are all associated with less favorable outcome when observed in combination with IDH-wildtype status. 2,3 The presence of one of these three markers allows the diagnosis of "molecular" glioblastoma even when tumors appear histologically lower grade, and 80% of glioblastomas exhibit TERT promotor mutations. 4 Whether TERT promotor mutations are of prognostic value in IDH-wildtype glioblastomas which otherwise yet fulfill the diagnostic (histopathological or molecular) criteria for glioblastoma is unclear. Here, we explored such an association based upon a well-annotated glioblastoma cohort from 7 international neuro-oncological centers participating in the RANO resect group.
With approval of the ethics committee of the Ludwig-Maximilians-University (Munich, Germany; AZ-21-0996), the RANO resect group compiled a retrospective database of newly diagnosed IDH-wildtype glioblastomas treated between 2003 and 2022 with a follow-up of ≥3 months. 5 For the current study, individuals were selected when information on TERT promotor mutation status was available for review. Demographics, molecular information, clinical data, and outcome were extracted; and date of progression was determined per RANO criteria.
We did therefore not find evidence that TERT promotor status adds prognostic information in IDH-wildtype glioblastomas exhibiting classical histopathological hallmarks (or other mutations) sufficient for glioblastoma diagnosis. This is in line with previous reports on IDH-wildtype glioblastomas, 4,6,7 although these studies have either not controlled for clinical and molecular confounders 4,6 or were substantially limited in sample size. 4,7 Notably, IDH wt / TERT wt glioblastomas may identify a subset with a distinct

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(epi-)genetic and molecular profile compared to IDH wt / TERT mut tumors and may benefit from different, personalized treatment strategies. 2,4,6 These biological findings, however, to date do not result in different clinical outcomes. Thus, up to now our retrospective data argue against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria. This might change in the future whenever TERT-directed therapies emerge.

Funding
No funding to report.