360O - Telomerase reverse transcriptase (TERT) promoter mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation-mediated sensitivity to temozolomide in IDH-wildtype glioblastoma: Is there a link?

Background

Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is essentially limited to patients with O⁶-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Recent studies suggest that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations.

Methods

MGMT promoter methylation and TERT promoter mutation status were assessed in an exploratory prospective cohort of IDH-wildtype glioblastoma patients of the German Glioma Network (GGN) (n=298) and validated in a retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n=302).

Results

In the GGN discovery cohort of patients with MGMT promoter-unmethylated tumors, TERT promoter mutation showed a trend towards inferior outcome (p=0.085). TERT promoter mutations were not associated with improved outcome in patients with MGMT promoter-methylated tumors. The same patterns were seen when the analysis was restricted to patients intended to be treated with TMZ. Different TERT promoter hotspot mutations were not associated with distinct outcomes. These results were confirmed in the retrospective validation cohort.

Conclusions

Analysis of two independent cohorts of glioblastoma patients, including the prospective GGN cohort, 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 IDH-wildtype glioblastoma patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

German Cancer Aid.

Disclosure

M. Weller: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AbbVie; Research grant/Funding (self): Adastra; Research grant/Funding (self): Dracen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Sharp & Dohme (MSD); Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck (EMD); Research grant/Funding (self): Novocure; Honoraria (self), Advisory/Consultancy: Medack; Honoraria (self), Advisory/Consultancy: Basilea; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb (BMS); Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Nerviano Medical Sciences; Honoraria (self), Advisory/Consultancy: Orbus; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Tocagen. P. Roth: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Debiopharm; Honoraria (self), Advisory/Consultancy: Medac, Merck; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novocure; Honoraria (self), Advisory/Consultancy: QED; Honoraria (self), Advisory/Consultancy: Roche. T. Pietsch: Honoraria (self): Chugai; Honoraria (self): Mayo Clinic. M. Sabel: Honoraria (self): Novocure; Honoraria (self): Integra. G. Reifenberger: Honoraria (self), Advisory/Consultancy: AbbVie. All other authors have declared no conflicts of interest.