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TERT Promoter Mutations May Not Be Indicative of Sensitivity To Temozolomide

TERT promoter mutation may not be linked to MGMT promoter methylation-mediated sensitivity to temozolomide in IDH-wildtype glioblastoma
20 Sep 2020
Anticancer agents & Biologic therapy;  Central nervous system malignancies;  Personalised medicine

While temozolomide is known to be active in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma and O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours, this chemosensitivity may not be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations as reported in recent studies. These findings from an analysis of prospective data were presented by Michael Weller of the Department of Neurology and Brain Tumour Centre, University Hospital Zurich in Zurich, Switzerland at ESMO Virtual Congress 2020.  

Dr Weller commented that the benefit from temozolomide chemotherapy in the treatment of IDH-wildtype glioblastoma is primarily limited to patients with MGMT promoter-methylated tumours. He noted that recent findings suggest that TERT promoter hotspot mutations may modulate the impact of the MGMT status on chemosensitivity.

Results from the prospective discovery cohort were validated by retrospective data from a cohort of similar patients

Prompted by these reports, the study team investigated MGMT promoter methylation and TERT promoter mutation status prospectively in an exploratory discovery cohort of 298 patients in the German Glioma Network (GGN) with IDH-wildtype glioblastoma. Data from this investigation were then validated using retrospective data from a similar cohort of 302 patients from Düsseldorf, Germany and Zurich, Switzerland.

In patients with MGMT promoter-methylated tumours TERT promoter mutations did not associate with improved outcome

The GGN discovery cohort comprised patients with MGMT promoter-unmethylated and MGMT promoter-methylated tumours.

The cohort of patients having MGMT promoter-unmethylated tumours and a TERT promoter mutation demonstrated a non-statistically significant trend towards inferior outcome (p = 0.085).

In the cohort of patients with MGMT promoter-methylated tumours, this analysis did not find an association between TERT promoter mutations and improved outcome in patients. Similar patterns in outcome were observed in an analysis that included only patients in this cohort who were designated to receive temozolomide. In this analysis, no association was observed between different TERT promoter hotspot mutations and distinct outcomes.

TERT-Promoter-Mutations-May-Not-Be-Indicative-of-Sensitivity-To-Temozolomide-360O

Outcome by MGMT promoter methylation and TERT promoter mutation status in the prospective GGN cohort. Overall survival curves are shown in patients with tumours without (A) or with (B) MGMT promoter methylation in the whole patient cohort.

© Michael Weller, Dorothee Gramatzki.

Findings from the analysis of data from the discovery cohort were confirmed in the retrospective validation cohort.

Conclusions

According to the authors, this analysis of two independent cohorts of patients with glioblastoma, including the prospective GGN cohort, did not confirm previous data suggesting that TERT promoter mutations confer an enhanced benefit from temozolomide in patients with MGMT promoter-methylated glioblastoma.

Based on these findings, they concluded that diagnostic testing for TERT promoter mutations may not be required for prediction of temozolomide sensitivity in patients with IDH-wildtype glioblastoma.

This study was funded by German Cancer Aid. 

Reference

360O – Weller M, Gramatzki D, Felsberg J, et al. Telomerase reverse transcriptase (TERT) promoter mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation-mediated sensitivity to temozolomide in IDH-wildtype glioblastoma: ESMO Virtual Congress 2020.

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