P11.28.ATERT C228T: A NOVEL MOLECULAR INDEPENDENT PROGNOSTIC FACTOR IN PATIENTS WITH GLIOBLASTOMA IDH WILD TYPE
Authors: Gorría T , Crous C , Mariño C , Hernandez A , Sanz C , Doménech M , Parra G , Esteve-Codina A , Carrato C , Meléndez B , Aldecoa I , Jares P , González J , Esteve A , Cerda G , Alameda F , Muñoz-Mármol A , López-Martos R , Valduvieco I , González-Ortiz S , Pineda E , Balaña C 
Published: September 2023

Abstract

BACKGROUND
TERT promoter (TERTp) variants regulate TERT expression and are the most frequent mutations in glioblastoma (GB), specifically c. -124C&gt;T and c.-146C&gt;T, known as C228T and C250T respectively. The role on prognosis of TERTp mutation is unclear and its clinical impact remains unknown. We assess the association of the status of TERTp considering the mutation subtype (C228T vs C250T vs TERTp wild type (WT)) with outcomes in patients (pts) with GB IDH-WT.

MATERIAL AND METHODS
We expanded a retrospective multicenter study to include pts with GB treated between 2010-2022 with standard treatment (radiotherapy with concomitant and adjuvant temozolomide). Clinical, molecular, and histological data were collected from medical reports. C228T and C250T TERTp mutations were assesed by PCR/Sanger sequencing (93%) or NGS (7%). MGMTp methylation and IDH mutation were tested by MS-PCR and immunohistochemistry/sequencing, respectively. Median overall survival (mOS) was estimated using the Kaplan-Meier method and compared between strata through the log-rank test. Multivariate Cox regression models were performed to adjust the effect of C228T mutation by MGMTp methylation, age, Karnofsky (KPS) and type of surgery and to assess the potential role of the interaction of both molecular factors

RESULTS
A total of 255 pts have been enrolled with a median follow up of 14.2 months; 63% were male, 35% older than 65 years old, 70% had a Karnofsky Index &gt;80%, 40% had gross total resection and 51% had MGMTp methylation. A total of 86 pts (34%) were treated with bevacizumab in latter lines.The presence of TERTp mutation C228T was observed in 54.7% (N=140), C250T in 22.7% (N=58) and the rest (N=57) were TERTp WT. The median OS was 16.4 months (95% CI 14.7 - 18). The C250T mutation was significantly associated with better OS 21.7 months (95% CI 16.1 - 32; p=0.041). Multivariate analysis confirmed that C228T TERTp mutation confers worse prognosis independently of methylation status, age, KPS and type of surgery (HR 1.55; 1.07-2.24 p=0.02). In a further multivariate analysis to assess the potential role of the interaction between both molecular factors, pts with GB unmethylated MGMTp/C228T TERTp mutation had the worse prognoses (HR = 2.83, 95% CI: 1.59-5.03, p &lt; 0.001), followed by the unmethylated MGMTp/C250T (HR = 2.06, 95% CI: 1.08 - 3.94, p = 0.028), and methylated MGMTp/C228T TERTp (HR = 1.80, 95% CI: 1.01 - 3.17, p = 0.041).

CONCLUSION
We report that TERTp C228T mutation is an independent prognostic factor of worse survival regardless of MGMT methylation status, age, KPS and type of surgery, in pts with GB IDH-WT treated homogeneously with standard treatment. We purpose to consider it as an important new prognostic molecular factor in the design of new clinical trials.