scholarly journals 363P Clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and MGMT promoter methylation status in newly diagnosed and recurrent IDHwildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study

2021 ◽  
Vol 32 ◽  
pp. S523
Author(s):  
G. Lombardi ◽  
S. Giunco ◽  
F. Cavallin ◽  
C. Angelini ◽  
M. Caccese ◽  
...  
Keyword(s):  
Telomere Length ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Telomerase Reverse Transcriptase ◽  
Newly Diagnosed ◽  
Tert Promoter Mutations ◽  
Mgmt Promoter ◽  
Promoter Mutations ◽  
Mgmt Promoter Methylation Status

The clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in newly diagnosed and recurrent IDH-wildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2053-2053
Author(s):  
Giuseppe Lombardi ◽  
Silvia Giunco ◽  
Francesco Cavallin ◽  
Chiara Angelini ◽  
Mario Caccese ◽  
...  
Keyword(s):  
Telomere Length ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Mgmt Promoter ◽  
Promoter Mutations ◽  
Mgmt Promoter Methylation Status

2053 Background: the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large mono-institutional study to better investigate their impact and their interaction on clinical outcomes Methods: TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio Results: characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0-1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07-0.40). No gene interaction was significant. Conclusions: for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status.

PL02.5.A The clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in newly diagnosed and recurrent IDHwildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii1-ii2
Author(s):  
G Lombardi ◽  
S Giunco ◽  
F Cavallin ◽  
C Angelini ◽  
M Caccese ◽  
...  
Keyword(s):  
Telomere Length ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Mgmt Promoter ◽  
Promoter Mutations ◽  
Mgmt Promoter Methylation Status

Abstract BACKGROUND the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large monoinstitutional study to better investigate their impact and their interaction on clinical outcomes MATERIAL AND METHODS TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio RESULTS characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0–1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4–11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64–1.64) and 0.99 (95% CI 0.89–1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40–0.71) and 0.47 (95% CI 0.34–0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0–1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68–8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07–0.40). No gene interaction was significant CONCLUSION for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

2014 ◽  
Vol 37 (6) ◽  
pp. E4 ◽  
Author(s):  
Giuseppe M. V. Barbagallo ◽  
Sabrina Paratore ◽  
Rosario Caltabiano ◽  
Stefano Palmucci ◽  
Hector Soto Parra ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Group A ◽  
Group B ◽  
Mgmt Promoter Methylation Status

Object The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. Methods A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m2 starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30–72 years (mean 56.1 years), received 150 mg/m2 for 5 days every 28 days for more than 6 cycles (range 7–101 cycles). The 18 patients in Group B, aged 46–82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. Results All patients but 1 in Group A survived at least 18 months (range 18–101 months), and patients in Group B survived no more than 17 months (range 2–17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. Conclusions This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

scholarly journals Prospective Biomarker Study in Newly Diagnosed Glioblastoma: Cyto-C Clinical Trial

2021 ◽  
Author(s):  
Corinne E Griguer ◽  
Claudia R Oliva ◽  
Christopher S Coffey ◽  
Merit E Cudkowicz ◽  
Robin A Conwit ◽  
...  
Keyword(s):  
Survival Time ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Abstract Background Glioblastoma (GBM) has a 5-year survival rate of 3–5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome c oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival time (OS), and the secondary end point was progression-free survival time (PFS). Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a sub-group of GBM patients with improved long term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

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