ACT-10 TREATMENT FOR GLIOBLASTOMA RECURRED AFTER CONCOMITANT CHEMORADIATION THERAPY WITH TEMOZOLOMIDE AND THEIR PROGNOSIS

Abstract There are few data about treatment for glioblastoma recurred after concomitant chemoradiation therapy with temozolomide (TMZ). We retrospectively examined treatment and prognosis of recurred glioblastoma patients who registered Kansai molecular diagnosis network for central nervous system tumors, and whose clinical information were available. One hundred and fifty-seven patients that were clinically diagnosed as recurrence between November 2007 and April 2019 were included. Their median age at primary diagnosis was 52 years old and median KPS was 80%. Proportion of methylated MGMT promoter was 43.3% (65 patients), and mutated IDH was 5.4% (8 patients). Median overall survival after recurrence (mSAR) was 8.2 months. One hundred and sixteen patients (73.9%) were received any anticancer treatment and their mSAR was 10.5m. Combination of TMZ and bevacizumab (Bev) were most frequently used for 33 patients, followed by Bev monotherapy for 17 patients, surgery + TMZ + Bev for 15 patients, surgery + TMZ for 12 patients, and TMZ monotherapy for ten. Their mSAR were 8.0m, 7.5m, 10.5m, 13.0m, and 8.0m, respectively. Using univariate analysis, MGMT promoter methylation (p=0.0007), TMZ (p=0.00933), surgery (p=0.0126), re-radiation (p=0.0367), and surgery+TMZ+Bev (p=0.0493) significantly affected prognosis. By multivariate analysis, MGMT promoter methylation, TMZ, and re-radiation were statistically significant (p=0.000138, 0.00161, 0.00403, respectively). These data showed that relatively young patients with good performance status would receive anti-cancer treatment beyond progression and MGMT promoter methylation might be one of prognostic factor for longer survival. In this cohort, re-radiation was performed for few patients and nitrosourea such as nimustine was almost not used. Further study would be needed whether these treatments have any positive effect or not.

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Immunotherapeutic early-phase clinical trials and malignant gliomas: a single-center experience and comprehensive immunophenotyping of circulating leukocytes

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab160 ◽

2021 ◽

Author(s):

Matteo Simonelli ◽

Pasquale Persico ◽

Arianna Capucetti ◽

Claudia Carenza ◽

Sara Franzese ◽

...

Keyword(s):

Clinical Trials ◽

Promoter Methylation ◽

Early Phase ◽

Univariate Analysis ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Control Group ◽

Large Expansion ◽

Mgmt Promoter ◽

Early Phase Clinical Trials

Abstract Background Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of p <0.1. Results Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti PD-1, anti CSF-1R, anti TGFβ, anti cereblon), fifteen patients combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than six years. Univariate analysis identified O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

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Characteristics of glioblastoma long-term survivors

Neuro-Oncology ◽

10.1093/neuonc/noab195.037 ◽

2021 ◽

Vol 23 (Supplement_4) ◽

pp. iv15-iv15

Author(s):

Tamara Ali ◽

Farouk Olubajo ◽

Nitika Rathi ◽

Piyali Pal ◽

Michael Jenkinson ◽

...

Keyword(s):

Promoter Methylation ◽

Performance Status ◽

Outcome Data ◽

Mgmt Promoter Methylation ◽

Small Subset ◽

Who Grade ◽

Number Of Patients ◽

Mgmt Promoter ◽

Long Term Survivors

Abstract Aims Glioblastoma (GBM) is the commonest and most aggressive primary malignant brain tumour in adults. A small number of patients survive for >5 years and are referred to as long-term survivors (LTS). This study aimed to quantify and characterise GBM LTS in a single large UK centre. Method A retrospective observational cohort study was performed. Patients diagnosed with GBM in a single UK centre between 2000–2011 (inclusive) who survived >5 years from diagnosis were included. Histopathological samples were re-examined as per the WHO 2016 classification criteria and tested for molecular biomarkers including MGMT promoter methylation, IDH1/2 mutations, 1p19q codeletion and ATRX. Demographic, imaging, treatment and outcome data were collected. Results 1130 patients diagnosed with GBM were identified, 30 of whom survived for >5 years. Twenty-three were re-confirmed as GBM histologically and seven were reclassified as anaplastic oligodendroglioma or anaplastic astroctyoma. Median overall survival for this cohort was 6.2 years. We report a 2% 5-year survival, and a 0.7% 7-year survival. LTS-associated factors were younger age (<65 years old), frontal unilateral tumours, maximal management (surgery and chemoradiotherapy), good post-operative performance status (WHO <2), MGMT promoter methylation and IDH1/2 mutation. Conclusion A small subset of GBM patients survive for >5 years. Most still succumb to the disease, implying 5-year survival is not indicative of a cure. On applying current molecular markers, a quarter of previously diagnosed glioblastoma in this LTS population were revised to be WHO grade III gliomas.

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Survival in Patients with Newly Diagnosed Conventional Glioblastoma: A Modified Prognostic Score Based on a Single-Institution Series

Tumori Journal ◽

10.1177/030089161209800613 ◽

2012 ◽

Vol 98 (6) ◽

pp. 756-761 ◽

Cited By ~ 3

Author(s):

Federica Bertolini ◽

Elena Zunarelli ◽

Caterina Baraldi ◽

Antonella Valentini ◽

Cinzia Del Giovane ◽

...

Keyword(s):

Promoter Methylation ◽

Prognostic Score ◽

Performance Status ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Class I ◽

Survival Times ◽

Promoter Methylation Status ◽

Mgmt Promoter ◽

Mgmt Promoter Methylation Status

Aims and background Recursive partioning analysis (RPA) is commonly used to define the stratification of patients with glioblastoma. Epigenetic silencing of the O6-methylguanine methyltransferase (MGMT) gene by promoter methylation plays an important role in regulating MGMT expression in gliomas and this is an established independent prognostic factor. We tested a prognostic scoring system including all clinical variables used by RPA classification (age, ECOG performance status and type of surgery) and MGMT gene promoter methylation status. Methods Seventy-eight consecutive patients with newly diagnosed, histopathologically confirmed conventional glioblastoma were included. Information about MGMT promoter methylation status was available for all of them. Based on the patients' age (<50 vs ≥50 years), ECOG performance status (0 vs ≥1), type of surgery (gross tumor resection versus partial resection/biopsy) and MGMT promoter methylation status (methylated versus unmethylated), three classes of risk were generated where the prognostic score was defined assigning 1 point to every favorable parameter (Class I: ≥3; Class II: 2; Class III: 0–1). All classes were correlated with overall survival. Results The median survival times were 32.4, 8.6 and 8.8 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 69%, 13.5% and <1%. The same analysis was performed on 54 patients treated with postoperative concomitant chemoradiotherapy. The median survival times were 32.5, 13.4 and 8.9 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 68.6%, 26.9% and <1%. In both groups of 78 and 54 patients the differences in survival between Class I and III were statistically significant (P <0.0001). Conclusions The proposed prognostic scoring system including clinical variables and MGMT promoter methylation status proved valuable in patients with primary conventional glioblastoma, especially those treated with postoperative chemoradiotherapy.

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Faculty Opinions recommendation of Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718120909.793486641 ◽

2013 ◽

Author(s):

Marc Chamberlain

Keyword(s):

Promoter Methylation ◽

Predictive Value ◽

Idh1 Mutation ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Prognostic significance of MGMT promoter methylation in diffuse glioma patients

Biotechnology & Biotechnological Equipment ◽

10.1080/13102818.2019.1604158 ◽

2019 ◽

Vol 33 (1) ◽

pp. 639-644

Author(s):

Nikola Jovanović ◽

Tatjana Mitrović ◽

Vladimir J. Cvetković ◽

Svetlana Tošić ◽

Jelena Vitorović ◽

...

Keyword(s):

Promoter Methylation ◽

Prognostic Significance ◽

Mgmt Promoter Methylation ◽

Diffuse Glioma ◽

Mgmt Promoter

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Fast Routine Assessment of MGMT Promoter Methylation

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa170 ◽

2020 ◽

Author(s):

Ivana Bratic Hench ◽

Rosa Della Monica ◽

Lorenzo Chiariotti ◽

Michel Bihl ◽

Markus Tolnay ◽

...

Keyword(s):

Promoter Methylation ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter ◽

Routine Assessment

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MGMT promoter methylation is associated with patient age and 1p/19q status in IDH-mutant gliomas

Neuro-Oncology ◽

10.1093/neuonc/noab039 ◽

2021 ◽

Author(s):

Craig Horbinski ◽

Kathleen McCortney ◽

Roger Stupp

Keyword(s):

Promoter Methylation ◽

Mgmt Promoter Methylation ◽

Patient Age ◽

Patient Âgé ◽

Mgmt Promoter

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MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System

International Journal of Molecular Sciences ◽

10.3390/ijms22083845 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3845

Author(s):

Sarah Teuber-Hanselmann ◽

Karl Worm ◽

Nicole Macha ◽

Andreas Junker

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Alkylating Agents ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Demyelinating Diseases ◽

Brain Diseases ◽

Tumor Biomarker ◽

Mgmt Promoter ◽

First Time

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.

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