Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.

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Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma

Neuro-Oncology ◽

10.1093/neuonc/noaa033 ◽

2020 ◽

Vol 22 (8) ◽

pp. 1162-1172 ◽

Cited By ~ 6

Author(s):

Antje Wick ◽

Tobias Kessler ◽

Michael Platten ◽

Christoph Meisner ◽

Michael Bamberg ◽

...

Keyword(s):

Promoter Methylation ◽

Methylation Status ◽

Predictive Biomarker ◽

Copy Number Variations ◽

Mgmt Promoter Methylation ◽

Prognostic Impact ◽

Term Outcome ◽

Long Term Outcome ◽

Mgmt Promoter

Abstract Background O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. Methods This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. Results In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0–10.0] months for TMZ treatment versus 9.4 [8.1–10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76–1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2–4.1) months vs 4.6 (4.2–5.0) months] did not differ, with HR = 1.02 (0.83–1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9–24.4] mo and 8.5 [6.9–13.3] mo) versus RT (9.6 [6.4–13.7] mo and 4.8 [4.3–6.2] mo, HR 0.44 [0.27–0.70], P < 0.001 for OS and 0.46 [0.29–0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. Conclusion MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

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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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Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BMC Cancer ◽

10.1186/1471-2407-9-101 ◽

2009 ◽

Vol 9 (1) ◽

Cited By ~ 24

Author(s):

Alessandra Fabi ◽

Giulio Metro ◽

Michelangelo Russillo ◽

Antonello Vidiri ◽

Carmine Maria Carapella ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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NIMG-39. UTILITY OF PHYSIOLOGIC MR METRICS IN DISTINGUISHING TRUE-PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMAS STRATIFIED BY MGMT PROMOTER METHYLATION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.652 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii156-ii156

Author(s):

Sanjeev Chawla ◽

Sumei Wang ◽

Amir Nazem ◽

Morgan Burke ◽

Nasrallah MacLean ◽

...

Keyword(s):

Mr Imaging ◽

Promoter Methylation ◽

Cerebral Blood Volume ◽

Mean Diffusivity ◽

Gene Promoter ◽

Threshold Value ◽

Mgmt Promoter Methylation ◽

P Value ◽

Methyl Transferase ◽

Mgmt Promoter

Abstract BACKGROUND Methylation of O6-methyl-guanine-methyl transferase MGMT gene promoter is associated with favorable prognosis in glioblastoma (GBM) patients treated with surgery and chemoradiation therapy (CRT). OBJECTIVE To investigate potential of diffusion and perfusion MR imaging in distinguishing TP from PsP in GBM patients stratified by MGMT status. METHODS A cohort of 92 patients demonstrating new/increasing enhancing lesions within six months of completion of CRT underwent 3T MR imaging. Median values of mean diffusivity (MD), fractional anisotropy (FA), anisotropy coefﬁcients [linear(CL), planar (CP), and spherical (CS)] and maximum relative cerebral blood volume (rCBVmax) were computed from enhancing lesions. Patients were classified as TP (n=65) and PsP (n=27) based on histopathology or follow-up MRI scans. Mann-Whitney, independent-sample T-tests and receiver operating characteristic (ROC) curve analyses were performed to distinguish TP from PsP. Of 92 patients, MGMT status was available from 60 patients [MGMT-methylated (n=23) and MGMT-unmethylated (n=37)]. Statistical analyses were also performed in distinguishing TP (n=15) and PsP (n=8) from MGMT-methylated and MGMT-unmethylated subgroups (TP=28; PsP=9). A p-value of 0.05 was considered significant. RESULTS Significantly higher rCBVmax and FA and a trend towards higher CP were observed in TP compared to PsP. Among these parameters, rCBVmax had the best sensitivity=62%, specificity=68% and accuracy=67% in distinguishing TP from PsP. ROC analysis revealed sensitivity=54%, specificity=78% and accuracy=68% after combination of these parameters. In MGMT methylated patients, only rCBVmax was significantly higher in TP than in PsP with sensitivity=79%, specificity=67% and accuracy=74% at a threshold rCBVmax value of 2.23. In MGMT unmethylated group, a trend towards higher rCBVmax was observed in TP than in PsP with sensitivity=67%, specificity=77%, accuracy=69%, threshold value=2.89. CONCLUSION Physiologic imaging parameters demonstrate variable diagnostic values for detecting PsP in GBM patients stratified by MGMT status. The best parameter in distinguishing TP from PsP was rCBVmax in patients demonstrating MGMT promoter methylation.

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Detection of MGMT promoter methylation in malignant gliomas.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e23131 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e23131-e23131

Author(s):

Michelle Afkhami ◽

Vandana Sharma ◽

Maria Cuellar ◽

Massimo D'Apuzzo ◽

Behnam Badie ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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MGMT promoter methylation in malignant gliomas

Targeted Oncology ◽

10.1007/s11523-010-0153-6 ◽

2010 ◽

Vol 5 (3) ◽

pp. 161-165 ◽

Cited By ~ 43

Author(s):

Markus J. Riemenschneider ◽

Monika E. Hegi ◽

Guido Reifenberger

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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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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Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2027 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2027-2027

Author(s):

Michael Weller ◽

Bettina Hentschel ◽

Matthias Simon ◽

Manfred Westphal ◽

Gabriele Schackert ◽

...

Keyword(s):

Promoter Methylation ◽

Mgmt Promoter Methylation ◽

Molecular Characteristics ◽

Wild Type ◽

Who Grade ◽

Term Survival ◽

Long Term Survival ◽

Tp53 Mutations ◽

Mgmt Promoter

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

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