Diagnostic Accuracy of Immunohistochemistry in Detecting MGMT Methylation Status in Patients with Glioma

Abstract BACKGROUND the significance of TERT promoter mutations, telomere length and their interactions with MGMT methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a monoinstitutional study to better investigate their impact and their interaction on clinical outcomes. METHODS TERTmutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation were assessed in 278 newly-diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated from Dec2016 to Jan2020. We explored association between gene characteristics and neuroradiological response, PFS, 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 PS0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMTmet in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). ORR was reported in 15% of PTS, medianOS was 15 ms (95% CI 13-18 ms), medianPFS was 8 ms (95% CI 7-9 ms). At multivariable analysis, TERT mutations and RTL were not associated with clinical outcomes; about OS, TERT 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; MGMTmet 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 PS0-1 in 60% of PTS, MGMTmet in 37%, TERT mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMTmet tumors resulted significantly associated to prolonged OS(HR0.16;95%CI0.07-0.40). No gene interaction was significant. CONCLUSIONS we analyzed the impact of TERT mutations, RTL and MGMT in newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT status and RTL were not associated with clinical outcomes. MGMT was the only prognostic factor. No significant interaction was demonstrated between TERT mutations, RTL and MGMT

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Preoperative MRI-radiomics features improve prediction of survival in glioblastoma patients over MGMT methylation status alone

Oncotarget ◽

10.18632/oncotarget.26578 ◽

2019 ◽

Vol 10 (6) ◽

pp. 660-672 ◽

Cited By ~ 15

Author(s):

Florent Tixier ◽

Hyemin Um ◽

Dalton Bermudez ◽

Aditi Iyer ◽

Aditya Apte ◽

...

Keyword(s):

Methylation Status ◽

Mgmt Methylation ◽

Prediction Of Survival

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Towards the definition of a prognostic score based on MGMT methylation status in patients with glioblastoma: do not lose the forest looking at the tree

Annals of Oncology ◽

10.1093/annonc/mdw345.15 ◽

2016 ◽

Vol 27 ◽

pp. iv111

Author(s):

E. De Carlo ◽

L. Gurrieri ◽

G. De Maglio ◽

L. Gerratana ◽

V. Buoro ◽

...

Keyword(s):

Prognostic Score ◽

Methylation Status ◽

Mgmt Methylation ◽

Definition Of

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First steps in the definition of a prognostic score based on MGMT methylation status in patients with glioblastoma

Annals of Oncology ◽

10.1093/annonc/mdw367.17 ◽

2016 ◽

Vol 27 ◽

pp. vi108

Author(s):

E. De Carlo ◽

L. Gurrieri ◽

G. De Maglio ◽

L. Gerratana ◽

V. Buoro ◽

...

Keyword(s):

Prognostic Score ◽

Methylation Status ◽

Mgmt Methylation ◽

Definition Of

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HOUT-02. TREATMENT PATTERNS AND OUTCOMES FOR PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME IN A US COMMUNITY ONCOLOGY SETTING

Neuro-Oncology ◽

10.1093/neuonc/noz175.467 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi112-vi112

Author(s):

Alex Fu ◽

Nicholas Robert ◽

Trang Pham ◽

Alexander Marshall ◽

Srinivas Annavarapu

Keyword(s):

Glioblastoma Multiforme ◽

Clinical Outcomes ◽

Dna Methyltransferase ◽

Treatment Options ◽

Methylation Status ◽

Treatment Patterns ◽

Newly Diagnosed ◽

Mgmt Methylation ◽

The Us ◽

Newly Diagnosed Glioblastoma

Abstract BACKGROUND This study aims to describe real world characteristics and outcomes of newly-diagnosed glioblastoma multiforme (GBM) patients in relationship to O6-methylguanine DNA methyltransferase promoter (MGMT) testing and methylation status, in the US. METHODS Patients receiving care for GBM were identified in the US Oncology Network database from 1/1/2013 to 6/30/2018 and followed up to 9/30/2018. Structured data and chart reviews were used to assess demographic and clinical characteristics, treatment patterns, type of surgery, MGMT methylation, and clinical outcomes. RESULTS Of 600 patient charts planned for review, 195 have been randomly selected and reviewed thus far. Of these, 165 (84.6%) had surgical resection and 30 (15.4%) had biopsy only. Eighty-eight (45.1%) patients were tested for MGMT status and 107 (54.9%) were not. Of those tested, 33 (37.5%) were methylated, and 45 (51.1%) unmethylated. Median ages in the overall (including tested and untested), methylated and unmethylated cohorts were 63.7, 58.8, and 66.7 years, respectively. Most common first-line (1L) treatment in overall, methylated, and unmethylated cohorts was radiation concurrent with temozolomide received by 86.2%, 93.9%, and 91.1%, respectively. Median duration of 1L treatment in the overall cohort was 15.1 weeks (95% confidence interval [CI]: 11.9, 21.6) and higher in the methylated vs. unmethylated cohort (25.9 [18.1, 34.6] vs. 15.1 [9.3, 23.4] weeks, p=0.0375). Unadjusted median overall survival and progression-free survival in the overall cohort were 11.4 [9.4, 14.0] months and 5.2 [3.9, 5.8] months, and higher in the methylated vs. unmethylated cohort (20.5 [14.9, not realized] vs. 12.2 [7.1, 17.0] months, p=0.0052, and 9.4 [5.6, 14.0] vs. 5.5 [3.3, 6.8], p=0.0092, respectively). CONCLUSIONS Fewer than half of GBM patients were tested for MGMT methylation in the US community. Clinical outcomes, while better among patients with methylated MGMT, remain poor and current treatment options are limited.

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WP1-18 Risk factors and patterns of recurrence of low grade glioma: a systematic review

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-abn.19 ◽

2019 ◽

Vol 90 (3) ◽

pp. e6.3-e6

Author(s):

V Narbad ◽

JP Lavrador ◽

A Elhag ◽

S Acharya ◽

J Hanrahan ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Tp53 Mutation ◽

Methylation Status ◽

Low Grade Glioma ◽

Low Grade ◽

Diffuse Glioma ◽

Idh Mutation ◽

Mgmt Methylation ◽

Inclusion Criteria

ObjectivesTo review the risk factors and patterns of progression/recurrence of low grade glioma (LGG).DesignSystematic review of the published literature.SubjectsInclusion criteria were peer reviewed publications of cohort studies of recurrent/progressive LGG. Studies of wider populations were included if relevant LGG data could be analysed separately.MethodsMedline and Cochrane databases were searched using MeSH and non-MeSH terms, including ‘glioma’, ‘astrocytoma’, ‘oligoastrocytoma’, ‘diffuse glioma’, ‘oligodendroglioma’, ‘low grade’ and ‘disease recurrence’ by two independent reviewers.ResultsOverall, 917 studies were screened, of which 57 studies met the inclusion criteria. The most frequently described risk factor for recurrent LGG was suboptimal extent of resection (EOR) of the initial tumour (in 20 studies); recurrence was also associated with the patient’s age (2), tumour location (4), neurological status (3), tumour volume (6), bihemispherical tumour (3) and astrocytic histology (6). IDH mutation was associated with recurrence in 1 out of 3 studies, but TP53 mutation (2 of 4) and MGMT methylation status (4) were not. Malignant transformation was associated with TP53 mutations (3), IDH mutation (1) and EOR (1). Favourable progression free survival (PFS) and/or overall survival (OS) were associated with greater EOR (16), oligodendroglioma histology (2 of 4), initial KPS (3) and the use of adjuvant therapies (9 of 14). IDH mutation was associated with improved PFS and OS (3 of 4). TP53 mutation improved PFS in 1 of 3 studies. MGMT methylation and 1 p/19q codeletion may predict treatment response but their effects on survival are unclear.ConclusionsAstrocytoma histology, IDH and TP53 mutation statuses and surgical treatment (EOR) are essential in determining the time to recurrence or progression in LGG.

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Do we really know who has an MGMT methylated glioma? Results of an international survey regarding use of MGMT analyses for glioma

Neuro-Oncology Practice ◽

10.1093/nop/npz039 ◽

2019 ◽

Vol 7 (1) ◽

pp. 68-76 ◽

Cited By ~ 4

Author(s):

Annika Malmström ◽

Małgorzata Łysiak ◽

Bjarne Winther Kristensen ◽

Elizabeth Hovey ◽

Roger Henriksson ◽

...

Keyword(s):

Dna Methyltransferase ◽

Clinical Decision Making ◽

Methylation Status ◽

Clinical Decision ◽

International Survey ◽

Mgmt Methylation ◽

International Consensus ◽

Methylguanine Dna Methyltransferase ◽

Cpg Sites ◽

International Consensus Guidelines

Abstract Background Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results. Methods We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff. Results The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing. Conclusion Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

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