scholarly journals PATH-04. INFLUENCE OF INDIVIDUAL CpG METHYLATION STATUS OF THE MGMT PROMOTOR ON OUTCOME IN ADULT PATIENTS WITH GLIOBLASTOMA MULTIFORME RECEIVING ALKYLATING AGENT TREATMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi143-vi143
Author(s):  
Sebastian Siller ◽  
Michael Lauseker ◽  
Armin Giese ◽  
Joerg-Christian Tonn ◽  
Karim-Maximilian Niyazi ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Mrna Expression ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Tumor Resection ◽  
Cpg Sites ◽  
Cpg Site ◽  
Promotor Region ◽  
The Individual

Abstract BACKGROUND Methylation of O-6-methylguanine-DNA-methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG-site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG-sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG-sites 74–98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents. METHODS Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection was assessed by the Sanger-sequencing approach. Methylation of CpG-sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine/thymine peak > 50%. The total number of methylated CpG-sites was correlated with outcome using proportional hazards models. In a subset of 34 patients, a correlation between individual CpG-site methylation and MGMT mRNA-expression was performed. RESULTS Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6months, respectively. The cumulative total number of methylated loci within the CpG-sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p< 0.001). Furthermore, a linear coherence between the total number of methylated CpG-sites 74–98 and survival parameters could be observed. Moreover, low number of methylated CpG-sites was observed in tumor specimen with a high mRNA-expression and vice versa (Spearman-correlation-coefficient: -0.62). CONCLUSION Our data suggest a strong linear coherence between outcome and the total number of methylated CpG-sites 74–98, thus an up-front analysis of the individual GpC-site methylation status prior to initiation of alkylating chemotherapy might help improving treatment response in GBM patients.

scholarly journals P14.02 Influence of individual CpG methylation status on outcome in adult patients with glioblastoma multiforme receiving alkylating agent treatment

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii66-iii66
Author(s):  
S Siller ◽  
M Lauseker ◽  
A Giese ◽  
J Tonn ◽  
K Niyazi ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Mrna Expression ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Tumor Resection ◽  
Cpg Methylation ◽  
Karnofsky Performance Score ◽  
Cpg Sites ◽  
Promotor Region ◽  
The Individual

Abstract Background: Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG sites 74–98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents. Material and Methods: Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection (OTR) was assessed by the Sanger sequencing (Sseq) approach. Methylation of CpG sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine /thymine peak >50%. The total number of methylated CpG sites as well as clinical factors such as age, Karnofsky Performance Score (KPS) and mode of surgical procedure were correlated with outcome using proportional hazards models. In a subset of 34 patients, a correlation between individual CpG methylation and MGMT mRNA expression was performed. Results: Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6 months, respectively. Alongside younger age, KPS> 80 and OTR, the cumulative total number of methylated loci within the CpG sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p <0.001). Furthermore, a linear coherence between the total number of methylated CpG sites 74–98 and survival parameters could be observed. Moreover, low number of methylated CpG sites was observed in tumor specimen with a high mRNA expression and vice versa (Spearman correlation coefficient: -0.62). Conclusion: In contrast to the concept of dichotomizing the MGMT promotor status into ‘methylated’ and ‘non-methylated’, our approach shows a clear heterogeneity within the methylation status of the CpG sites 74–98 within the GBM tumor specimens. Our data suggest a strong correlation between outcome and the total number of methylated CpG sites, thus an up-front analysis of the individual GpC site methylation status prior to initiation of alkylating chemotherapy might help to improve treatment response in GBM patients.

scholarly journals PATH-28. EXTENT AND PROGNOSTIC VALUE OF MGMT PROMOTOR METHYLATION DEPEND ON IDH MUTATION AND 1p19q CO-DELETION IN GLIOMA WHO GRADE II

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii170-ii170
Author(s):  
Philipp Karschnia ◽  
Nico Teske ◽  
Sebastian Siller ◽  
Mario M Dorostkar ◽  
Jonathan Weller ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Malignant Progression ◽  
Wild Type ◽  
Who Grade ◽  
Cpg Sites ◽  
Idh Mutations ◽  
Promotor Region ◽  
Grade Ii

Abstract INTRODUCTION Methylation of the promotor region of the O6-methylguanin-DNA-methyltransferase (MGMT) gene is associated with increased survival in low- and high-grade glioma. It is unknown whether this association also applies to the 2016 WHO categories of glioma WHO grade II. MATERIAL AND METHODS We retrospectively searched the institutional database of the Center for Neuro-Oncology for patients with glioma WHO grade II. Patients were assigned to one of three groups according to the 2016 WHO classification system: 1. 1p19q co-deleted oligodendroglioma, IDH mutant; 2. 1p19q non-codeleted astrocytoma, IDH mutant; 3. 1p19q non-codeleted astrocytoma, IDH wild-type. MGMT methylation status was analysed using Sanger sequencing of the CpG sites 74-98 within the MGMT promotor region. The total number of methylated CpG sites was calculated for each patient. RESULTS 155 patients with glioma WHO grade II were encountered, including 81 1p19q co-deleted, IDH mutant oligodendrogliomas; 54 IDH mutant astrocytomas; and 20 IDH wild-type astrocytomas. The mean number of methylated CpG sites among oligodendrogliomas was significantly higher when compared to IDH mutant astrocytomas (18.9 ± 0.4 vs. 16.3 ± 0.6; p = 0.001). In turn, the number of methylated CpG sites among IDH mutant astrocytomas was higher when compared to IDH wild-type astrocytomas (16.3 ± 0.6 vs. 12.3 ± 1.9; p = 0.007). Median follow-up was estimated at 35 months. Median time to malignant progression was 87 months for all patients, and median overall survival was not reached. In the entire cohort, a larger number of methylated CpG sites was prognostic of overall survival and time to malignant progression. When analysed separately for the three WHO subgroups, a similar association was only retained in IDH wild-type astrocytoma. CONCLUSION In our series of WHO II gliomas, MGMT promotor methylation appeared strongly associated with 1p19q codeletion and IDH mutations. MGMT promotor methylation was only prognostic in IDH wild-type astrocytoma.

scholarly journals The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sebastian Siller ◽  
Michael Lauseker ◽  
Philipp Karschnia ◽  
Maximilian Niyazi ◽  
Sabina Eigenbrod ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Promoter Region ◽  
Proportional Hazards ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Tumor Resection ◽  
Absolute Number ◽  
Cumulative Number ◽  
Cpg Sites ◽  
A Site

AbstractMGMT-promoter methylation is associated with favorable outcome in glioblastoma. The aim of this study was to determine whether the absolute number of methylated Cytosine-Guanine-dinucleotide-(CpG-)sites within the DMR-2 island of the MGMT-promoter may correlate with outcome in a qualitative or quantitative fashion. In a cohort of newly diagnosed glioblastoma patients treated with stereotactic biopsy or open tumor resection plus concomitant chemoradiotherapy, we assessed MGMT-promoter methylation by methylation-specific polymerase-chain-reaction (MSP). Methylation of the CpG-sites 74–98 within the MGMT-promoter region was additionally analysed by Sanger sequencing, and the total number of methylated CpG-sites was correlated with outcome using proportional hazards models. 215 patients with glioblastoma were identified and stratified per MSP (positive: 53%, negative: 47%). Among MSP-positive tumors, hierarchical clustering identified three subgroups with different methylation rates (median: 80% vs. 52% vs. 47%), indicating a site-dependent methylation propagation. The methylation status of a given CpG-site indicated a neighborhood-dependent methylation propagation. Survival was linearly associated with the cumulative number of methylated CpG-sites. This was particularly true in patients who received at least one adjuvant cycle of temozolomide. Notably, all CpG-sites analyzed contributed similarly to effect size; this enabled a further predictive substratification of MSP-positive tumors with median OS ranging from as low as 17.1 months (< 18 methylated CpG-sites) to as high as 26.2 months (≥ 18 methylated CpG-sites) in the overall cohort. All in all, total number of methylated CpG-sites may correlate with outcome in a linear fashion. Such analysis may therefore add further predictive value to conventional methods of determining the MGMT-promoter status.

scholarly journals MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Review

2021 ◽  
Author(s):  
Sebastian Brandner ◽  
Alexandra McAleenan ◽  
Claire Kelly ◽  
Francesca Spiga ◽  
Hung-Yuan Cheng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dna Methyltransferase ◽  
Meta Analysis ◽  
Alkylating Agents ◽  
Cochrane Review ◽  
Predictive Biomarker ◽  
Test Method ◽  
Sufficient Information ◽  
Cpg Sites ◽  
Hazard Ratios

Abstract BACKGROUND The DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT) causes resistance of tumour cells to alkylating agents. It is a predictive biomarker in high grade gliomas treated with temozolomide, however there is no consensus on which test method, methylation sites, and cut-off values to use. METHODS We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; where MGMT status was determined in tumour tissue, and assessed by one or more technique; and where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios. Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS We cannot draw strong conclusions about use of frozen tissue versus formalin-fixed paraffin embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and Pyrosequencing at CpG sites ranging from 72 to 95. A cut-off threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies. 190 studies were identified presenting hazard ratios from survival analysis in patients in which MGMT methylation was measured by one technique only.

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

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.

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

2019 ◽  
Vol 7 (1) ◽  
pp. 68-76 ◽  
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.

MGMT methylation in newly-diagnosed glioblastoma multiforme (GBM): From the S0001 phase III study of radiation therapy (RT) and O6-benzylguanine, (O6BG) plus BCNU versus RT and BCNU alone for newly diagnosed GBM

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1512-1512 ◽  
Author(s):  
D. T. Blumenthal ◽  
M. Wade ◽  
C. J. Rankin ◽  
F. Fitzpatrick ◽  
K. Stelzer ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Median Survival ◽  
Promoter Methylation ◽  
Promoter Region ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Tissue Samples ◽  
Mgmt Promoter

1512 Background: Glioblastoma multiforme (GBM) is a high grade primary brain neoplasm associated with a median survival of less than a year. Historically, one-third of patients seem to benefit from treatment with alkylating chemotherapy. This minority may correspond to a population with decreased levels of active O6-methylguanine- methyltransferase enzyme (MGMT). MGMT repairs tumor DNA damaged by chemotherapy, allowing continued replication after exposure to treatment. Patients with low tumor MGMT activity may be more likely to respond to alkylating treatment. Hypermethylation of the MGMT promoter region leads to decreased transcription of the enzyme and is associated with improved outcome in GBM patients treated with radiation and alkylating chemotherapy. Methods: We studied a patient cohort with newly diagnosed GBM registered on Southwest Oncology Group protocol S0001, a phase III randomized, two arm clinical trial investigating an inhibitor of MGMT (O6-benzylguanine, O6BG). Both groups received standard radiation and BCNU (carmustine). The experimental group additionally received O6BG. We determined polymerase chain reaction (PCR) methylation status of the promoter region of MGMT in 88 patients with adequate tissue samples. In 41 cases, we were able to obtain successful PCR results. Results: 28 of 41 samples (68%) were found to be unmethylated and 13 of 41 (32%, 95% c. i. 18% to 50%) were methylated. Patients with methylated MGMT had a median survival of 12.6 months (95% c.i. of 7.8–15.8 months). Patients with unmethylated MGMT had a median survival of 10.6 months (95% c.i. of 8.7–12.0 months). Median progression-free survivals were 4.5 and 3.1 months respectively, for the methylated and unmethylated groups. Conclusions: This result is consistent with prior studies which showed that approximately two-thirds of patients express MGMT, and accordingly, are resistant to alkylating agents. The subgroup of patients without promoter methylation may be more likely to benefit from treatment with O6BG. Analysis of MGMT promoter methylation status per study treatment group, and correlation with median survival and progression-free survival will be presented. No significant financial relationships to disclose.

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and relation to 1p/19q loss in low grade gliomas: A GICNO study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20064-20064 ◽  
Author(s):  
L. Nicolardi ◽  
R. Bertorelle ◽  
L. Bonaldi ◽  
A. Compostella ◽  
A. Roma ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Tumor Localization ◽  
Response To Chemotherapy ◽  
Mgmt Promoter ◽  
The Impact

20064 Background: 1p and 19q deletions have been associated with a favorable response to chemotherapy and a good prognosis in patients (pts) with oligodendroglioma. MGMT promoter methylation has been associated with a longer survival in pts with glioblastoma who receive alkylating agents. As yet, there are no data on the expression of MGMT, and on the relationship between 1p/19q deletions and MGMT promoter methylation in low grade glioma (LGG). Methods: Pts that received a first line chemotherapy regimen with temozolomide for progressive LGG were enrolled in the study, designed to investigate the correlation between MGMT methylation status and 1p/19q deletions in this setting. 1p/19q deletions were analysed by FISH, and MGMT promoter methylation by methylation specific PCR (MSP). Results: Seventy-five pts (26 females, 49 males; median age 42 years: range 22–68 years) were accrued. Of these, 48 (64%) had oligodendrogliomas (O), 19 (25.3%) astrocytomas (A), and 8 (10.6%) oligoastrocytomas (OA); 44 (58.7%) had a history of epilepsy, 41 (54.7%) had a frontal tumor localization, 27 (36%) had MRI contrast enhancing lesions, and 35 (46.7%) had been pre-treated with radiotherapy. 1p/19q deletions, evaluable in 58 pts (77.3%), were both present in 36 pts (62%), (3 being A and 2 OA); 18 pts (31%) had no loss; 1 pt (1.7%) had 1p loss; 3 pts (5.2%) 19q loss. Combined 1p and 19q loss was not correlated with a frontal localization (p = 0.12), median age (0.47) and/or gender (0.62). MGMT promoter methylation, present in 17 (56.6%) of 30 assessable cases, was significantly associated with combined 1p/19q deletions (p = 0.03). MGMT promoter methylation was not significantly associated with age (p = 0.46), gender (p = 0.2), tumor localization (p = 0.12) and/or histology (0.37). Conclusions: 1p/19q deletions are strictly correlated to histology and to MGMT promoter methylation; further prospective trials are required to clarify the impact of these molecular signatures on clinical outcome. No significant financial relationships to disclose.

Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2000-2000 ◽  
Author(s):  
R. Stupp ◽  
R. Goldbrunner ◽  
B. Neyns ◽  
U. Schlegel ◽  
P. Clement ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Tumor Resection ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Liver Function Tests ◽  
Mri Imaging ◽  
Mgmt Gene ◽  
Grade 3

2000 Background: To evaluate safety, toxicity, and efficacy of the combination of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, in addition to standard temozolomide (TMZ) and radiotherapy (RT). Methods: 52 pts (PS 0–1: 92%, 2: 8%; median age 57 yrs) after tumor resection (n=43/83%) or biopsy (n= 9/17%) were treated with standard TMZ/RT (Stupp et al. NEJM 2005). In addition cilengitide (500 mg i.v., 2x/week) was started one week before TMZ/RT and given throughout for the duration of chemotherapy or until progression. The primary endpoint was progression free survival rate at 6 months (target: 65%). Pts were followed with MRI every 2 months. Histopathologic diagnosis and MRI imaging were independently reviewed, O6-Methylguanine- DNA methyltransferase (MGMT) promotor methylation status was assessed in 45 (86.5%) pts. Results: 46 pts (92%) completed RT, = 90% of concomitant TMZ was received by 42 pts and cilengitide by 45 pts. 20 pts (3 ongoing) completed 6 cycles of maintenance TMZ and cilengitide. Observed hematological grade 3 and 4 toxicities were: lymphopenia (28/52, 53.8%), thrombocytopenia (7/52 pt. 13.4%) and neutropenia (5/52, 9.6%). Treatment related non-hematologic grade 3/4 toxicities were reported for n=3/52 (5.7%) patients: constitutional symptoms (asthenia, fatigue, anorexia, n=3); elevated liver function tests (n=1), deep venous thrombosis and pulmonary embolism (n=1). One patient with a history of sigmoid diverticulosis experienced sigmoid perforation (grade 2). In total, 34/52 (65.4% [95% CI, 50.9–78.0%]) of the pts were progression free at 6 months. Pts with MGMT gene-promotor methylation in the tumor were more likely to reach 6 months PFS endpoint. Conclusions: The study reached its primary endpoint. The combination of the integrin inhibitor RGD peptide Cilengitide and TMZ/RT was well tolerated, PFS at 6 months is encouraging. MGMT gene promoter methylation correlates with outcome. At the time of ASCO, updated results and survival estimates after a minimum follow-up of at least 1 year will be available. [Table: see text]

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