scholarly journals ACTR-37. ASSOCIATION BETWEEN MGMT PROMOTER METHYLATION SCORE AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi21-vi21
Author(s):  
Carlos Romo ◽  
Pavan Shah ◽  
Yuqing Sun ◽  
Xiaobu Ye ◽  
Stuart Grossman
Keyword(s):  
Promoter Methylation ◽  
Cox Regression ◽  
Methylation Status ◽  
Positive Association ◽  
Primary Objective ◽  
Mgmt Promoter Methylation ◽  
Specific Pcr ◽  
Mgmt Promoter ◽  
Methylation Score ◽  
Group 2

Abstract BACKGROUND MGMT promoter methylation is associated with longer survival in patients with high-grade gliomas who receive alkylating therapy. Methylation status is commonly determined by methylation-specific PCR and results are reported in two forms: a dichotomization of “present” or “not present,” and as a methylation score (MGMT/beta-actinx1000). The primary objective of this study is to determine the association between the degree of methylation and overall survival (OS) in newly diagnosed patients with glioblastoma. METHODS A retrospective IRB-approved study was conducted of 684 patients treated at Johns Hopkins from 2007–2015. Adults with a histologically confirmed glioblastoma treated with standard therapy were included in the analysis. OS was estimated from the date of diagnosis to time of death or last follow up using the Kaplan–Meier method. Cox regression model was used to assess possible positive association between MGMT score and OS. For purposes of this analysis IDH1-mutated patients were excluded. RESULTS In 100 evaluable patients, median age at diagnosis was 56 years [45–77]. Fifty-two patients were MGMT promoter methylated (score ≥2.00) and 48 were unmethylated. The median OS was 31 months in the methylated patients and 15 months in the unmethylated (p=0.0001). Methylated patients had MGMT scores ranging from 2.53-1278. The methylated scores were classified into 3 groups; #1: 0-25th percentile, #2: 25-75th percentiles, and #3: >75th percentile. mOS was: 30.8 months for group 1 (n=13); 34.8 months for group 2 (n=27); and 20.9 months for group 3 (n=12) (p=0.19). Difference in mOS between groups 1 and 3 was not statistically significant (HR 0.819 [95% CI, 0.3–2.2], p=0.69). DISCUSSION The prognostic value of MGMT promoter methylation in patients with glioblastoma was replicated in our study sample. The degree of methylation reported as a score on routine testing does not appear to be directly related to OS in this patient population.

scholarly journals BIOM-31. PROGNOSTIC VALUE OF MGMT METHYLATION IN IDH MUTANT GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Keng Lam ◽  
Blaine Eldred ◽  
Bryan Kevan ◽  
Matthew Ji ◽  
Jerry Lou ◽  
...  
Keyword(s):  
Los Angeles ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Cox Regression ◽  
Methylation Status ◽  
Hazard Ratio ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Cox Regression Analysis ◽  
Mgmt Promoter

Abstract BACKGROUND Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those with IDH wildtype. Previous studies have also shown the predictive value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma. However, little is known in the prognostic value of MGMT methylation status for IDH mutant gliomas. METHODS We retrospectively identified IDH mutant gliomas patients from University of California Los Angeles and Kaiser Permanente Los Angeles that had been tested for MGMT methylation status. We performed Kaplan-Meier and Cox regression analyses of overall survival (OS) to compare the MGMT methylated versus MGMT unmethylated patients. RESULTS We identified a total of 375 IDH mutant gliomas with MGMT testing. Subgroups include 52 glioblastoma, 191 astrocytoma, and 132 oligodendroglioma. The median OS for all MGMT methylated patients was 20.0 years and for unmethylated patients 14.3 years (log-rank P=0.008). Cox regression analysis also confirmed patients with MGMT methylated to have better survival than those with MGMT unmethylated (hazard ratio of 0.47, P= 0.005). During subgroup analysis, MGMT methylated glioblastoma patients have a median OS of 13.7 years compared to MGMT unmethylated patients 3.2 years (log-rank P=0.004) with a hazard ratio of 0.14 (P=0.005). However, we see no difference yet for astrocytoma (hazard ratio of 1.09, P= 0.81) and oligodendrogliomas (hazard ratio of 0.36, P= 0.193), possibly as a result of immature survival data. CONCLUSIONS MGMT promoter methylation is associated with better outcomes in IDH mutant glioblastoma patients. Progression free survival will be analyzed to determine predictive benefit of MGMT methylation for other glioma subtypes.

A novel MGMT methylation-based prognostic score in patients with glioblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2048-2048
Author(s):  
Lorenzo Gerratana ◽  
Giuseppe Lombardi ◽  
Elisa De Carlo ◽  
Vanessa Buoro ◽  
Giovanna De Maglio ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Prognostic Value ◽  
Cox Regression ◽  
Prognostic Score ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Quantitative Detection ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Mgmt Promoter

2048 Background: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with improved outcome in glioblastoma (GBM) patients (pts). Pyrosequencing (PSQ) has been reported to be an accurate method for quantitative detection of CpG islands (CpGs) methylation, but the role of methylation heterogeneity among different CpGs sites is still unclear. Aim of this study was to evaluate on a large multicentric cohort a novel prognostic score based on the evaluation of the MGMT promoter methylation at 10 different CpGs sites. Methods: We retrospectively analyzed a series of 185 pts with GBM treated at the University Hospital of Udine and Istituto Oncologico Veneto in Padua between 2006 and 2015. The methylation level of 10 CpGs (74 – 83) was determined by PSQ. The cut-off point of 9% was used to define a CpG as methylated. One point was assigned to each methylated CpG, with a total score from 0 (all CpGs < 9%) to 10 (all CpGs ≥ 9%). A threshold capable to detect a favorable outcome (Overall Survival, OS > 24 months) has been identified through ROC analysis as 6 by a previous study conducted at our center. The prognostic impact was explored through Cox regression. Results: After a median follow-up of 59 months, the median OS and Progression Free Survival (PFS) in the whole population were 16.41 and 9.67 months, respectively. A score ≥ 6 identified pts with a considerably better median OS (24.85 vs 12.99 months, p < .0001) and PFS (11.44 vs 8.22 months, p < .0001). On multivariate analysis, it remained independently associated with a favorable prognosis (HR 0.38, 95% CI 0.27-0.55, p < 0.0001) after adjustment for IDH1 mutational status (HR 0.42, 95% CI 0.20-0.87, p = .02), age ( > 70 vs ≤ 70 years HR 2.20, 95% CI 1.48-3.28, p = .0001) and ECOG performance status (2-3 vs 0-1 HR 2.35, 95% CI 1.59-3.49, p < .0001). The score’s prognostic value was maintained in all the explored subgroups. Conclusions: Combining methylation data from multiple CpGs increases the prognostic value of the MGMT promoter methylation assessment. The study confirmed the independent prognostic value of a novel score system based on the evaluation of the MGMT promoter methylation at 10 different CpGi sites.

Elderly glioblastoma patients: Survival analysis according adjuvant therapy and tumor molecular analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14046-e14046
Author(s):  
Maria Angeles Vaz ◽  
Isaac Ceballos Lenza ◽  
Sonia Del Barco Berron ◽  
Maria Cruz Martin Soberón ◽  
Oscar Gallego Rubio ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Adjuvant Therapy ◽  
Surgical Resection ◽  
Promoter Methylation ◽  
Systemic Treatment ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter ◽  
Mgmt Promoter Status ◽  
Mgmt Promoter Methylation Status

e14046 Background: Glioblastoma (GBM) grade IV represents the most frequent and aggressive primary brain tumor. Despite complete surgical resection, GBM infiltrative potential leads to local recurrence rates of around 100%. Standard treatment with adjuvant chemotherapy (CT) and radiotherapy (RT) according Stupp regimen aims to reduce relapse and improve survival, but toxicities associated with these therapies represent a problem in elderly unfit population. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been recognized as a predictive factor of response to alkylating agents as temozolomide. We aimed to compare overall survival (OS) results in elderly GBM patients according with MGMT promoter status and systemic treatment after surgery. Methods: We performed a database from the information available from RETSINE (Registro Nacional Español de Tumores de Sistema Nervioso Central). We selected ≥ 65 years GBM diagnosed patients. Relevant information was tumor MGMT promoter methylation status and adjuvant CT and/or RT after resection. Kaplan- Meier analysis was performed. Selected outcome was OS and 95% confidence intervals (CI) and p value < 0.05 were used as measures of statistical significance. Results: We identified 400 eligible GBM patients diagnosed ≥ 65 years (male = 232- 58%; female = 168-42% ). According tumor MGMT status: 125 (31.3%) methylated tumors, 115 (28.7%) non methylated and 160 unknown MGMT status. Included population median age was 72 years (65-88 years). Median global population OS was 7.93 months (IC95% 6.84-9.02). Survival analysis showed better OS for methylated tumors group, median OS 7.33 (IC 95%4.1-10.56) vs. unmethylated OS 7.06 (IC95% 4.9-9.1) (p = 0.021). Survival analysis in methylated patients showed improved OS in patients treated with RT + CT vs. no adjuvant therapy. Median OS for methylated patients treated with CT + RT was 11.46m (IC95%7.6-15.9) vs 9.6 months with only RT(IC95%3.67-7.26) and 2.1m with no treatment (IC95%2.03-3.76) p = 0,00. Unmethylated patients median OS was 9.36m (IC95%3.67-7.26) for RT-CT, 5.4 m (IC95%2.37-8.42) for RT only and 2.76 (IC95% 1.37-4.15) for no treatment p = 0.00. Conclusions: Elderly GBM patients have similar treatment options than young patients and comprise surgical resection, RT and alkylating CT with temozolomide. Comorbidities and performance status have relevant implications in elderly population treatment decisions. The MGMT promoter status has been described as a prognostic and predictive marker of response to temozolomide. In our series both methylated and unmethylated patients can benefit with systemic treatment.

P04.22 Tumor treating fields in high-grade glioma patients: A retrospective single-center study

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii23-ii23
Author(s):  
R Lucaciu ◽  
B Suchorska ◽  
M Wettig ◽  
S Jung ◽  
M Scholz
Keyword(s):  
Promoter Methylation ◽  
Daily Life ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Therapeutic Modality ◽  
High Grade ◽  
Newly Diagnosed ◽  
Non Invasive ◽  
Tumor Treating Fields ◽  
Mgmt Promoter

Abstract BACKGROUND Tumor-treating fields (TTFields) are a modern anti-mitotic, non-invasive therapy for the treatment of patients with recurrent and newly diagnosed glioblastoma multiforme (GBM). In Europe, Optune® recieved in 2015 the CE certification. TTFields are a low-intensity (1–3 V/cm) approved therapeutic modality using a non-invasive application of intermediate frequency (200 kHz) alternating electric fields through four transducer arrays directly applied to the skin. The EF-14 study has shown that the addition of TTFields to temozolomide chemotherapy in patients with newly diagnosed GBM significantly improved overall survival (OS) and progression-free survival (PFS) without additional adverse events, apart from mild to moderate skin irritations (Stupp et al., JAMA 2017). MATERIAL We retrospectively analyzed data from TTFields-treated patients (2015–2020) that were treated at our department. Patient characteristics such as MGMT promoter methylation status, age, and diagnosis, as well as treatment duration and TTFields therapy usage, were evaluated for this study. RESULTS 29 patients were treated with TTFields therapy between 2015 and 2020 at our hospital. Most patients received TTFields as primary treatment together with temozolomide maintenance therapy. In detail, 48% of patients were diagnosed with newly diagnosed GBM, 41% received TTFields therapy after tumor recurrence and 10% were diagnosed with other high-grade gliomas. In summary, patients could integrate TTFields therapy into their daily life and showed high adherence to the therapy.Particularly, one of our patients (with MGMT-promoter methylation positive) receives TTFields therapy now for almost 1229 days (approx. 41 months) and is still on therapy. Additionally, this patient shows a high usage rate of 86% indicating well integration of the therapy into daily life. CONCLUSION Taken together, our data provided the outcomes of using TTFields together with chemotherapy in the treatment of recurrent and newly diagnosed GBM in our department. Therapy with TTFields has been showing to provide significant clinical benefit for GBM patients.

scholarly journals NIMG-38. NON-INVASIVE PREDICTION OF MGMT PROMOTER METHYLATION USING COMBINED FET PET/MRI RADIOMICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii156-ii156
Author(s):  
Philipp Lohmann ◽  
Anna-Katharina Meissner ◽  
Jan-Michael Werner ◽  
Gabriele Stoffels ◽  
Martin Kocher ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Test Dataset ◽  
Fet Pet ◽  
Promoter Methylation Status ◽  
Non Invasive ◽  
Mgmt Promoter ◽  
Amino Acid Pet ◽  
Mgmt Promoter Methylation Status

Abstract BACKGROUND Recently, the Response Assessment in Neuro-Oncology (RANO) Working Group emphasized the additional diagnostic value of amino acid PET in addition to MRI. However, the number of studies using amino acid PET/MRI radiomics is still low. We investigated the potential of combined O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/MRI radiomics for the non-invasive prediction of the O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation status in glioma patients. METHODS Seventy-one patients with newly diagnosed glioma (predominantly WHO grade III and IV glioma, 82%) underwent a hybrid FET PET/MRI scan. Forty-six patients (65%) had a methylated MGMT promoter. The tumor and tumor subregions were manually segmented on conventional MRI. In total, 199 standardized features were obtained from FET PET, contrast-enhanced T1-weighted, T2-weighted, and fluid attenuated inversion recovery (FLAIR) MRI. After feature extraction and data normalization, patients were randomly assigned to a training and a test dataset for final model evaluation in a ratio of 70/30, with a balanced distribution of the MGMT promoter methylation status. Feature selection was performed by recursive feature elimination using random forest regressors. For the final model generation, the number of features was limited to seven to avoid data overfitting. Different algorithms for model generation were compared, and the model performance in the training data was assessed by 5-fold cross-validation. Finally, the best performing models were applied to the test dataset to evaluate the robustness of the models. RESULTS In the test dataset, the best radiomics signatures obtained from MRI or FET PET alone achieved diagnostic accuracies for the prediction of the MGMT promoter methylation of 64% and 70%, respectively. In contrast, the highest diagnostic accuracy of 83% was obtained by combining FET PET and MRI features. CONCLUSION Combined FET PET/MRI radiomics allows the non-invasive prediction of the MGMT promoter methylation status in patients with gliomas, providing more diagnostic information than either modality alone.

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

2020 ◽  
Vol 22 (8) ◽  
pp. 1162-1172 ◽  
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 &gt;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 &lt; 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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