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 >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.

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

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2013-2013
Author(s):  
Wolfgang Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Published Data ◽  
Global Methylation ◽  
Methyl Transferase ◽  
Mgmt Promoter

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.

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.

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

2014 ◽  
Vol 37 (6) ◽  
pp. E4 ◽  
Author(s):  
Giuseppe M. V. Barbagallo ◽  
Sabrina Paratore ◽  
Rosario Caltabiano ◽  
Stefano Palmucci ◽  
Hector Soto Parra ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Group A ◽  
Group B ◽  
Mgmt Promoter Methylation Status

Object The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. Methods A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m2 starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30–72 years (mean 56.1 years), received 150 mg/m2 for 5 days every 28 days for more than 6 cycles (range 7–101 cycles). The 18 patients in Group B, aged 46–82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. Results All patients but 1 in Group A survived at least 18 months (range 18–101 months), and patients in Group B survived no more than 17 months (range 2–17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. Conclusions This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

scholarly journals Prospective Biomarker Study in Newly Diagnosed Glioblastoma: Cyto-C Clinical Trial

2021 ◽  
Author(s):  
Corinne E Griguer ◽  
Claudia R Oliva ◽  
Christopher S Coffey ◽  
Merit E Cudkowicz ◽  
Robin A Conwit ◽  
...  
Keyword(s):  
Survival Time ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Abstract Background Glioblastoma (GBM) has a 5-year survival rate of 3–5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome c oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival time (OS), and the secondary end point was progression-free survival time (PFS). Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a sub-group of GBM patients with improved long term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Analysis of MGMT promoter methylation status in high grade glioma patients with long term and conventional survival times: A retrospective study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2084-2084 ◽  
Author(s):  
M. Preusser ◽  
M. Hassler ◽  
K. Elandt ◽  
E. Gelpi ◽  
J. Hainfellner ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Tumor Tissue ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
High Grade ◽  
Survival Times ◽  
Significant Difference ◽  
Mgmt Promoter ◽  
Methylated Mgmt Promoter

2084 Background: Response to alkylating chemotherapy in patients with high grade gliomas (HGG) has been found correlated to epigenetic silencing of the DNA repair gene MGMT (O6-methylguanine-DNA methyltransferase) in the tumor tissue. Patients with HGG expressing a methylated MGMT promoter benefited from alkylating chemotherapy in terms of a prolonged survival as compared to patients with unmethylated MGMT promoter. Methods: Our study cohort comprised 47 patients with HGG, all treated with concomitant chemotherapy and radiotherapy in our institution. 23/47 patients (8 women, 15 men, aged 22.4–64.5 years, median 36.3) survived longer than 36 months (range of survival times 36–137 months, in median 46.9 months) and were defined as long term survivors (LS). 24/47 patients (5 women and 19 men, aged 18.3–73.3 years, median 47.7) with early tumor relapse who survived in median for 23.5 months were defined as HGG patients with conventional survival (CS). In all cases, we extracted DNA from formalin-fixed and paraffin-embedded tumor tissue samples. The methylation status of the MGMT promoter was determined by bisulfide modification of the DNA and methylation-specific polymerase-chain- reaction (MSP). MSP results were rated by 4 independent observers. Results: There was high interobserver agreement at interpretation of MSP results (range of kappa values: 0.71–0.87). Among LS, we found MGMT promoter methylation in 13/24 (81.5%) patients and an unmethylated MGMT promoter in 3 patients, whereas the MSP results were not interpretable in 7 patients of this patient subgroup. Among CS, we found promoter methylation in 16 patients (66.6%), unmethylated promoter in 6 patients and uninterpretable results in one patient. There was no statistically significant difference in MGMT promoter methylation rate between LS and CS. Conclusions: The proportion of gliomas with methylated MGMT promoter in this series is unexpectedly high, particularly for CS patients. Potential explanations for this finding are methodological differences due to the use of paraffin-embedded tumors instead of frozen tumor material as in most published series and a potential random accumulation of MGMT positive tumors in the patients with CS survival. No significant financial relationships to disclose.

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.

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