OS01.7 MGMT promoter methylation status independently predicts progression-free survival in NRG Oncology/RTOG 9802: a phase III trial of RT vs RT + PCV in high-risk low-grade gliomas

In adults, pilocytic astrocytomas (PA) account for less than 2% of gliomas, resulting in uncertainty regarding the clinical course and optimal treatment, particularly in cases where gross total resection (GTR) could not be achieved. Moreover, information on molecular markers and their prognostic impact is sparse. In order to improve risk stratification, we analyzed our institutional series of 58 patients aged 17 years and older with histology-proven intracranial PA World Health Organization grade I for clinical and molecular prognosticators. Anaplastic and NF1-associated tumors were excluded. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was determined by pyrosequencing or 450k/850k DNA methylation array. A univariate log-rank test and multivariate StepAIC were applied to identify prognostic factors. The median age was 30 years (range 17–66). Tumors were located in the cerebral/cerebellar hemispheres, midline structures and cerebello-pontine angle in 53%, 38% and 9%. MGMT promoter methylation was present in eight patients (14%). GTR (39/58 patients) significantly reduced the likelihood of tumor recurrence (p = 0.0001). Tumor relapse occurred in 16 patients (28%) after a median progression-free survival (PFS) of 135 months (range 6–153 months); there was one tumor-related death. PFS at 5 and 10 years was 67% and 53%. In multivariate analysis, PFS was significantly prolonged in patients with GTR (HR 0.1; CI 0.03–0.37; p < 0.001), unmethylated MGMT promoter (HR 0.18; CI 0.05–0.64; p = 0.009) and midline tumors (HR 0.21; CI 0.06–0.78; p = 0.02). In conclusion, MGMT promoter methylation status and tumor location were identified as novel prognostic factors in adult PAs, pointing at distinct molecular subtypes and detecting patients in need of close observance and intensified treatment.

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Postoperative concurrent radiochemotherapy versus radiotherapy in high-risk SCCA of the head and neck: Results of the German phase III trial ARO 96–3

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5507 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5507-5507 ◽

Cited By ~ 38

Author(s):

R. Fietkau ◽

C. Lautenschläger ◽

R. Sauer ◽

J. Dunst ◽

A. Becker ◽

...

Keyword(s):

High Risk ◽

Acute Toxicity ◽

Head And Neck ◽

Progression Free Survival ◽

Distant Metastases ◽

Phase Iii ◽

Phase Iii Trial ◽

Free Survival ◽

Tumor Bed ◽

Grade 3

5507 Background: Despite resection and postoperative irradiation high-risk (3 or more involved lymph nodes, extra-capsular disease and/or microscopically involved mucosal margins of resection) squamous cell carcinomas (SCCAs) of the head and neck frequently recur in the tumor bed. Postoperatively radiochemotherapy (RCT) with cis-Platin (CDDP)/5-FU versus radiotherapy (RT) alone was compared in a randomized trial. Methods: Between 5/97 and 12/04, 440 patients who had high-risk SCCAs of the head and neck were enrolled in this prospectively randomized phase III trial. Following resection and neck dissection, 214 patients were randomly assigned to RT (66 Gy/33 Fx/6.6 weeks) and 226 patients to identical RT plus CDDP (20 mg/m2 on day 1–5, 29–33) and 5-FU (600 mg/m2 on day 1–5, 29–33). Results: The 5 year local-regional control rate is 72.2 ± 3.7% following RT and 88.6 ± 2.4% for the RCT group (p = 0.00259; 5-year progression free survival 50.1 ± 4.0% and 62.4 ± 4.4% (p = 0.024) and 5-year overall survival 48.6 ± 4.4% vs. 58.1 ± 4.6% (p = 0.11). There was no difference in the 5 year incidence of distant metastases (19.3 ± 3.6% vs 25.5 ± 4.6%; p = 0.45). The incidence of grade 3+ acute toxicity was higher during RCT: mucositis 12.6% vs. 20.8% (p = 0.04), leucopenia 0% vs. 4.4% (p = 0.007). Conclusions: Acute toxicity is increased to an acceptable level by RCT. Postoperative RCT compared to RT improves locoregional control and progression free survival; thus survival as a trend is improved by 10% after 5 years. Supported by Deutsche Krebshilfe 70–2140. No significant financial relationships to disclose.

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TMIC-14. PD-L1 EXPRESSION IS NEGATIVELY CORRELATED TO OUTCOMES IN PATIENTS WITH MGMT METHYLATED PROMOTERS IN GBM

Neuro-Oncology ◽

10.1093/neuonc/noz175.1048 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi250-vi250

Author(s):

Siddhartha Srivastava ◽

John Choi ◽

Michael Lim

Keyword(s):

Negative Correlation ◽

Immune Checkpoint ◽

Methylation Status ◽

Progression Free Survival ◽

Significant Negative Correlation ◽

Mgmt Promoter Methylation ◽

Free Survival ◽

Significant Difference ◽

Mgmt Promoter ◽

Methylated Mgmt Promoter

Abstract BACKGROUND Glioblastoma is a high-grade glioma and is considered the most aggressive primary brain tumor with a median overall survival of 11–15 months. Methylation of the promoter of the MGMT gene, which encodes a DNA repair protein, has been shown to be a good prognostic indicator for GBM survival. It is known that GBM has elevated expression of several immune checkpoint molecules that allow the tumor to evade anti-tumor immune response. Therefore, it is important to elucidate connections between prognostic factors like methylation status and immunologic markers in the tumor microenvironment (TME) that might lead to immunosuppression. METHODS Patients with resected GBM tumor samples were identified by pathology reports as having tumors with either methylated or unmethylated MGMT promoters. Corresponding patient tumor biopsy samples were embedded in paraffin, sectioned, and then stained using specific antibodies for known immune checkpoint molecules: PD-1, PD-L1, LAG-3, TIM-3, CSF1R, and IDO-1. RESULTS In our cohort of 34 patients, 17 had methylated MGMT promoter regions and 17 did not. We found no statistically significant difference between methylated and unmethylated MGMT promoter status for immune checkpoint expression. However, we did find a statistically significant negative correlation (P< 0.05) between the degree of PD-L1 expression in the TME and the progression free survival of patients with the MGMT promoter methylation phenotype. CONCLUSION Our study examined the relationship between immune checkpoint markers and methylation status of MGMT promoters in GBM. While there was no statistically significant difference between these two groups within the immunological framework of this study, there was a statistically significant negative correlation showing that increased PD-L1 expression in patients with methylated MGMT promoter tumors correlated to a worse progression free survival. Future studies are indicated to investigate the correlation between PD-L1 expression in relation to GBM treatment prognosis and its dependence on MGMT promoter methylation.

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Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital

Scientific Reports ◽

10.1038/s41598-020-75477-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Larraitz Egaña ◽

Jaione Auzmendi-Iriarte ◽

Joaquin Andermatten ◽

Jorge Villanua ◽

Irune Ruiz ◽

...

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Progression Free Survival ◽

Mgmt Promoter Methylation ◽

Mgmt Methylation ◽

Free Survival ◽

Methylguanine Dna Methyltransferase ◽

Mgmt Promoter ◽

Newly Diagnosed Glioblastoma

Abstract O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

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Prognostic and Clinical Values of Chaperone Protein P4HB in Malignant Glioma

10.21203/rs.3.rs-808854/v1 ◽

2021 ◽

Author(s):

Stella Sun ◽

Karrie Mei-Yee Kiang ◽

Gilberto Ka-Kit Leung

Keyword(s):

Promoter Methylation ◽

Clinical Decision Making ◽

Methylation Status ◽

Progression Free Survival ◽

High Grade Glioma ◽

Mgmt Promoter Methylation ◽

Clinicopathological Parameters ◽

Who Grade ◽

Free Survival ◽

Mgmt Promoter

Abstract Introduction. Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified by our group to play important roles in association with glioma malignancy and temozolomide (TMZ) resistance through the unfolded protein response (UPR). The present study focused on the prognostic value of P4HB in glioma. Methods. P4HB expression was assessed by immunohistochemical staining and semi-quantified by pathologist visual scoring in 73 WHO grade I-IV gliomas. Results were correlated with clinicopathological data. Results. Our results show that P4HB expression was significantly associated several clinicopathological parameters including age (p=0.035), tumour grade (p=0.002), and the number of TMZ treatment cycles received (p=0.043). Using Kaplan-Meier analysis, P4HB expression was positively correlated with mortality (p=0.014) and disease progression (p=0.026). In patients treated with TMZ, high P4HB expression level was significantly associated with poorer overall survival (OS) (p=0.014) and progression free survival (PFS) (p=0.027). The association between MGMT promoter methylation and P4HB expression was also interrogated. Patients with MGMTMethP4HBLow tumours had the most favourable progression free survival (48 months) than patients with other combination of MGMT methylation status and P4HB expression (log rank p=0.001). Multivariate analysis revealed that P4HB was an independent prognostic indicator for OS (p=0.048). Conclusions. P4HB could constitute an independent prognostic marker, especially for high grade glioma with the potential for informing a nuanced pathological stratification during clinical decision-making with respect to MGMT promoter methylation status and TMZ treatment.

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ENGOT-ov54/Swiss-GO-2/MATAO including LOGOS (Low-Grade Ovarian cancer Sub-study): MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer—A randomized, double-blinded, placebo-controlled, multicenter phase III Trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps5598 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS5598-TPS5598

Author(s):

Viola A. Heinzelmann-Schwarz ◽

Christian Kurzeder ◽

Seraina Schmid ◽

Natalie Gabriel ◽

Andreas Mueller ◽

...

Keyword(s):

Ovarian Cancer ◽

Maintenance Therapy ◽

Maintenance Treatment ◽

Progression Free Survival ◽

Final Analysis ◽

Phase Iii ◽

Low Grade ◽

Phase Iii Trial ◽

Free Survival ◽

Double Blinded

TPS5598 Background: The prognosis of advanced epithelial ovarian cancer (OC) is poor with a relapse rate of 75% at 5 years. Some 80% of OC express estrogen receptor (ER). This is the first trial that wants to capitalize on this and prospectively evaluates letrozole, a potent aromatase inhibitor, as initial maintenance treatment for high and low grade OC. Methods: Eligible pts have primary OC, FIGO Stage II-IV with low or high grade serous or endometrioid histology, with (interval) debulking surgery, ECOG-status 0-2, Positivity (≥ 1%) for ER expression, and at least 4 cycles of platinum-based chemotherapy (neoadjuvant allowed). Pts are allowed to undergo concurrent maintenance treatment with bevacizumab and PARP inhibitors. Extensive quality of life (QoL) questionnaires via an App and physical activity measurements by a tracking device as well as G8 geriatric score, ESGO surgery questionnaire, and Charleson Comorbidity Index are routinely assessed. Primary objective is to evaluate the efficacy of letrozole maintenance therapy after standard surgical and chemotherapy treatment as measured by Progression Free Survival (PFS) compared to no maintenance therapy (placebo). Primary outcome is PFS, defined as time from date of first letrozole/placebo administration until date of progression or death by any cause. Stratification for high and low grade histologies and ER measurement is performed via a digital centralized pathology review process. Final analysis will be performed for the whole cohort and for the subgroup of low grade ovarian cancers (LOGOS subprotocol). Secondary objectives and outcomes are overall survival (OS), quality adjusted progression free survival (QAPFS), time to first subsequent treatment (TFST), quality adjusted time without symptoms (TWiST), and health related QoL. Study is designed as international, randomized (1:1 ratio), two-arm, multi-centric, double-blinded, placebo-controlled superiority phase III trial. In total, 528 pts will be randomly assigned to letrozole or placebo for 5 yrs or until unacceptable toxicity, progression of underlying disease, or study discontinuation. Final analysis is planned after 5 years without interval analysis and follow-up is collected for up to 10yr and for the low-grade cohort for up to 12yr. Clinical trial information: NCT04111978.

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Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status–Based Treatment Stratification

Blood ◽

10.1182/blood.v116.21.3313.3313 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3313-3313

Author(s):

Bruno C. Medeiros ◽

Holbrook E Kohrt ◽

Richa Rajwanshi ◽

Jason Gotlib ◽

Steven Coutre ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Promoter Methylation ◽

Low Dose ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Clinical Activity ◽

Promoter Methylation Status ◽

Mgmt Promoter ◽

Mgmt Promoter Methylation Status

Abstract Abstract 3313 Introduction: Temozolomide sensitivity is determined by the methylation status of the MGMT promoter. As most AML patients have an unmethylated MGMT promoter, response rates to temozolomide have been very disappointing in the past. We designed this exploratory study to determine whether temozolomide therapy can be tailored according to the MGMT promoter status and to test the hypothesis that protracted, low-dose temozolomide can “prime” leukemia blasts to conventional doses of temozolomide in patients with unmethylated MGMT promoter. Patients and Methods: Elderly patients (>60 years of age) with AML and high-risk features (relapsed/refractory, secondary AML or de novo with intermediate or unfavorable cytogenetics) were stratified according to MGMT promoter methylation status. Patients with methylated MGMT promoters received temozolomide 200mg/m2 orally for 7 days, while patients with unmethylated promoters received temozolomide 100mg/m2 orally for 14 days followed by temozolomide 200mg/m2 orally for 7 days. Results: 36 patients (median age, 75 years) were treated with temozolomide and 31 (86%) were found to have an unmethylated MGMT promoter. Overall response rate for the entire cohort was 36% (CR – 22%, CRp – 8%, LFS- 6%). The median duration of response and median overall survival among responding patients were 29 weeks and 35 weeks, respectively. No differences in outcomes (CR rate, OS rate and duration of remission) were noted among the 2 stratification groups (Table-1) Induction deaths (within 42 days of treatment initiation) occurred in 25% (9/36) of patients and were mostly caused by disease progression. Patients with low HCT-CI scores (≤ 2) had higher ORR 43% vs.0%, fewer induction deaths (17% vs. 67%, respectively) and longer median OS (94 days vs. 25.5 days). Hematological toxicities were the most commonly observed adverse events and difficult to distinguish from disease-related cytopenias. Conclusion: Temozolomide therapy, stratified according to MGMT promoter methylation status, demonstrated clinical activity in elderly patients with AML and high-risk features. Protracted low-dose temozolomide may reverse the temozolomide-resistant phenotype in patients with unmethylated MGMT promoters. Future studies in better-defined populations or in combination are warranted. This trial was registered at ClinicalTrials.gov as NCT00611247. Disclosures: Medeiros: Schering-Plough: Research Funding. Off Label Use: Temozolomide for elderly AML.

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Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide

JAMA Oncology ◽

10.1001/jamaoncol.2018.1977 ◽

2018 ◽

Vol 4 (10) ◽

pp. 1405 ◽

Cited By ~ 51

Author(s):

Erica H. Bell ◽

Peixin Zhang ◽

Barbara J. Fisher ◽

David R. Macdonald ◽

Joseph P. McElroy ◽

...

Keyword(s):

High Risk ◽

Promoter Methylation ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Survival Outcomes ◽

Promoter Methylation Status ◽

Mgmt Promoter ◽

Mgmt Promoter Methylation Status

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RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.810 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii194-ii194

Author(s):

Ingo Mellinghoff ◽

Martin van den Bent ◽

Jennifer Clarke ◽

Elizabeth Maher ◽

Katherine Peters ◽

...

Keyword(s):

High Risk ◽

Dose Escalation ◽

Objective Response ◽

Data Monitoring Committee ◽

Progression Free Survival ◽

High Risk Population ◽

Low Grade ◽

Who Grade ◽

Free Survival ◽

Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

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