Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122994 | GEO | 2019/10/31
REPOSITORIES: GEO
Similar Datasets
Project description:The data contains Illumina 450k/EPIC array methylation files from 104 patients of the NOA-08 study comparing temozolomide alone vs. radiotherapy in elderly patients with glioblastoma
2019-10-31 | GSE122920 | GEO
Project description:Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]
| PRJNA507175 | ENA
Project description:Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group
| PRJNA506921 | ENA
Project description:BackgroundO6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups.MethodsThis 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.ResultsIn 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.ConclusionMGMT 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.
| S-EPMC7594575 | biostudies-literature
Project description:BackgroundThe number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients.MethodsPrevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial.ResultsIDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival.ConclusionsDespite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.
| S-EPMC3714152 | biostudies-literature
Project description:Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O6-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.
| S-EPMC6048353 | biostudies-literature
Project description:O6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O6-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis in a manner that was highly dependent on MGMT status. Temozolomide induced growth delay, DNA double-strand breaks, and G2-M cell-cycle arrest, which led to ATR-dependent phosphorylation of Chk1; this effect was dependent on reduced MGMT expression. Treatment of MGMT-deficient cells with temozolomide increased sensitivity to ATR inhibitors both in vitro and in vivo across numerous tumor cell types. Taken together, this study reveals a novel approach for selectively targeting MGMT-deficient cells with ATR inhibitors and temozolomide. As ATR inhibitors are currently being tested in clinical trials, and temozolomide is a commonly used chemotherapeutic, this approach is clinically actionable. Furthermore, this interaction potently exploits a DNA-repair defect found in many cancers. SIGNIFICANCE: Monofunctional alkylating agents sensitize MGMT-deficient tumor cells to ATR inhibitors.
| S-EPMC6810597 | biostudies-literature
Project description:Abstract Background While the NOA-08 trial and the NORDIC Elderly trial suggested an O6-methylguanine DNA-methyl transferase (MGMT) status-tailored use of radiotherapy (RT) and temozolomide (TMZ), recent data from the NCIC CE.6/EORTC 26062 showed that hypofractionated RT plus TMZ was superior to RT for unselected elderly patients with an impact of MGMT for the effect of TMZ. Material and Methods This is the long-term update of the NOA-08 trial (German Cancer Trials Registry ID 386 and NCT01502241) that compared efficacy and safety of RT alone to TMZ alone in elderly patients with anaplastic astrocytoma (AA) or glioblastoma (GB), both isocitrate dehydrogenase wildtype, using overall survival (OS) as primary endpoint and event-free survival (EFS) as well as efficacy according to MGMT status as major secondary endpoints. NOA-08 had randomized patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score ? 60 in electronically generated blocks of variable length without stratification to receive standard RT to 60 Gy in 30 x 2 Gy fractions or TMZ dosed according to tolerance in a one week on/one week off schedule with tolerability dependent dosing. The trial finished enrolment Nov 2 2009 and demonstrated non-inferiority of TMZ compared with RT (p=0·033). Results In the long-term analysis with a data cut-off Apr 1 2018 median 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 did not differ between both arms. Also, median EFS [3·4 [3·2–4·1] months versus 4·6 [4·2–5·0] months did not differ with a HR=1·02 (0·83-1·25)]. MGMT promoter methylation tested in tumor tissue (82/221 patients, 37·1%) was associated with prolonged OS [13·6 [10·1–16·5] versus 8·0 [6·9-9·9] months; HR=0·53 (0·40-0·70), p<0·0001]. Patients with MGMT promoter methylation 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). Patients without MGMT promoter methylation had shorter EFS and a shorter OS with the usual testing not significant when treated with TMZ (6·7 [5·6–8·2] months and 3·0 [2·6-3·3] months) versus with RT (10·2 [8·0–12·0] months and 4·6 [3·7-6·4] months), HR 1·33 [0·95-1·87], p=0·099 for OS and 1·86 [1·32-2·62], p<0·001 for EFS). Conclusion Also in the long-term analyses, NOA-08 confirms the non-inferiority of TMZ compared with RT in the treatment of elderly patients with WHO grade III or IV astrocytic gliomas. To improve OS and EFS, MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ and offers unexpectedly favorable long-term outcome with initial TMZ monotherapy.
| S-EPMC6144530 | biostudies-literature
Project description:Malignant gliomas are a heterogeneous group of primary central nervous system neoplasms that represent less than 2% of all cancers yet carry a significant burden to society. They are frequently associated with considerable and progressive neurological disability and are ultimately intractable to all forms of treatment. Temozolomide (TMZ) is a new second generation DNA alkylating agent that has become part of malignant astrocytoma management paradigms because of its proven efficacy, ease of administration, and favorable toxicity profile.To review the role of TMZ in the management of malignant astrocytomas (World Health Organization grades III and IV) including newly diagnosed (n) and recurrent (r) anaplastic astrocytomas (AA) and glioblastomas.A series of pivotal clinical trials have established a role for TMZ in the treatment of malignant astrocytomas. A large phase II trial examining the role of TMZ in rAA showed a response rate of 35%, and a 6-month progression-free survival of 46%. This led to the accelerated approval of TMZ by the FDA and the EU for the treatment of rAA. Evidence for a role of TMZ in nAA is currently limited but research is ongoing in this area. The role of TMZ in the management of glioblastoma at the time of recurrence (rGBM) is less impressive but evidence for its activity was demonstrated in two large phase II trials that led to the approval of TMZ for this indication in Europe and Canada but not in the US. A recent large prospective randomized phase III trial showed that the addition of TMZ during and after radiation therapy (RT) in newly diagnosed (nGBM) patients prolonged median overall survival by 2.5 months; perhaps more importantly, the 2-year survival rate for patients receiving TMZ and RT was 26% compared with 10% for those receiving RT alone. Concurrent TMZ with RT followed by adjuvant TMZ has become the standard of care for nGBM patients. Based on the evidence presented in this trial, TMZ received approval from the FDA and the EU for patients with nGBM in 2005.THERE IS EVIDENCE TO SUPPORT THE USE OF TMZ FOR THE FOLLOWING DISEASES IN THE ORDER OF MOST TO LEAST CONVINCING: nGBM, rAA, rGBM, and nAA. This order may quickly change as more trials are being designed and implemented, particularly with novel TMZ dosing schedules.
| S-EPMC2899776 | biostudies-other
Project description:BackgroundResistance to temozolomide (TMZ) is due in part to enhanced DNA repair mediated by high expression of O6-methyl guanine DNA methyltransferase (MGMT) that is often characterised by unmethylated promoter. Here, we investigated pre-treatment of glioblastoma (GBM) cells with the 26S-proteasome inhibitor bortezomib (BTZ) as a strategy to interfere with MGMT expression and thus sensitise them to TMZ.MethodsCell lines and patient GBM-derived cells were examined in vitro, and the latter also implanted orthotopically into NOD-SCID C.B.-Igh-1b/lcrTac-Prkdc mice to assess efficacy and tolerability of BTZ and TMZ combination therapy. MGMT promoter methylation was determined using pyrosequencing and PCR, protein signalling utilised western blotting while drug biodistribution was examined by LC-MS/MS. Statistical analysis utilised Analysis of variance and the Kaplan-Meier method.ResultsPre-treatment with BTZ prior to temozolomide killed chemoresistant GBM cells with unmethylated MGMT promoter through MGMT mRNA and protein depletion in vitro without affecting methylation. Chymotryptic activity was abolished, processing of NFkB/p65 to activated forms was reduced and corresponded with low MGMT levels. BTZ crossed the blood-brain barrier, diminished proteasome activity and significantly prolonged animal survival.ConclusionBTZ chemosensitized resistant GBM cells, and the schedule may be amenable for temozolomide refractory patients with unmethylated MGMT promoter.
| S-EPMC6888814 | biostudies-literature