MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma

Sadones, Jan; Michotte, Alex; Veld, Pieter In 'T; Chaskis, Cristo; Sciot, Raf; Menten, Johan; Joossens, Eric; Strauven, Theo; D’Hondt, Lionel; Sartenaer, D.; Califice, Stéphane; Bierau, Katja; Svensson, Cecilia; Grève, Jacques De; Neyns, Bart

doi:10.1016/j.ejca.2008.09.002

Cited by 54 publications

(37 citation statements)

References 31 publications

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“…Others have shown that patients with low MGMT protein expression had significantly improved survival compared with those with high expression (Brell et al, 2005;Chinot et al, 2007;Nagane et al, 2007). Vlassenbroeck et al (Vlassenbroeck et al, 2008) used a real-time MSP assay to determine a clinically relevant cut-off for stratification of glioblastomas into two distinct populations, with prognostic significance in recurrent anaplastic astrocytoma but not glioblastomas treated with temozolomide (Sadones et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

et al. 2009

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BACKGROUND: Epigenetic silencing of O 6 -methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre. METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas. RESULTS: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation 4non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS. CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.

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Section: Discussionmentioning

confidence: 99%

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

et al. 2009

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“…Although patients with MGMT-methylated tumors did show some improved survival in these series, no such effect was noted in a more recent study that specifically examined this question. 9,13 Many patients with recurrent glioblastoma may not meet criteria to be considered viable candidates for reoperation. It remains unclear, however, whether more patients would be offered reoperation if validated prognostic criteria, such as the NIH Recurrent Glioma Scale, 5 were uniformly applied.…”

Section: Discussionmentioning

confidence: 99%

Residual tumor volume and patient survival following reoperation for recurrent glioblastoma

Yong

Mihatov

et al. 2014

JNS

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Object Maximal safe tumor resection is part of the standard of care for patients with newly diagnosed glioblastoma. The role of reoperation in the care of patients with recurrent glioblastoma is less clear, and less than a quarter of patients undergo a second surgery. Previous studies have identified preoperative variables associated with the improved survival of patients following reoperation, and guidelines for the selection of patients for reoperation have been devised and validated. In this study, the authors analyzed the relative survival benefit of maximal safe tumor removal in a series of patients with recurrent glioblastoma who all underwent reoperation. Methods In this longitudinal study, the clinical and radiological data of 97 consecutive patients who underwent reoperation for recurrent glioblastoma were prospectively collected. Multiple regression analyses and Kaplan-Meier plotting were performed to identify pre- and postoperative clinical and radiological variables associated with increased survival following reoperation. Results The median postoperative survival of all patients following reoperation was 12.4 months (95% confidence interval [CI] 9.0–15.6 months). Multiple Cox regression analysis revealed that patients with large (> 3 cm3) residual tumors following reoperation had significantly decreased survival relative to those with residual tumors that were small (> 0–3 cm3; hazard ratio [HR] = 3.10, 95% CI 1.69–5.70; p < 0.001) or radiologically absent (0 cm3; HR = 5.82, 95% CI 2.98–11.37; p < 0.001). Large residual tumors had faster rates of subsequent regrowth than small (odds ratio [OR] = 4.22, 95% CI 1.19–14.97; p = 0.026) or radiologically absent (OR = 11.00, 95% CI 2.79–43.43; p = 0.001) residual tumors, and a faster regrowth rate was significantly associated with decreased survival (HR = 4.01, 95% CI 2.26–7.14; p < 0.001). Conclusions The overall survival of patients with recurrent glioblastoma who underwent reoperations increased with decreasing postoperative residual tumor volumes. For patients meeting prognostic criteria for reoperation, the surgical goal should be to minimize residual tumor volume to maximize overall survival. Clinical trial registration no.: NCT00060541 (ClinicalTrials.gov).

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“…Nevertheless, patients with MGMT-methylated tumors still showed improved survival in these series, although no such effect was seen in a recent study from Belgium. 50 Selection for loss of mismatch repair proteins, such as MSH6, could be involved in a minority of patients. [51][52][53] In vivo evidence for the direct involvement of MGMT in the response of glioblastoma to alkylating agents has been provided by The Cancer Genome Atlas.…”

Section: The Role Of Mgmt In Glioma Subtypes Glioblastomamentioning

confidence: 99%

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

et al. 2009

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The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile.Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

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MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma

Cited by 54 publications

References 31 publications

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

Residual tumor volume and patient survival following reoperation for recurrent glioblastoma

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

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