Correlation Between O<sup>6</sup>-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

Chinot, Olivier; Barrié, Maryline; Fuentès, S.; Eudes, Nathalie; Lancelot, Sophie; Métellus, Philippe; Muracciole, Xavier; Braguer, Diane; Ouafik, L’Houcine; Martin, Pièrre‐Marie; Dufour, Henry; Figarella‐Branger, Dominique

doi:10.1200/jco.2006.07.4807

Cited by 182 publications

(139 citation statements)

References 23 publications

(17 reference statements)

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“…Some studies of high-grade glioma patients treated with alkylating agents, including GBM patients, have reported significant association of MGMT expression by IHC with patient outcome. [15][16][17][18] However, in other recent studies of cohorts of GBM patients treated by radiotherapy plus temozolomide, no correlation between MGMT expression and patient survival was found. 7,11,19 In this study, we compare the analytical performances and the predictive values of 5 techniques (MS-PCR, methylation-sensitive high-resolution melting, pyrosequencing, MethyLight, and IHC) for MGMT analysis in a series of 100 newly diagnosed GBM patients treated with temozolomide.…”

Section: Introductionmentioning

confidence: 90%

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Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Quillien

Lavenu

Karayan‐Tapon

et al. 2012

Cancer

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BACKGROUND: There is a strong need to determine the best technique for O 6 -methylguanine-DNA-methyltranferase (MGMT) analysis, because MGMT status is currently used in clinical trials and occasionally in routine clinical practice for glioblastoma patients. METHODS:The authors compared analytical performances and predictive values of 5 techniques in a series of 100 glioblastoma patients who received standard of care treatment (Stupp protocol). RESULTS: MGMT promoter was considered methylated in 33%, 33%, 42%, and 60% of patients by methylation-sensitive high-resolution melting, MethyLight, pyrosequencing (with an optimal risk cutoff at 8% for the average percentage of the 5 CpGs tested), and methylation-specific polymerase chain reaction (MS-PCR), respectively. Fifty-nine percent of the samples had <23% (the optimal risk cutoff) of MGMT-positive tumor cells. The best predictive values for overall survival (OS), after adjustment for age and performance status, were obtained by pyrosequencing (hazard ratio [HR], 0.32; P < .0001), MS-PCR (HR, 0.37; P < .0001), and immunohistochemistry (HR, 0.43; P ¼ .0005) as compared with methylation-sensitive high-resolution melting (HR, 0.52 P ¼ .02) and MethyLight (HR, 0.6; P ¼ .05). For progression-free survival (PFS), the best predictive values were obtained with pyrosequencing (HR, 0.35; P < .0001), methylation-sensitive high-resolution melting (HR, 0.46; P ¼ .002), and MS-PCR (HR, 0.49; P ¼ .002). Combining pyrosequencing and immunohistochemistry slightly improved predictive power for OS, but not for PFS. Poor reproducibility and interobserver variability were, however, observed for immunohistochemistry. CONCLUSIONS: Good prediction of survival in addition to high reproducibility and sensitivity made pyrosequencing the best among the 5 techniques tested in this study. Cancer 2012;118:4201-11.

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Section: Introductionmentioning

confidence: 90%

“…The staining was performed as previously described. 18 The percentage of positive tumor cells was determined by Dominique Figarella-Branger as follows. The percentage of the tumor immunoreactive nuclei was counted at high magnification.…”

Section: Immunohistochemistry For Mgmt Protein Analysismentioning

confidence: 99%

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Quillien

Lavenu

Karayan‐Tapon

et al. 2012

Cancer

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186

165

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“…42,43 However, it is a predictive marker of a favorable outcome in patients with temozolomide-treated glioblastomas. [44][45][46][47] Temozolomide also reportedly enhances radiation responsiveness in MGMTnegative human glioblastoma cell lines. 48 …”

Section: Temozolomidementioning

confidence: 97%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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“…The early studies that used immunofluorescence detection in malignant gliomas, 6,7 as well as more-recent studies in progressive low-grade oligodendroglial tumors 23 or newly diagnosed glioblastoma, 9 reported that low MGMT protein levels had predictive value for the response to alkylating agents. The clinical value of immunohistochemical detection of MGMT protein in human gliomas, however, remains controversial for several reasions.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…9 Decreased levels of MGMT protein can be attributed to epigenetic silencing mediated by MGMT gene promoter methylation, which can be assessed by a simple methylation-specific PCR (MSP). A correlation with survival was demonstrated when glioma patients were treated with nitrosoureas 10 or temozolomide, 11 strongly suggesting that MGMT promoter methylation assessment could provide a prognostic or predictive biomarker for benefit from alkylator-based chemotherapy added to radiotherapy.…”

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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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Correlation Between O⁶-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

Cited by 182 publications

References 23 publications

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Treatment of pituitary neoplasms with temozolomide

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

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Correlation Between O6-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

Cited by 182 publications

References 23 publications

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Treatment of pituitary neoplasms with temozolomide

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

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Correlation Between O⁶-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide