Clinical Significance of Molecular Biomarkers in Glioblastoma (original) (raw)
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Biomedicines
Glioblastoma is the most malignant central nervous system tumor, which represents 50% of all glial tumors. The understanding of glioma genesis, prognostic evaluation, and treatment planning has been significantly enhanced by the discovery of molecular genetic biomarkers. This study aimed to evaluate survival in patients with primary glioblastoma concerning O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation and other clinical factors. The study included 41 newly diagnosed glioblastoma patients treated from 2011 to 2014 in the 10th Military Research Hospital and Polyclinic, Poland. All patients underwent surgical resection followed by radiation and chemotherapy with alkylating agents. The MGMT promoter methylation was evaluated in all patients, and 43% were found to be methylated. In 26 and 15 cases, gross total resection and subtotal resection were conducted, respectively. Patients with a methylated MGMT promoter had a median survival of 504 days, while those without ...
Prognostic Impact of MGMT Promoter Methylation in Glioblastoma - A Systematic Review
Journal of Cancer Science & Therapy, 2014
MGMT promoter methylation is currently considered the main prognostic biomarker in glioblastoma, yet some concerns remain about its actual impact on outcome. The aim of the present study was to analyze literature data on this topic. Therefore, a systematic review and analysis of recently published glioblastoma cohorts examining the relationship between MGMT methylation and prognosis was performed. We found that only 19/28 studies (68%) confirmed the prognostic value of MGMT methylation and/or its role in predicting response to temozolomide. In these studies, however, the population showed significantly lower rates of unfavorable prognosticators as compared with studies where MGMT methylation was not prognostic/predictive. Moreover, studies demonstrating a better prognosis for MGMT methylated cases had significantly lower rates of deaths at 3 and 6 months. Multivariate analysis showed that the 3-month and 6-month deaths are significantly associated with the prognostic/predictive value of MGMT methylation, and that the percent of MGMT methylated tumors and of patients treated with alkylating drugs trend towards statistical significance if modeled with the 6-month but not with the 3-month mortality rate.
Scientific reports, 2018
O-methylguanine-DNA methyltransferase (MGMT) promoter methylation and its subsequent loss of protein expression has been identified to have a variable impact on clinical outcome of glioma patients indicated for chemotherapy with alkylating agents (Temozolomide). This study investigated methylation status of MGMT gene along with in situ protein expression in malignant glioma patients of different histological types to evaluate the associated clinical outcome vis-a-vis use of alkylating drugs and radiotherapy. Sixty three cases of glioma were evaluated for MGMT promoter methylation by methylation-specific PCR (MS-PCR) and protein expression by immunostaining (IHC). Methylation status of MGMT and loss of protein expression showed a very high concordant association with better survival and progression free survival (PFS) (p < 0.0001). Multivariate Cox regression analysis showed both MGMT methylation and loss of protein as significant independent prognostic factors in glioma patients ...
Molecular Analysis in a Glioblastoma Cohort—Results of a Prospective Analysis
Journal of Personalized Medicine
The prognostic role of epidermal growth factor receptor variant III (EGFRvIII), a constitutively activated oncogenic receptor, in glioblastoma is controversial. We performed a prospective study enrolling 355 patients operated on for de novo glioblastoma at a large academic center. The molecular profile, including EGFRvIII status, MGMT promoter methylation, and VEGF expression, was assessed. Standard parameters (age, clinical status and extent of surgical resection) were confirmed to hold prognostic value. MGMT promoter methylation portended a slightly improved survival. In the whole series, confirming previous results, EGFRvIII was not associated with worsened prognosis. Interestingly, female sex was associated with a better outcome. Such findings are of interest for the design of future trials.
Scientific Reports, 2020
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.
…, 2010
Glioblastoma is the most frequent and malignant brain tumor with most patients dying within 1 year after diagnosis. O 6 -Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ). In general, epigenetic silencing of the MGMT gene by promoter methylation is associated with loss of MGMT protein expression. We investigated the correlation between MGMT protein expression and MGMT methylation status and the prognostic relevance of TP53 and Ki-67 in a series of glioblastomas. A total of twenty-eight patients between 2008 and 2011 were included in this study. Nineteen patients (68%) showed nuclear TP53 immunopositivity, and mean Ki-67 index was 27%. Immunohistochemistry for MGMT protein revealed high expression (¤30% positive cells) in 11 tumors, and low expression (‹30% positive cells) in 17 tumors. There was a good correlation between immunoreactivity for MGMT protein, Ki-67 index and tumor extent. MGMT promoter methylation as well as MGMT protein expression was completely uncorrelated to survival prediction; neither TP53 nor Ki-67 were correlated to survival. Our study confirms the role of the Ki-67 index and the extent of tumor as two important factors associated with prognosis of glioblastoma. In contrast, MGMT protein expression as well as the MGMT promoter methylation status does not provide prognostically relevant information.
Journal of Neuro-Oncology
Objective To assess the recurrence interval and predictive significance of TP53 expression and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas treated with radiotherapy and combined chemotherapies, including temozolomide, lomustine, procarbazine and bevacizumab. Method We reviewed the clinical outcomes of 52 totally resected glioblastoma patients, who received conventional radiotherapy and temozolomide with other chemotherapeutic agents. Correlation of TP53 expression and MGMT promotor methylation with recurrence interval was analyzed using Kaplan Meier estimates. Results No significant association was found between MGMT promotor methylation and TP53 expression in glioblastomas (P-value = 0.158). Patients with non-methylated MGMT who received temozolomide chemotherapy with other chemotherapeutic agents showed significantly later recurrence (P-value = 0.007) compared with patients with non-methylated MGMT who received temozolomide alone. No signifi...
The Oncologist, 2017
Background MGMT methylation status represents a powerful prognostic factor in newly diagnosed glioblastoma (GBM). Recently, its role in recurrent tumors has also been suggested; however, few data investigating the stability of this biomarker during the clinical course of the disease are available. In this study, we evaluated the rate of change of MGMT methylation status between diagnosis and first recurrence in patients who received tumor resection for recurrent GBM. Methods We included patients who received temozolomide concurrent with and adjuvant to radiotherapy after diagnosis of GBM and had a second surgery performed at least 3 months after radiotherapy completion. Other eligibility criteria were age ≥18 years and Eastern Cooperative Oncology Group performance status 0–2. We evaluated the MGMT methylation status by methylation-specific polymerase chain reaction. Results From our institutional data warehouse, 295 patients with recurrent GBM who underwent second surgery were eval...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen. Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m(2) per day)/one week off] or Arm B [3 weeks on (80 mg/m(2) per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR. Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome i...
A practical review of prognostic correlations of molecular biomarkers in glioblastoma
Neurosurgical Focus, 2015
G lioblastoma (GBM) is a WHO Grade IV tumor with a poor prognosis, significant comorbidity, and limited therapeutic options. It was originally classified as either primary, arising de novo, or secondary, arising from low-grade glioma. Mutations important to the classification of these tumors have been shown to be important in gliomagenesis. 25 Some genes critical to the understanding of GBM tumorigenesis and prognosis in clude O-6-methylguanine-DNA-methyltransferase (MGMT), iso citrate dehydrogenase gene 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q (Fig. 1 and Table 1). These genes serve as biomarkers of disease aggressiveness, provide insight into the pathophysiology of the disease, and may serve as potential sites for targeted treatment. In this review we aimed to evaluate the clinical impact of these gene markers as assessed on pathological tissue and how they impact prognosis as well as clinical decision making for the everyday clinician. Recent interest in personalized medicine has spurred an investigation into individualized disease treatment through biomarker stratification. 37 The US Food and Drug Administration defines a valid biomarker as "a biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of test results." Biomarkers in GBM have been investigated for their use in stratifying prognosis, guiding the development of targeted treatment, and attempting to personalize clinical treatment. More specifically, prognostic biomarkers provide information on the natural history of the disease, and tests can be designed to distinguish disease recurrence in marker-positive and marker-negative patients regardless of clinical treatment. Alternatively, predictive markers are useful in identifying AbbreviAtioNs AA = anaplastic astrocytoma; GBM = glioblastoma; MGMTm = MGMT promoter methylation; OS = overall survival; PFS = progression-free survival.