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Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

ABSTRACT: BACKGROUND:Previous studies addressing the influence of surgery on the outcome of patients with glioblastomas (GBM) have not addressed molecular markers. The value of surgery versus the tumor's major biological markers remains unclear. OBJECTIVE:We investigate the extent of resection as a prognosticator for patients with newly diagnosed primary GBM with the incorporation of molecular diagnostics as per the updated WHO 2016 diagnostic criteria for GBM. METHODS:Patients with newly diagnosed GBM who underwent resection were prospectively included within a database. We analyzed patients with newly diagnosed GBM and excluded patients who presented with IDH1 R132H mutations. Gross total resection (GTR) was defined as complete removal of enhancing disease. RESULTS:One hundred seventy-five patients were included within the analysis. One hundred four patients (59.4%) had GTR, 71 patients (40.6%) had subtotal or partial resection. Eighty patients (45.7%) displayed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, 95 patients (54.3%) showed no MGMT promoter methylation. In Cox regression analysis, MGMT promoter methylation (hazard ratio [HR] 1.55; 95% confidence interval [CI], 1.01-2.19; P = .0133) and GTR (HR 1.48; 95% CI, 1.06-2.07; P = .0206) were significantly associated with favorable progression-free survival. MGMT promoter methylation (HR 2.13; 95% CI, 1.45-3.12; P = .0001) and GTR (HR 1.81; 95% CI, 1.24-2.63; P = .002) were associated with favorable overall survival (OS). Of other risk factors analyzed, age (>60 vs ? 60 yr) was significantly associated with progression-free survival (HR 1.60; 95% CI, 1.14-2.24; P = .006) and OS (HR 2.19; 95% CI, 1.51-3.19; P < .0001). CONCLUSION:GTR and MGMT promoter methylation are independent prognosticators for improved overall and progression-free survival in a homogeneous cohort of newly diagnosed patients with IDH wild-type glioblastoma.

SUBMITTER: Gessler F

PROVIDER: S-EPMC6500906 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

Gessler Florian F Bernstock Joshua D JD Braczynski Anne A Lescher Stephanie S Baumgarten Peter P Harter Patrick N PN Mittelbronn Michel M Wu Tianxia T Seifert Volker V Senft Christian C

Neurosurgery 20190101 1

<h4>Background</h4>Previous studies addressing the influence of surgery on the outcome of patients with glioblastomas (GBM) have not addressed molecular markers. The value of surgery versus the tumor's major biological markers remains unclear.<h4>Objective</h4>We investigate the extent of resection as a prognosticator for patients with newly diagnosed primary GBM with the incorporation of molecular diagnostics as per the updated WHO 2016 diagnostic criteria for GBM.<h4>Methods</h4>Patients with ...[more]

PMID: 29617848

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Project description:BackgroundThe clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients.Patients and methodsWe included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and -146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients.ResultsMedian overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P = 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant.ConclusionsOur findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.

Dataset Information

Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

Publications

Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

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