Prognostic impact of O⁶‐methylguanine‐DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation

Abstract

BACKGROUND: O6‐methylguanine‐DNA methyltransferase (MGMT) is a key enzyme in the DNA repair process after alkylating agent action. Epigenetic silencing of the MGMT gene by promoter methylation has been associated with longer survival in patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. In this study, the authors evaluated the prognostic value of different biomarkers in recurrent GBM and analyzed the changes in MGMT status between primary tumors and recurrent tumors. METHODS: Twenty‐two patients who had recurrent GBM and who underwent surgery with carmustine wafer implantation were enrolled prospectively between 2005 and 2007. The authors investigated the correlation between MGMT silencing in the tumor at recurrence and survival taking into account other clinically recognized prognostic factors. MGMT status was determined by using methylation‐specific polymerase chain reaction analysis, a high‐throughput quantitative methylation assay, and immunohistochemistry. In addition, expression analyses of human mutL homolog 1, human mutS homolog 2, and tumor necrosis factor α‐induced protein 3 at recurrence were conducted with regard to their prognostic impact. RESULTS: The median progression‐free survival (PFS) and overall survival (OS) rates after recurrence were 3.6 months and 9.9 months, respectively, and the 6‐month PFS rate after recurrence was 27.2%. On multivariate analysis, only age (P = .04) and MGMT promoter hypermethylation at recurrence, as determined by MethyLight technology (P = .0012) and methylation‐specific polymerase chain reaction (MSP) analysis (P = .004), were correlated with better PFS. On multivariate analysis, only MGMT promoter hypermethylation at recurrence, as determined by using MethyLight technology (P = .019) and MSP analysis (P = .046), was associated with better OS. CONCLUSIONS: MGMT methylation status was an important prognostic factor in patients with recurrent GBM who underwent surgery plus carmustine wafer implantation; therefore, it was useful in predicting the outcome of GBM therapy at recurrence. Cancer 2009. © 2009 American Cancer Society.

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

“…A small randomized trial from Finland in glioblastoma or anaplastic astrocytoma patients aged > 65 showed a median survival of 171 days after resection versus 85 days after biopsy (p=0.035). 25 This study has been criticized because of small patient numbers (n=30 enrolled, 13 versus 10 patients per arm evaluable) and major KPS imbalances between arms.…”

“…[15][16][17][18][19] The demonstration of promoter methylation of the MGMT gene assessed by methylation-specific PCR or pyrosequencing of bisulfite-modified DNA is associated with superior outcome in anaplastic glioma patients treated with radiotherapy or alkylating agent chemotherapy 19,20 and with specific benefit from temozolomide (TMZ) in glioblastoma patients. [21][22][23][24] Retesting the MGMT status at recurrence is not necessary since the methylation status remains stable, at least in glioblastoma, 25,26 …”

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

“…13 All primers and probes have been published elsewhere. 21 The differences in amounts of input genomic DNA were normalized by the collagen type II, alpha 1 gene (COL2A1).…”

“…Pyrosequencing is a sequence-by-synthesis method that is the only method analyzing methylation levels at each CpG separately (for review and comparison of techniques, see Weller et al 2 and Preusser 3 ). Currently, among these alternative techniques, only pyrosequencing 11,12 and MethyLight 13 have been shown to have predictive value for GBM patients. Furthermore, a realtime quantitative MS-PCR approach, proposed by MDxHealth (formerly Oncomethylome Sciences), is being used in several international clinical trials.…”

Canadian Recommendations for the Treatment of Recurrent or Progressive Glioblastoma Multiforme

“…Preliminary evidence suggests that survival may be improved in patients with mgmt promoter hypermethylation at recurrence 39 . Survival in those cases is reported to be in the range of 25-35 weeks 40 , but may be adversely affected by postoperative complications such as bone marrow suppression, infection, and poor wound healing 41,42 .…”