Prognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort

Abstract

Background: O(6)-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 alpha-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.