Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide

Abstract

Background: Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O 6 -methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival. 2 /day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response. Results: The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P ¼ 0.016) and OS (P ¼ 0.019) compared to those with high expression. Both low MGMT expression (P ¼ 0.040) and re-resection at relapse (P ¼ 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%). Conclusions: The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.

Therapeutic options in recurrent glioblastoma—An update

“…Both trials used a schedule of TMZ 150-200 mg/m 2 for 5 out of 28 days. Other prospective studies mainly without previous TMZ treatment using this schedule showed similar PFS-6 rates ranging from 21 to 24% [64][65][66][67].…”

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

“…Wiewrodt et al (Wiewrodt et al, 2008) showed that patients expressing p30 fmol mg À1 MGMT protein in the pre-treatment tumour volume had a significantly better response to alkylating therapy than those with MGMT protein above this level. Others have shown that patients with low MGMT protein expression had significantly improved survival compared with those with high expression (Brell et al, 2005;Chinot et al, 2007;Nagane et al, 2007). Vlassenbroeck et al (Vlassenbroeck et al, 2008) used a real-time MSP assay to determine a clinically relevant cut-off for stratification of glioblastomas into two distinct populations, with prognostic significance in recurrent anaplastic astrocytoma but not glioblastomas treated with temozolomide (Sadones et al, 2009).…”

Is the absolute value of O6-methylguanine-DNA methyltransferase gene messenger RNA a prognostic factor, and does it predict the results of treatment of glioblastoma with temozolomide?

“…The absolute value of MGMT mRNA seems to coincide more with enzyme activity than with DNA methylation status. In contrast, an analysis at the protein level of MGMT 20 determined that immunohistochemistry shows low specificity and is also not quantitative. Although mRNA levels measured by RT-PCR may not always correlate with enzyme activity, MGMT activity itself seems to be more strongly correlated with clinical resistance to nitrosoureas than to mRNA expression.…”