MGMT promoter methylation analysis for allocating combined CCNU/TMZ chemotherapy: Lessons learned from the CeTeG/NOA-09 trial

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Theophilos Tzaridis - , University of Bonn, Sanford Burnham Prebys Medical Discovery Institute (Author)
  • Niklas Schäfer - , University of Bonn (Author)
  • Johannes Weller - , University of Bonn (Author)
  • Joachim Peter Steinbach - , University Hospital Frankfurt (Author)
  • Uwe Schlegel - , Ruhr University Bochum (Author)
  • Sabine Seidel - , Ruhr University Bochum (Author)
  • Michael Sabel - , Heinrich Heine University Düsseldorf (Author)
  • Peter Hau - , University of Regensburg (Author)
  • Clemens Seidel - , Leipzig University (Author)
  • Dietmar Krex - , Department of Neurosurgery, TUD Dresden University of Technology (Author)
  • Roland Goldbrunner - , University of Cologne (Author)
  • Jörg Christian Tonn - , Ludwig Maximilian University of Munich (Author)
  • Oliver Grauer - , University of Münster (Author)
  • Sied Kebir - , University of Bonn, University of Duisburg-Essen (Author)
  • Matthias Schneider - , University of Bonn (Author)
  • Christina Schaub - , University of Bonn (Author)
  • Hartmut Vatter - , University of Bonn (Author)
  • Christoph Coch - , University of Bonn (Author)
  • Martin Glas - , University of Bonn, University of Duisburg-Essen (Author)
  • Rolf Fimmers - , University of Bonn (Author)
  • Torsten Pietsch - , University of Bonn (Author)
  • Guido Reifenberger - , Heinrich Heine University Düsseldorf (Author)
  • Ulrich Herrlinger - , University of Bonn (Author)
  • Jörg Felsberg - , Heinrich Heine University Düsseldorf (Author)

Abstract

The CeTeG/NOA-09 trial showed a survival benefit for combined CCNU/TMZ therapy in MGMT-promoter-methylated glioblastoma patients (quantitative methylation-specific PCR [qMSP] ratio > 2). Here, we report on the prognostic value of the MGMT promoter methylation ratio determined by qMSP and evaluate the concordance of MGMT methylation results obtained by qMSP, pyrosequencing (PSQ) or DNA methylation arrays (MGMT-STP27). A potential association of qMSP ratio with survival was analyzed in the CeTeG/NOA-09 trial population (n = 129; log-rank tests, Cox regression analyses). The concordance of MGMT methylation assays (qMSP, PSQ and MGMT-STP27) was evaluated in 76 screened patients. Patients with tumors of qMSP ratio > 4 showed superior survival compared to those with ratios 2-4 (P =.0251, log-rank test). In multivariate analysis, the qMSP ratio was not prognostic across the study cohort (hazard ratio [HR] = 0.88; 95% CI: 0.72-1.08). With different cutoffs for qMSP ratio (4, 9, 12 or 25), the CCNU/TMZ benefit tended to be larger in subgroups with lower ratios (eg, for cutoff 9: HR 0.32 for lower subgroup, 0.73 for higher subgroup). The concordance rates with qMSP were 94.4% (PSQ) and 90.2% (MGMT-STP27). Discordant results were restricted to tumors with qMSP ratios ≤4 and PSQ mean methylation rate ≤25%. Despite a shorter survival in MGMT-promoter-methylated patients with lower methylation according to qMSP, these patients had a benefit from combined CCNU/TMZ therapy, which even tended to be stronger than in patients with higher methylation rates. With acceptable concordance rates, decisions on CCNU/TMZ therapy may also be based on PSQ or MGMT-STP27.

Details

Original languageEnglish
Pages (from-to)1695-1707
Number of pages13
JournalInternational journal of cancer
Volume148
Issue number7
Publication statusPublished - 1 Apr 2021
Peer-reviewedYes

External IDs

PubMed 33113214

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • CCNU/TMZ, glioblastoma, MGMT promoter methylation