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

Theophilos Tzaridis, Niklas Schäfer, Johannes Weller, Joachim-Peter Steinbach, Uwe Schlegel, Sabine Seidel, Michael Sabel, Peter Hau, Clemens Seidel, Dietmar Krex, Roland Goldbrunner, Jörg-Christian Tonn, Oliver Grauer, Sied Kebir, Matthias Schneider, Christina Schaub, Hartmut Vatter, Christoph Coch, Martin Glas, Rolf Fimmers, Torsten Pietsch, Guido Reifenberger, Ulrich Herrlinger, Jörg Felsberg, Theophilos Tzaridis, Niklas Schäfer, Johannes Weller, Joachim-Peter Steinbach, Uwe Schlegel, Sabine Seidel, Michael Sabel, Peter Hau, Clemens Seidel, Dietmar Krex, Roland Goldbrunner, Jörg-Christian Tonn, Oliver Grauer, Sied Kebir, Matthias Schneider, Christina Schaub, Hartmut Vatter, Christoph Coch, Martin Glas, Rolf Fimmers, Torsten Pietsch, Guido Reifenberger, Ulrich Herrlinger, Jörg Felsberg

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.

Trial registration: ClinicalTrials.gov NCT01149109.

Keywords: CCNU/TMZ; MGMT promoter methylation; glioblastoma.

© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

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