Antje Wick1, Tobias Kessler1,2, Michael Platten1,3,4,5, Christoph Meisner6, Michael Bamberg7, Ulrich Herrlinger8, Jörg Felsberg9, Astrid Weyerbrock10,11, Kirsten Papsdorf12, Joachim P Steinbach13, Michael Sabel14, Jan Vesper14, Jürgen Debus15, Jürgen Meixensberger16, Ralf Ketter17, Caroline Hertler18, Regine Mayer-Steinacker19, Sarah Weisang1, Hanna Bölting1, David Reuss20, Guido Reifenberger9, Felix Sahm21, Andreas von Deimling21, Michael Weller18, Wolfgang Wick1,2. 1. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. 2. Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. 3. Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. 4. Department of Neurology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. 5. General Neurology, Tübingen, Germany. 6. Institute for Clinical Epidemiology and Applied Biometry, Tübingen, Germany. 7. Radiation Oncology, and German Cancer Consortium, partner site Tübingen, University of Tübingen, Tübingen, Germany. 8. Department of Neurology and Neurooncology, University of Bonn, Bonn, Germany. 9. Institute of Neuropathology, Heinrich Heine University, German Cancer Consortium, partner site Essen/Düsseldorf, Düsseldorf, Germany. 10. Neurosurgery Clinic, University Clinic Freiburg, and German Cancer Consortium, partner site Freiburg, Freiburg, Germany. 11. Kantonsspital St Gallen, Neurosurgery Clinic, St-Gallen, Switzerland. 12. Departments of Radiation Oncology, Leipzig, Germany. 13. Dr Senckenbergisches Institute for Neurooncology, and German Cancer Consortium, partner site Frankfurt, University of Frankfurt, Frankfurt, Germany. 14. Department of Neurosurgery, Heinrich Heine University and German Cancer Consortium, partner site Essen/Düsseldorf, Düsseldorf, Germany. 15. Radiation Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. 16. Neurosurgery, University Hospital Leipzig, Leipzig, Germany. 17. Department of Neurosurgery, University of Homburg, Homburg/Saar, Germany. 18. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. 19. Department of Internal Medicine III, University of Ulm, Ulm, Germany. 20. Germany Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany. 21. Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
Abstract
BACKGROUND: O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. METHODS: This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. RESULTS: In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0-10.0] months for TMZ treatment versus 9.4 [8.1-10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76-1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2-4.1) months vs 4.6 (4.2-5.0) months] did not differ, with HR = 1.02 (0.83-1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] mo and 8.5 [6.9-13.3] mo) versus RT (9.6 [6.4-13.7] mo and 4.8 [4.3-6.2] mo, HR 0.44 [0.27-0.70], P < 0.001 for OS and 0.46 [0.29-0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. CONCLUSION: MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.
BACKGROUND:O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. METHODS: This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. RESULTS: In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0-10.0] months for TMZ treatment versus 9.4 [8.1-10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76-1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2-4.1) months vs 4.6 (4.2-5.0) months] did not differ, with HR = 1.02 (0.83-1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] mo and 8.5 [6.9-13.3] mo) versus RT (9.6 [6.4-13.7] mo and 4.8 [4.3-6.2] mo, HR 0.44 [0.27-0.70], P < 0.001 for OS and 0.46 [0.29-0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. CONCLUSION:MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.
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