Elke Pfaff1,2, Tobias Kessler3,4, Gnana Prakash Balasubramanian1,5,6, Anne Berberich3,4, Daniel Schrimpf7,8, Antje Wick4, Jürgen Debus9,10,11,12, Andreas Unterberg13, Martin Bendszus14, Christel Herold-Mende15, David Capper16, Irini Schenkel17, Andreas Eisenmenger17, Susan Dettmer17, Benedikt Brors5,6,18, Michael Platten19,20, Stefan M Pfister1,2, Andreas von Deimling7,8, David T W Jones1, Wolfgang Wick3,4, Felix Sahm7,8. 1. Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. 2. Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany. 3. Clinical Cooperation Unit Neuro-oncology, DKTK, DKFZ, Heidelberg, Germany. 4. Department of Neurology and Neuro-oncology Program, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany. 5. Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany. 6. National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. 7. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 8. Clinical Cooperation Unit Neuropathology, DKTK, DKFZ, Heidelberg, Germany. 9. Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany. 10. National Center for Radiation Oncology, Heidelberg Institute for Radiation Oncology, Heidelberg, Germany. 11. Clinical Cooperation Unit Radiation Oncology, DKFZ, Heidelberg, Germany. 12. Heidelberg Ion-Beam Therapy Center, Heidelberg, Germany. 13. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany. 14. Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany. 15. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany. 16. Department of Neuropathology, Charité Universitätsmedizin Berlin, Berlin, Germany. 17. NCT Trial Center, National Center for Tumor Diseases, DKFZ, Heidelberg, Germany. 18. DKTK, Heidelberg, Germany. 19. Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZ, Heidelberg, Germany. 20. Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Abstract
Background: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma patients. Glioblastoma without hypermethylated MGMT promoter is largely resistant to treatment with temozolomide. These patients are in particular need of new treatment approaches, which are offered by biomarker-driven clinical trials with targeted drugs based on molecular characterization of individual tumors. Methods: In preparation for an upcoming clinical study, a comprehensive molecular profiling approach was undertaken on tissues from 43 glioblastoma patients harboring an unmethylated MGMT promoter at diagnosis. The diagnostic pipeline covered various levels of molecular characteristics, including whole-exome sequencing, low-coverage whole-genome sequencing, RNA sequencing, as well as microarray-based gene expression profiling and DNA methylation arrays. Results: Complex multilayer molecular diagnostics were feasible in this setting with a median turnaround time of 4-5 weeks from surgery to the molecular tumor board. In 35% of cases, potentially relevant therapeutic decisions were derived from the data. Alterations were most frequently found in receptor tyrosine kinases, members of the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin and mitogen-activated protein kinase pathway as well as cell cycle control and p53 regulation cascades. Individual tumors harbored clonal alterations such as oncogenic fusions of tyrosine kinases which constitute promising targets for targeted therapies. A prioritization algorithm is proposed to allocate patients with multiple targets to the potentially best treatment option. Conclusion: With this feasibility study, a comprehensive molecular profiling approach for patients with newly diagnosed glioblastoma harboring an unmethylated MGMT promoter is presented. Analyses in this pilot cohort serve as a basis for trials based on targetable alterations and on the question of allocation of patients to the best treatment arm.
Background: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastomapatients. Glioblastoma without hypermethylated MGMT promoter is largely resistant to treatment with temozolomide. These patients are in particular need of new treatment approaches, which are offered by biomarker-driven clinical trials with targeted drugs based on molecular characterization of individual tumors. Methods: In preparation for an upcoming clinical study, a comprehensive molecular profiling approach was undertaken on tissues from 43 glioblastomapatients harboring an unmethylated MGMT promoter at diagnosis. The diagnostic pipeline covered various levels of molecular characteristics, including whole-exome sequencing, low-coverage whole-genome sequencing, RNA sequencing, as well as microarray-based gene expression profiling and DNA methylation arrays. Results: Complex multilayer molecular diagnostics were feasible in this setting with a median turnaround time of 4-5 weeks from surgery to the molecular tumor board. In 35% of cases, potentially relevant therapeutic decisions were derived from the data. Alterations were most frequently found in receptor tyrosine kinases, members of the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin and mitogen-activated protein kinase pathway as well as cell cycle control and p53 regulation cascades. Individual tumors harbored clonal alterations such as oncogenic fusions of tyrosine kinases which constitute promising targets for targeted therapies. A prioritization algorithm is proposed to allocate patients with multiple targets to the potentially best treatment option. Conclusion: With this feasibility study, a comprehensive molecular profiling approach for patients with newly diagnosed glioblastoma harboring an unmethylated MGMT promoter is presented. Analyses in this pilot cohort serve as a basis for trials based on targetable alterations and on the question of allocation of patients to the best treatment arm.
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