Farshad Nassiri1,2, Yasin Mamatjan2, Suganth Suppiah1,2, Jetan H Badhiwala2, Sheila Mansouri2, Shirin Karimi2, Olli Saarela3, Laila Poisson4, Irina Gepfner-Tuma5, Jens Schittenhelm6, Ho-Keung Ng7, Houtan Noushmehr8, Patrick Harter9, Peter Baumgarten10, Michael Weller11, Matthias Preusser12, Christel Herold-Mende13, Marcos Tatagiba14, Ghazaleh Tabatabai5, Felix Sahm15, Andreas von Deimling15, Gelareh Zadeh1,2,16, Kenneth D Aldape1,2,17. 1. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada. 2. MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. 3. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 4. Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA. 5. Interdisciplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research & Center for CNS Tumors, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany. 6. Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany. 7. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China. 8. Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA. 9. Edinger Institute (Institute of Neurology), Goethe-University, Frankfurt am Main, Germany. 10. Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany. 11. Department of Neurology, University Hospital Zurich, Zurich, Switzerland. 12. Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center CNS Unit, Medical University of Vienna, Vienna, Austria. 13. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany. 14. Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany. 15. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. 16. Division of Neurosurgery, University Health Network, Toronto, Ontario, Canada. 17. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Abstract
BACKGROUND: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. METHODS: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. RESULTS: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications. CONCLUSIONS: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
BACKGROUND: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. METHODS: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. RESULTS: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications. CONCLUSIONS: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
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