Björn Scheffler1,2, Sied Kebir3,4,1,2, Martin Glas5,6,7,8, Lazaros Lazaridis3,4,1,2, Teresa Schmidt3,4,1,2, Christoph Oster3,4,1,2, Tobias Blau4,9, Daniela Pierscianek4,10, Jens T Siveke4,11,12,13, Sebastian Bauer4,14, Hans-Ulrich Schildhaus4,15, Ulrich Sure4,10, Kathy Keyvani4,9, Christoph Kleinschnitz3,4, Martin Stuschke4,16, Ken Herrmann4,17, Cornelius Deuschl4,18. 1. DKFZ-Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 2. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Division of Clinical Neurooncology, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 4. German Cancer Consortium (DKTK), Partner Site University Medicine Essen, Hufelandstr. 55, 45147, Essen, Germany. 5. Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Division of Clinical Neurooncology, University Medicine Essen, University Duisburg-Essen, Essen, Germany. Martin.Glas@uk-essen.de. 6. German Cancer Consortium (DKTK), Partner Site University Medicine Essen, Hufelandstr. 55, 45147, Essen, Germany. Martin.Glas@uk-essen.de. 7. DKFZ-Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Medicine Essen, University Duisburg-Essen, Essen, Germany. Martin.Glas@uk-essen.de. 8. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Martin.Glas@uk-essen.de. 9. Institute of Neuropathology, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 10. Department of Neurosurgery and Spine Surgery, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 11. Bridge Institute of Experimental Tumor Therapy, West German Cancer Center (WTZ), University Medicine Essen, University Duisburg-Essen, Essen, Germany. 12. Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. 13. Department of Medical Oncology, West German Cancer Center (WTZ), University Medicine Essen, University Duisburg-Essen, Essen, Germany. 14. Department of Medical Oncology, Sarcoma Center, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 15. Institute of Pathology, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 16. Department of Radiotherapy, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 17. Department of Nuclear Medicine, University Medicine Essen, University Duisburg-Essen, Essen, Germany. 18. Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Medicine Essen, University Duisburg-Essen, Essen, Germany.
Abstract
PURPOSE: When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. METHODS: We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. RESULTS: The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357). CONCLUSION: These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.
PURPOSE: When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. METHODS: We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. RESULTS: The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357). CONCLUSION: These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.
Authors: Sara A Byron; Nhan L Tran; Rebecca F Halperin; Joanna J Phillips; John G Kuhn; John F de Groot; Howard Colman; Keith L Ligon; Patrick Y Wen; Timothy F Cloughesy; Ingo K Mellinghoff; Nicholas A Butowski; Jennie W Taylor; Jennifer L Clarke; Susan M Chang; Mitchel S Berger; Annette M Molinaro; Gerald M Maggiora; Sen Peng; Sara Nasser; Winnie S Liang; Jeffrey M Trent; Michael E Berens; John D Carpten; David W Craig; Michael D Prados Journal: Clin Cancer Res Date: 2017-10-26 Impact factor: 12.531
Authors: T Hedley Carr; Robert McEwen; Brian Dougherty; Justin H Johnson; Jonathan R Dry; Zhongwu Lai; Zara Ghazoui; Naomi M Laing; Darren R Hodgson; Francisco Cruzalegui; Simon J Hollingsworth; J Carl Barrett Journal: Nat Rev Cancer Date: 2016-04-26 Impact factor: 60.716
Authors: Tracy T Batchelor; Paul Mulholland; Bart Neyns; L Burt Nabors; Mario Campone; Antje Wick; Warren Mason; Tom Mikkelsen; Surasak Phuphanich; Lynn S Ashby; John Degroot; Rao Gattamaneni; Lawrence Cher; Mark Rosenthal; Franz Payer; Juliane M Jürgensmeier; Rakesh K Jain; A Gregory Sorensen; John Xu; Qi Liu; Martin van den Bent Journal: J Clin Oncol Date: 2013-08-12 Impact factor: 44.544
Authors: Kenneth Aldape; Kevin M Brindle; Louis Chesler; Rajesh Chopra; Amar Gajjar; Mark R Gilbert; Nicholas Gottardo; David H Gutmann; Darren Hargrave; Eric C Holland; David T W Jones; Johanna A Joyce; Pamela Kearns; Mark W Kieran; Ingo K Mellinghoff; Melinda Merchant; Stefan M Pfister; Steven M Pollard; Vijay Ramaswamy; Jeremy N Rich; Giles W Robinson; David H Rowitch; John H Sampson; Michael D Taylor; Paul Workman; Richard J Gilbertson Journal: Nat Rev Clin Oncol Date: 2019-08 Impact factor: 66.675
Authors: Floris P Barthel; Kevin C Johnson; Frederick S Varn; Anzhela D Moskalik; Georgette Tanner; Emre Kocakavuk; Kevin J Anderson; Olajide Abiola; Kenneth Aldape; Kristin D Alfaro; Donat Alpar; Samirkumar B Amin; David M Ashley; Pratiti Bandopadhayay; Jill S Barnholtz-Sloan; Rameen Beroukhim; Christoph Bock; Priscilla K Brastianos; Daniel J Brat; Andrew R Brodbelt; Alexander F Bruns; Ketan R Bulsara; Aruna Chakrabarty; Arnab Chakravarti; Jeffrey H Chuang; Elizabeth B Claus; Elizabeth J Cochran; Jennifer Connelly; Joseph F Costello; Gaetano Finocchiaro; Michael N Fletcher; Pim J French; Hui K Gan; Mark R Gilbert; Peter V Gould; Matthew R Grimmer; Antonio Iavarone; Azzam Ismail; Michael D Jenkinson; Mustafa Khasraw; Hoon Kim; Mathilde C M Kouwenhoven; Peter S LaViolette; Meihong Li; Peter Lichter; Keith L Ligon; Allison K Lowman; Tathiane M Malta; Tali Mazor; Kerrie L McDonald; Annette M Molinaro; Do-Hyun Nam; Naema Nayyar; Ho Keung Ng; Chew Yee Ngan; Simone P Niclou; Johanna M Niers; Houtan Noushmehr; Javad Noorbakhsh; D Ryan Ormond; Chul-Kee Park; Laila M Poisson; Raul Rabadan; Bernhard Radlwimmer; Ganesh Rao; Guido Reifenberger; Jason K Sa; Michael Schuster; Brian L Shaw; Susan C Short; Peter A Sillevis Smitt; Andrew E Sloan; Marion Smits; Hiromichi Suzuki; Ghazaleh Tabatabai; Erwin G Van Meir; Colin Watts; Michael Weller; Pieter Wesseling; Bart A Westerman; Georg Widhalm; Adelheid Woehrer; W K Alfred Yung; Gelareh Zadeh; Jason T Huse; John F De Groot; Lucy F Stead; Roel G W Verhaak Journal: Nature Date: 2019-11-20 Impact factor: 69.504