Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities.

Autor:	Gojo J; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Pavelka Z; Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Zapletalova D; Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.; International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia., Schmook MT; Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria., Mayr L; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Madlener S; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Kyr M; Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.; International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia., Vejmelkova K; Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.; International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia., Smrcka M; Department of Neurosurgery, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Czech T; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.; Department of Neurosurgery, Medical University of Vienna, Vienna, Austria., Dorfer C; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.; Department of Neurosurgery, Medical University of Vienna, Vienna, Austria., Skotakova J; Department of Pediatric Radiology, University Hospital Brno and Faculty of Medicine, Masaryk University, Vienna, Czechia., Azizi AA; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Chocholous M; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Reisinger D; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Lastovicka D; Department of Neurosurgery, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Valik D; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia., Haberler C; Institute of Neurology, Medical University of Vienna, Vienna, Austria., Peyrl A; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Noskova H; Laboratory of Tumor Biology, Department of Experimental Biology, School of Science, Masaryk University, Brno, Czechia., Pál K; Central European Institute of Technology, Masaryk University, Brno, Czechia., Jezova M; Department of Pathology, Faculty Hospital Brno, Brno, Czechia., Veselska R; Laboratory of Tumor Biology, Department of Experimental Biology, School of Science, Masaryk University, Brno, Czechia., Kozakova S; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia., Slaby O; Central European Institute of Technology, Masaryk University, Brno, Czechia.; Department of Pathology, Faculty Hospital Brno, Brno, Czechia., Slavc I; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria., Sterba J; Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.; International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia.; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2020 Jan 10; Vol. 9, pp. 1436. Date of Electronic Publication: 2020 Jan 10 (Print Publication: 2019).
DOI:	10.3389/fonc.2019.01436
Abstrakt:	Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort ( n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma. (Copyright © 2020 Gojo, Pavelka, Zapletalova, Schmook, Mayr, Madlener, Kyr, Vejmelkova, Smrcka, Czech, Dorfer, Skotakova, Azizi, Chocholous, Reisinger, Lastovicka, Valik, Haberler, Peyrl, Noskova, Pál, Jezova, Veselska, Kozakova, Slaby, Slavc and Sterba.)
Databáze:	MEDLINE
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