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Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities
J. Gojo, Z. Pavelka, D. Zapletalova, MT. Schmook, L. Mayr, S. Madlener, M. Kyr, K. Vejmelkova, M. Smrcka, T. Czech, C. Dorfer, J. Skotakova, AA. Azizi, M. Chocholous, D. Reisinger, D. Lastovicka, D. Valik, C. Haberler, A. Peyrl, H. Noskova, K....
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
NV16-34083A
MZ0
CEP - Centrální evidence projektů
NV16-34083A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Plný text - Článek
NLK
Directory of Open Access Journals
od 2011
Free Medical Journals
od 2011
PubMed Central
od 2011
Europe PubMed Central
od 2011
Open Access Digital Library
od 2011-01-01
Open Access Digital Library
od 2011-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2011
PubMed
31998633
DOI
10.3389/fonc.2019.01436
Knihovny.cz E-zdroje
- Publikační typ
- časopisecké články MeSH
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.
Central European Institute of Technology Masaryk University Brno Czechia
Department of Pathology Faculty Hospital Brno Brno Czechia
Institute of Neurology Medical University of Vienna Vienna Austria
Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czechia
Citace poskytuje Crossref.org
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