Abstract
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.
Highlights
Central nervous system (CNS) tumors represent the most common solid malignancies in childhood and are the leading cause of cancer-related death in this age group [1]
H3K27M mutations were confirmed in all cases (HIST1H3B 2/10, H3F3A 8/10)
With respect to alterations of the MAPK pathway, one case with BRAF(V600E) mutation was subjected to treatment with a combination of dabrafenib, trametinib, together with bevacizumab, and the patient harboring a tumor with KRAS(G12A) was subjected to treatment with trametinib [36,37,38,39]
Summary
Central nervous system (CNS) tumors represent the most common solid malignancies in childhood and are the leading cause of cancer-related death in this age group [1]. Diffuse midline gliomas (DMG) with histone H3 lysine27-to-methionine mutations (H3K27M glioma) represent a highly aggressive subtype of glioma, which predominantly arise in children and young adults [2,3,4]. The overall prognosis of H3K27M glioma is poor, displaying median survival rates of approximately 9 to 11 months irrespective of the tumor localization [5,6,7,8,9]. Based on its uniform fatal prognosis, the presence of H3K27M mutation has already been implemented into the new WHO classification as being diagnostic for high-grade gliomas [10]. Focal irradiation therapy remains the mainstay of therapy for H3K27M glioma, resulting in improved overall survival rates [11]. Novel, improved therapeutic strategies for H3K27M glioma are needed
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