Background The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multi-modal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. Methods We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. Results Nineteen patients were identified, with a median age of 11.7 years (range, 2.3–21.4). Histologic diagnoses included HGG (n=6), glioblastoma (n=3), anaplastic ganglioglioma (n=4), diffuse midline glioma (n=3), high-grade neuroepithelial tumor (n=1), anaplastic astrocytoma (n=1), and anaplastic astroblastoma (n=1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3–6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Conclusions Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.

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Background The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. Methods We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. Results Incidence Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low- (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. Conclusions A subset of pediatric gliomas are driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Purpose of reviewThe last few decades have seen an explosion in our understanding of the molecular drivers of childhood brain tumours. These insights have opened the possibility for precision medicine approaches for some tumour types. However, a different spectrum of tumours is more likely to occur in infants and young children, who face additional therapeutic challenges. This review focuses on recent advances in molecular genetics of common infant brain tumours and their implication for diagnosis, prognostication and utilization of precision oncology approaches.Recent findingsInfant tumours have different biology and outcomes than similar tumours in older children and adults. For low-grade gliomas, targeted MAPK inhibition is well tolerated and likely efficacious. In high-grade gliomas, common tyrosine kinase alterations offer compelling targets for inhibition that are currently being evaluated. Paediatric-specific sequencing and methylation analysis offer insights into the driving biology of infant medulloblastoma, atypical teratoid rhabdoid tumours, embryonal tumours with multilayered rosettes, ependymoma and choroid plexus tumours, with molecular subgrouping shedding insights into distinct driving biology and clinical outcomes.SummaryInfant brain tumours are rare and heterogenous, with overall poor outcomes. Advances in molecular genetics have been incorporated into their diagnostic criteria and allow for accurate subgrouping and improved prognostication. The utilization of targeted agents appears beneficial for many low-grade gliomas and a subset of high-grade gliomas, but further research is urgently needed to improve outcomes for other tumour entities.