Pilocytic astrocytomas (PAs) are low-grade gliomas that constitute approximately 20% of all pediatric central nervous system (CNS) tumors.1 PAs in children are often associated with genetic alterations, which result in constitutive activation of BRAF or the downstream MAPK pathway.2 The most common activating events in PAs are the fusion of KIAA1549 and BRAF resulting in an activated oncogene (65%–90%),3,4 and a single nucleotide variant in BRAF resulting in a valine-to-glutamate substitution in amino acid codon 600 (BRAF p.Val600Glu) (6%–9%).2,5 BRAF p.Val600Glu is frequently observed in other low-grade gliomas, including pleomorphic xanthoastrocytomas (50%–66%) and gangliogliomas (20%).6
Patients with PAs typically have 10-year survival rates of 80% to 100% with complete resection. However, tumors located along the midline and disseminated PAs have a suboptimal response to conventional chemotherapy and a relatively poor prognosis.7 There are several reports of successful treatment of low- and high-grade gliomas with BRAF inhibitors (vemurafenib and dabrafenib).8–13 There is only a single report of 2 patients with PAs who were treated with trametinib, a MAPK pathway inhibitor,5 and no reports on MAPK pathway–targeted therapy for disseminated PAs. This report presents a series of 5 patients with progressive disseminated PA, and discusses the clinical response to targeted molecular therapy in 2 patients.
Johnson KJ, Cullen J, Barnholtz-Sloan JS. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev 2014;23:2716–2736.
Penman CL, Faulkner C, Lowis SP. Current understanding of BRAF alterations in diagnosis, prognosis, and therapeutic targeting in pediatric low-grade gliomas. Front Oncol 2015;5:54.
Forshew T, Tatevossian RG, Lawson AR. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 2009;218:172–181.
Jones DT, Kocialkowski S, Liu L. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 2009;28:2119–2123.
Miller C, Guillaume D, Dusenbery K. Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response. J Neurosurg Pediatr 2016;19:1–6.
Schindler G, Capper D, Meyer J. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397–405.
Mazloom A, Hodges JC, Teh BS. Outcome of patients with pilocytic astrocytoma and leptomeningeal dissemination. Int J Radiat Oncol Biol Phys 2012;84:350–354.
Bautista F, Paci A, Minard-Colin V. Vemurafenib in pediatric patients with BRAF V600E mutated high-grade gliomas. Pediatr Blood Cancer 2014;61:1101–1103.
del Bufalo F, Carai A, Figa-Talamanca L. Response of recurrent BRAF V600E mutated ganglioglioma to vemurafenib as single agent. J Transl Med 2014;12:356.
Lassaletta A, Guerreiro Stucklin A, Ramaswamy V. Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma. Pediatr Blood Cancer 2016;63:2038–2041.
Robinson GW, Orr BA, Gajjar A. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 2014;14:258.
Skrypek M, Foreman N, Guillaume D. Pilomyxoid astrocytoma treated successfully with vemurafenib. Pediatr Blood Cancer 2014;61:2099–2100.
Gentilcore G, Madonna G, Mozzillo N. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer 2013;13:17.
White Y, Bagchi A, Van Ziffle J. KRAS insertion mutations are oncogenic and exhibit distinct functional properties. Nat Commun 2016;7:10647.
Jones DT, Hutter B, Jager N. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013;45:927–932.
Zhang J, Wu G, Miller CP. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013;45:602–612.
Gessi M, Engels AC, Lambert S. Molecular characterization of disseminated pilocytic astrocytomas. Neuropathol Appl Neurobiol 2016;42:273–278.
Sievert AJ, Lang SS, Boucher KL. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A 2013;110:5957–5962.