Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Alvaro Lassaletta Michal Zapotocky Matthew Mistry Vijay Ramaswamy Marion Honnorat Rahul Krishnatry Ana Guerreiro Stucklin Nataliya Zhukova Anthony Arnoldo Scott Ryall Catriona Ling Tara McKeown Jim Loukides James T Rutka Peter Dirks Michael D Taylor Shiyi Chen Ute Bartels Annie Huang Eric Bouffet Cynthia Hawkins and Uri Tabori The Hospital for Sick Children Toronto; Adam Fleming McMaster Children's Hospital McMaster University Hamilton; Shayna Zelcer Children's Hospital of Western Ontario London Ontario; David Eisenstat and Bev Wilson Stollery Children's Hospital University of Alberta Edmonton Alberta; Anne Sophie Carret Hospital Sainte Justine; Nada Jabado McGill University Montreal; Valerie Larouche Centre Hospitalier Universitaire de Québec Québec City Quebec Canada; Ofelia Cruz and Carmen de Torres Hospital Sant Joan de Déu Barcelona Spain; Cheng Ying Ho University of Maryland School of Medicine Baltimore MD; Roger J Packer Children's National Health System Washington DC; Ruth Tatevossian Ibrahim Qaddoumi Julie H Harreld James D Dalton and David W Ellison St Jude Children's Research Hospital Memphis TN; Jean Mulcahy Levy and Nicholas Foreman Children's Hospital Colorado Aurora CO; Matthias A Karajannis Shiyang Wang and Matija Snuderl New York University Langone Medical Center New York NY; Amulya Nageswara Rao and Caterina Giannini The Mayo Clinic Rochester MN; Mark Kieran and Keith L Ligon Dana Farber Cancer Institute Boston Children's Hospital Boston MA; Maria Luisa Garre Paolo Nozza Samantha Mascelli and Alessandro Raso Istituto Giannina Gaslini Genoa Italy; Sabine Mueller and Theodore Nicolaides University of California San Francisco San Francisco CA; Karen Silva and Romain Perbet Hospices Civils de Lyon; Alexandre Vasiljevic Cécile Faure Conter and Didier Frappaz Institute of Pediatric Hematology and Oncology Lyon France; Sarah Leary and Courtney Crane Seattle Children's Hospital Seattle WA; Aden Chan and Ho Keung Ng The Chinese University of Hong Kong Hong Kong; Zhi Feng Shi and Ying Mao Huashan Hospital Fudan University Shanghai People's Republic of China; Elizabeth Finch University of North Carolina School of Medicine Chapel Hill NC; Peter Hauser Semmelweis University Budapest Hungary; and David Sumerauer and Lenka Krskova University Hospital Motol Charles University 2nd Medical School Prague Czech Republic

Komentář v

J Clin Oncol. 2018 Jan 1;36(1):96. doi: 10.1200/JCO.2017.75.8987. PubMed

Komentář v

J Clin Oncol. 2018 Jan 1;36(1):97. doi: 10.1200/JCO.2017.76.0645. PubMed

Zobrazit více v PubMed

Ostrom QT, Gittleman H, Fulop J, et al. : CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol 17:iv1-iv62, 2015. (Suppl 4) PubMed PMC

Sievert AJ, Fisher MJ: Pediatric low-grade gliomas. J Child Neurol 24:1397-1408, 2009 PubMed PMC

Bergthold G, Bandopadhayay P, Bi WL, et al. : Pediatric low-grade gliomas: How modern biology reshapes the clinical field. Biochim Biophys Acta 1845:294-307, 2014 PubMed PMC

Jones DT, Hutter B, Jäger N, et al. : Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45:927-932, 2013 PubMed PMC

Zhang J, Wu G, Miller CP, et al. : Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602-612, 2013 PubMed PMC

Bergthold G, Bandopadhayay P, Hoshida Y, et al. : Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro-oncol 17:1486-1496, 2015 PubMed PMC

Romano E, Schwartz GK, Chapman PB, et al. : Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol 12:913-922, 2011 PubMed

Horbinski C, Nikiforova MN, Hagenkord JM, et al. : Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro-oncol 14:777-789, 2012 PubMed PMC

Dahiya S, Haydon DH, Alvarado D, et al. : BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol 125:901-910, 2013 PubMed

Ho CY, Mobley BC, Gordish-Dressman H, et al. : A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation. Acta Neuropathol 130:575-585, 2015 PubMed

Mistry M, Zhukova N, Merico D, et al. : BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 33:1015-1022, 2015 PubMed PMC

Berg M, Nordgaard O, Kørner H, et al. : Molecular subtypes in stage II-III colon cancer defined by genomic instability: Early recurrence-risk associated with a high copy-number variation and loss of RUNX3 and CDKN2A. PLoS One 10:e0122391, 2015 PubMed PMC

Alhejaily A, Day AG, Feilotter HE, et al. : Inactivation of the CDKN2A tumor-suppressor gene by deletion or methylation is common at diagnosis in follicular lymphoma and associated with poor clinical outcome. Clin Cancer Res 20:1676-1686, 2014 PubMed

Jacob K, Quang-Khuong DA, Jones DT, et al. : Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17:4650-4660, 2011 PubMed

Krishnatry R, Zhukova N, Guerreiro Stucklin AS, et al. : Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study. Cancer 122:1261-1269, 2016 PubMed

Hawkins C, Walker E, Mohamed N, et al. : BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17:4790-4798, 2011 PubMed

Lassaletta A, Scheinemann K, Zelcer SM, et al. : Phase II weekly vinblastine for chemotherapy-naïve children with progressive low-grade glioma: A Canadian Pediatric Brain Tumor Consortium study. J Clin Oncol 34:3537-3543, 2016 PubMed

Bouffet E, Jakacki R, Goldman S, et al. : Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 30:1358-1363, 2012 PubMed

Ryall S, Krishnatry R, Arnoldo A, et al. : Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun 4:93, 2016 PubMed PMC

Abraham J, Stenger M: Dabrafenib in advanced melanoma with BRAF V600E mutation. J Community Support Oncol 12:48-49, 2014 PubMed

Schindler G, Capper D, Meyer J, et al. : 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 121:397-405, 2011 PubMed

Dougherty MJ, Santi M, Brose MS, et al. : Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro-oncol 12:621-630, 2010 PubMed PMC

Dias-Santagata D, Lam Q, Vernovsky K, et al. : BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: Diagnostic and therapeutic implications. PLoS One 6:e17948, 2011 PubMed PMC

Qaddoumi I, Orisme W, Wen J, et al. : Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 131:833-845, 2016 PubMed PMC

Dimitriadis E, Alexiou GA, Tsotsou P, et al. : BRAF alterations in pediatric low-grade gliomas and mixed neuronal-glial tumors. J Neurooncol 113:353-358, 2013 PubMed

Gururangan S, Fisher MJ, Allen JC, et al. : Temozolomide in children with progressive low-grade glioma. Neuro-oncol 9:161-168, 2007 PubMed PMC

Ater JL, Zhou T, Holmes E, et al. : Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: A report from the Children’s Oncology Group. J Clin Oncol 30:2641-2647, 2012 PubMed PMC

Packer RJ, Lange B, Ater J, et al. : Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol 11:850-856, 1993 PubMed

Packer RJ, Ater J, Allen J, et al. : Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86:747-754, 1997 PubMed

Merchant TE, Kun LE, Wu S, et al. : Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 27:3598-3604, 2009 PubMed PMC

Lassaletta A, Guerreiro Stucklin A, Ramaswamy V, et al. : Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma. Pediatr Blood Cancer 63:2038-2041, 2016 PubMed

Rush S, Foreman N, Liu A: Brainstem ganglioglioma successfully treated with vemurafenib. J Clin Oncol 31:e159-e160, 2013 PubMed

del Bufalo F, Carai A, Figà-Talamanca L, et al. : Response of recurrent BRAFV600E mutated ganglioglioma to vemurafenib as single agent. J Transl Med 12:356, 2014 PubMed PMC

Skrypek M, Foreman N, Guillaume D, et al. : Pilomyxoid astrocytoma treated successfully with vemurafenib. Pediatr Blood Cancer 61:2099-2100, 2014 PubMed

Aguilera D, Janss A, Mazewski C, et al. : Successful retreatment of a child with a refractory brainstem ganglioglioma with vemurafenib. Pediatr Blood Cancer 63:541-543, 2016 PubMed

Chemotherapy in pediatric low-grade gliomas (PLGG)

Survival and functional outcomes in paediatric thalamic and thalamopeduncular low grade gliomas

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas