{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T01:16:26Z","timestamp":1777079786259,"version":"3.51.4"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Pediatric low-grade gliomas (pLGGs) have an overall survival of over 90%; however, patients harboring a BRAF<jats:sup>V600E<\/jats:sup> alteration may have worse outcomes, particularly when treated with classic chemotherapy. Combined BRAF\/MEK inhibition following incomplete resection demonstrated improved outcome in BRAF<jats:sup>V600E<\/jats:sup> altered pLGG compared to combined carboplatin\/vincristine chemotherapy and is now considered the standard FDA-approved treatment for this group of tumors. The aim herein was to investigate the efficacy and tolerability of single agent BRAF inhibitor treatment in BRAF<jats:sup>V600E<\/jats:sup> altered pLGG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A single institution retrospective chart review analysis was performed on patients, 0 to 21 years of age, with newly diagnosed and\/or progressive BRAF<jats:sup>V600E<\/jats:sup> mutated pLGGs (WHO Grade 1 or 2) at Children\u2019s Healthcare of Atlanta treated off-study with BRAF inhibitor monotherapy between 2013-2023. 2-year progression free survival (PFS) and objective tumor response was evaluated. All toxicities possibly associated with BRAF inhibition therapy were evaluated and described according to Common Terminology Criteria for Adverse Events version 5 (CTCAEv5). MRI brain imaging data at baseline and best response was\u00a0evaluated to identify patterns that may predict response to BRAF inhibition monotherapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifteen patients diagnosed with BRAF<jats:sup>V600E<\/jats:sup> mutated pLGG, treated with monotherapy BRAF inhibition, were identified. Median age of diagnosis: 3.8 years (0.2 \u201318.1). Histologic diagnosis: pilocytic astrocytoma (PA) (N=4); ganglioglioma (GGL) (N=3); GGL, atypical (N=3); pleomorphic xanthroastrocytoma (PXA) (N=2); low-grade neuroepithelial tumor (N=1); infiltrating glioma (N=1); and LGG (NOS) (N=1). Tumor locations included: hypothalamus\/optic chiasm (N=6); brainstem (N=4); third ventricle\/thalamus (N=2); parietal\/temporal lobe (N=2); and spinal cord (N=1). Mean duration of BRAF inhibitor monotherapy: 38.41 months (range 3.9-83.7). Median follow-up: 32.6 months (16 - 78.1). <jats:italic>Two-year PFS for patients on BRAFi monotherapy for at least 10 months: 90% (95% CI: 73.2%-100%). Objective Response (OR) for 15 evaluable patients on BRAF inhibitor (BRAFi) therapy: 73% (0\/15 CR + 6\/15 PR + 5\/15 MR) with Overall Response Rate (ORR=CR+PR): 40%.<\/jats:italic> Overall, patients tolerated treatment well with Grade 1 rash being the most common toxicity. Two of 15 patients (13%) discontinued therapy due to toxicities, and 2 other patients switched within drug class from vemurafenib to dabrafenib due to toxicities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In this small cohort of incompletely resected BRAF<jats:sup>V600E<\/jats:sup> mutated pLGGs, BRAFi monotherapy was effective and well tolerated with an ORR comparable to published prospective outcomes of dual MEK\/BRAF inhibitor therapy. This promising monotherapy treatment should be considered when choosing treatment for incompletely resected BRAF<jats:sup>V600E<\/jats:sup>-altered pLGGs.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2024.1505951","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T07:05:54Z","timestamp":1736233554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["BRAF inhibitor monotherapy in BRAFV600E-mutated pediatric low-grade glioma: a single center\u2019s experience"],"prefix":"10.3389","volume":"14","author":[{"given":"S. S.","family":"McThenia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. M.","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Damaraju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Castellino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z.","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Beer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Chien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. C.","family":"Castellino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. E.","family":"Goldman-Yassen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. R.","family":"Fangusaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.29907","article-title":"Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study","volume":"122","author":"Krishnatry","year":"2016","journal-title":"Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/PO.19.00298","article-title":"Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition","volume":"4","author":"Nobre","year":"2020","journal-title":"JCO Precis Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1177\/0883073815599259","article-title":"Low grade gliomas in children","volume":"31","author":"Chalil","year":"2016","journal-title":"J Child Neurol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.17_suppl.LBA2002","article-title":"Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600-mutant pediatric low grade glioma (pLGG)","volume":"40","author":"Bouffet","year":"2022","journal-title":"JCO"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.8726","article-title":"Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas","volume":"35","author":"Lassaletta","year":"2017","journal-title":"JCO"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature24040","article-title":"PAK signaling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanoma","volume":"550","author":"Lu","year":"2017","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2014.11.018","article-title":"Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF\/MEK cotargeting but result in melanoma drug addiction","volume":"27","author":"Moriceau","year":"2015","journal-title":"Cancer Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.3922","article-title":"BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma","volume":"33","author":"Mistry","year":"2015","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122391","article-title":"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","volume":"10","author":"Berg","year":"2015","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2175","article-title":"Inactivation of the CDKN2A tumor-suppressor gene by deletion or methylation is common at diagnosis in follicular lymphoma and associated with poor clinical outcome","volume":"20","author":"Alhejaily","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-0127","article-title":"Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas","volume":"17","author":"Jacob","year":"2011","journal-title":"Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac096","article-title":"Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma","volume":"24","author":"Rosenberg","year":"2022","journal-title":"Neuro Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1158\/1078-0432.CCR-23-1503","article-title":"FDA approval summary: dabrafenib in combination with trametinib for BRAFV600E mutation-positive low-grade glioma","volume":"30","author":"Barbato","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-2177","article-title":"Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I\/IIa study","volume":"25","author":"Hargrave","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27600","article-title":"Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002)","volume":"11","author":"Nicolaides","year":"2020","journal-title":"Oncotarget"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30064-4","article-title":"Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group","volume":"21","author":"Fangusaro","year":"2020","journal-title":"Lancet Oncol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"CNS28","DOI":"10.2217\/cns-2018-0007","article-title":"Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice","volume":"8","author":"Chukwueke","year":"2019","journal-title":"CNS Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70057-2","article-title":"Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas","volume":"12","author":"van den Bent","year":"2011","journal-title":"Lancet Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24562","article-title":"Challenges with defining response to antitumor agents in pediatric neuro-oncology: A report from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group","volume":"60","author":"Warren","year":"2013","journal-title":"Pediatr Blood Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.3541","article-title":"Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology Working Group","volume":"28","author":"Wen","year":"2010","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2303815","article-title":"Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations","volume":"389","author":"Bouffet","year":"2023","journal-title":"NEJM"},{"key":"B22","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.trecan.2020.05.009","article-title":"Clinical development of BRAF plus MEK inhibitor combinations","volume":"6","author":"Subbiah","year":"2020","journal-title":"Trends Cancer"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2024.1505951\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T16:17:18Z","timestamp":1738772238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2024.1505951\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,7]]},"references-count":22,"alternative-id":["10.3389\/fonc.2024.1505951"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2024.1505951","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,7]]},"article-number":"1505951"}}