Journal
JCO PRECISION ONCOLOGY
Volume 4, Issue -, Pages 561-571Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1200/PO.19.00298
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Funding
- Canadian Cancer Society [702296]
- Genome Canada
- Ontario Genomics Institute [OGI-121]
- Kid's Brain Tumor Cure/PLGA Foundation
- LivWise Foundation
- Brain Child Foundation
- Canadian Institutes for Health Research [159805]
- Elmaglachli Family Foundation
- Mckeddie Family Foundation
- Memorial Sloan Kettering Cancer Center [P30 CA008748]
- Henry R. Kravis Center for Molecular Oncology
- National Cancer Institute Cancer Center Core Grant [P30CA008748]
- Garron Family Cancer Centre
- SickKids Foundation
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- Meagan's Walk Fellowship in Pediatric Neuro-Oncology
- Garron Family Cancer Center Fellowship
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PURPOSEChildren with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors.PATIENTS AND METHODSWe collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries.RESULTSSixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02).CONCLUSIONUse of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.
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