Sustained response of three pediatric BRAFV600E mutated high-grade gliomas to combined BRAF and MEK inhibitor therapy

Toll, Stephanie; Tran, Hung N.; Cotter, Jennifer; Judkins, Alexander R.; Tamrazi, Benita; Biegel, Jaclyn A.; Dhall, Girish; Robison, Nathan; Waters, Kaaren; Patel, Palak; Cooper, Robert; Margol, Ashley

doi:10.18632/oncotarget.26560

Cited by 50 publications

(41 citation statements)

References 29 publications

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“…Additionally, targeted agents are particularly relevant in the pediatric population, for which long‐term sequelae from standard therapeutic modalities can be severe and may negatively affect the quality of life. Durable responses to targeted inhibitors have been reported in NTRK‐fusion positive and BRAF‐altered gliomas . Active investigations of the therapeutic potential of other targeted inhibitors are underway (Table ), including one trial integrating targeted therapy in the upfront setting (NCT02684058).…”

Section: Therapeutic Implications Of Fusion Testingmentioning

confidence: 99%

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Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Lake

Donson

Prince

et al. 2019

Pediatric Blood & Cancer

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Background The use of next‐generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long‐term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. Methods Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. Results We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI‐MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB‐ALK, CIC‐LEUTX, FGFR2‐KIAA159, and MN1‐CXXC5 and detail their morphological features. Conclusions Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

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Section: Therapeutic Implications Of Fusion Testingmentioning

confidence: 99%

“…Durable responses to targeted inhibitors have been reported in NTRK-fusion positive and BRAF-altered gliomas. 38,39 Active investigations of the therapeutic potential of other targeted inhibitors are underway ( Table 2), including one trial integrating targeted therapy in the upfront setting (NCT02684058).…”

Section: Therapeutic Implications Of Fusion Testingmentioning

confidence: 99%

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Lake

Donson

Prince

et al. 2019

Pediatric Blood & Cancer

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“…Recently, molecular therapy targeting the BRAF V600E mutation has been applied in clinical practice for malignant melanomas and other types of malignant tumors . For intracranial HGGs, the efficacy of BRAF inhibitors has been reported in laboratory and clinical studies . Although genetic analysis has been performed in several cases of spinal cord HGGs, most reports did not describe the BRAF V600E .…”

Section: Discussionmentioning

confidence: 99%

Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature

et al. 2020

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A 17‐year‐old female complained of lower extremity pain that progressed to low back pain accompanied by paraparesis. Magnetic resonance imaging revealed a mass in the conus medullaris of the spinal cord at the thoracic spine 11–12 level. The patient underwent resection of the mass. The pathological diagnosis was anaplastic astrocytoma based on the densely proliferating astrocytic tumor cells without necrosis or microvascular proliferation. The patient received chemoradiotherapy with oral temozolomide and a total of 54 Gy of local irradiation, followed by 24 courses of temozolomide as maintenance chemotherapy. The patient survived for 8 years without tumor recurrence following the initial treatment. Genetic analysis of the tumor revealed a BRAF V600E mutation that has not yet been reported in spinal cord high‐grade gliomas (HGGs). In recent years, the molecular therapy targeting the BRAF V600E mutation has been applied in clinical practice for several cancer types. Although the frequency in spinal cord HGGs is uncertain, it is necessary to investigate BRAF V600E mutation as a potential therapeutic target in the future.

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“…They also suggested combined BRAFi + MEKi therapy may prevent secondary RAS driven cancers, such as squamous cell carcinomas, which can be seen with monotherapy (91). Small series of combination in both pediatric and adult high grade glioma have also demonstrated occasional rapid and durable responses (31,92). A phase II trial (NCT02684058) is currently underway studying dabrafenib and trametinib in children and adolescent patients with BRAF V600E low grade glioma and adults with relapsed or refractory high grade glioma (92).…”

Section: Successes and Challenges In Targeting Brafmentioning

confidence: 99%

BRAF Alteration in Central and Peripheral Nervous System Tumors

2020

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BRAF (alternately referred to as v-raf murine sarcoma viral oncogene homolog B1) is a proto-oncogene involved in the mitogen-activated protein kinase (MAPK) pathway. BRAF alterations are most commonly missense mutations or aberrant fusions. These mutations are observed in numerous primary central nervous system tumors as well as metastases. This review discusses the prevalence of BRAF alteration within select notable CNS tumors, and their prognostic associations. Included are some novel entities such as diffuse leptomeningeal glioneuronal tumor (DLGNT), polymorphous low grade neuroepithelial tumor of the young (PLNTY), and multinodular and vacuolating neuronal tumor (MVNT). Knowledge of this gene's integrity in CNS and PNS tumors can have profound diagnostic and therapeutic implications. Also reviewed are the current state of targeted therapy against aberrant BRAF as it pertains mostly to the CNS and to a lesser extent in PNS, and certain diagnostic aspects.

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Sustained response of three pediatric BRAFV600E mutated high-grade gliomas to combined BRAF and MEK inhibitor therapy

Cited by 50 publications

References 29 publications

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature

BRAF Alteration in Central and Peripheral Nervous System Tumors

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