Reference Detail

Ref Type

Journal Article

PMID

(38922339)

Authors

Chen MF, Yang SR, Tao JJ, Desilets A, Diamond EL, Wilhelm C, Rosen E, Gong Y, Mullaney K, Torrisi J, Young RJ, Somwar R, Yu HA, Kris MG, Riely GJ, Arcila ME, Ladanyi M, Donoghue MTA, Rosen N, Yaeger R, Drilon A, Murciano-Goroff YR, Offin M

Title

Tumor-Agnostic Genomic and Clinical Analysis of BRAF Fusions Identifies Actionable Targets.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	30	17	2024 Sep 03	3812-3823	Clin Cancer Res

URL

Abstract Text

Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course.We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, and intact BRAF kinase domain).We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. Thirty-nine fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliogliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. Twenty-four patients spanning multiple histologies were treated with MAPK-directed therapies, of which 20 were evaluable for RECIST. Best response was partial response (N = 2), stable disease (N = 11), and progressive disease (N = 7). The median time on therapy was 1 month with MEK plus BRAF inhibitors [(N = 11), range 0-18 months] and 8 months for MEK inhibitors [(N = 14), range 1-26 months]. Nine patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N = 6), Erdheim-Chester disease (N = 1), extraventricular neurocytoma (N = 1), and melanoma (N = 1)]. Fifteen patients had acquired BRAF fusions.BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy, underscoring the importance of postprogression biopsies to optimize treatment at relapse in these patients.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF fusion	Erdheim-Chester disease	predicted - sensitive	Cobimetinib	Case Reports/Case Series	Actionable	In a retrospective analysis, Cotellic (cobimetinib) treatment resulted in a partial response with a tumor reduction of 67% in a patient with Erdheim-Chester disease harboring a BRAF fusion, with the patient remaining on treatment for at least 22 months (PMID: 38922339; NCT01775072).	38922339
BRAF fusion	high grade glioma	predicted - sensitive	Selumetinib	Case Reports/Case Series	Actionable	In a retrospective analysis, Koselugo (selumetinib) treatment resulted in a partial response with a tumor reduction of 52% in a patient with high grade neuroepithelial tumor harboring a BRAF fusion (PMID: 38922339; NCT01775072).	38922339