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

Abstract

Purpose: 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.

Experimental design: 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).

Results: 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.

Conclusions: 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.

Figure 1.

Prevalence of de novo BRAF fusions by histology. Histologies with ≥5 BRAF fusions and/or histologies with >5% prevalence and at least 5 cases in the institutional cohort were included. (Created with BioRender.com)

Figure 2.

BRAF fusion partners. A. Circos plot: inner track BRAF and fusion partner genes, outer track: chromosomes. B. Structures of novel BRAF fusions that had confirmatory RNA-sequencing and transcript IDs.

Figure 3.

Fusion partners by histology. A. 5’ gene fusion partners for de novo BRAF fusions. B. sunburst plot of 5’ gene fusion partners for de novo BRAF fusions. Histologies with at least 5 cases in the institutional cohort were included. Inner circle histology, outer circle 5’ gene fusion partner. CA: cancer; CRC: colorectal cancer; GBM: glioblastoma; NSCLC: non-small cell lung cancer.

Figure 4.

MAPK-pathway directed treatments. A. Swimmer’s plot of patients with de novo BRAF fusions treated with MAPK-pathway directed therapies. Dotted line is at 6 months from start of MAPK-pathway directed treatment. B. Waterfall plot of best change from baseline for 20 patients with follow-up target lesion measurements by RECIST v1.1.

Figure 5.

Acquired BRAF fusions. A. Prevalence of acquired BRAF fusions by histology. B. Sunburst plot of 5’ gene fusion partners for acquired BRAF fusions. Inner circle histology, outer circle 5’ gene fusion partner. C. Treatment, histology, and time before detection of BRAF fusion (adjusted to time 0 for all patients). Center: Histology. Dark blue (time on targeted treatment), grey (time on non-targeted treatment). (A, Created with BioRender.com)