Background: 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. Patients/methods: 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, intact BRAF kinase domain). Results: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5’ fusion partners spanning 52 histologies. 39 fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. 24 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). 9 patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N=6), Erdheim-Chester disease (N=1), extraventricular neurocytoma (N=1), 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 post-progression biopsies to optimize treatment at relapse in these patients.

中文翻译：

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BRAF 融合的肿瘤不可知基因组和临床分析确定了可行的靶点


背景：尽管 BRAF 融合越来越多地在标准多基因下一代测序面板中检测到，但很少有报告探讨其结构和对临床过程的影响。患者/方法：我们收集了通过 97,024 个样本的基因分型方案确定的 BRAF 融合阳性癌症患者的数据。对融合体进行表征并审查其致癌潜力（框内状态、非 BRAF 伴侣基因、完整 BRAF 激酶结构域）。结果：我们发现来自 212 名患者的 241 个 BRAF 融合阳性肿瘤，具有跨越 52 个组织学的 82 个独特的 5' 融合伙伴。 39 个融合伴侣以前没有报道过，61 个融合伴侣曾经被鉴定过。 BRAF 融合发生率在毛细胞星形细胞瘤、神经节瘤、低级别神经上皮肿瘤和胰腺腺泡细胞癌中较多。 24 名跨越多种组织学的患者接受了 MAPK 导向疗法，其中 20 名患者可进行 RECIST 评估。最佳缓解是部分缓解（N=2）、疾病稳定（N=11）和疾病进展（N=7）。 MEK 加 BRAF 抑制剂的中位治疗时间为 1 个月（[N=11]，范围 0-18 个月），MEK 抑制剂的中位治疗时间为 8 个月（[N=14]，范围 1-26 个月）。 9 名患者的治疗时间超过 6 个月 [毛细胞星形细胞瘤 (N=6)、Erdheim-Chester 病 (N=1)、室外神经细胞瘤 (N=1)、黑色素瘤 (N=1)]。 15 名患者获得了 BRAF 融合。结论：BRAF 融合存在于各种组织学中，代表了一个新兴的可行目标。 BRAF 融合有多种融合伙伴。观察到对 MAPK 疗法的持久反应，特别是在毛细胞星形细胞瘤中。 靶向治疗后发现获得性 BRAF 融合，强调了进展后活检对于优化这些患者复发时治疗的重要性。