Background NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. Patients and methods Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. Results Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. Conclusion These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. Clinical trial information Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).

中文翻译：

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NRG1通路的成功靶向表明转移性癌症的新治疗策略。

背景 NRG1 融合阳性肺癌已成为肺癌中潜在的可操作事件，但目前临床支持有限，并且没有证据表明这种方法对肺癌以外的癌症有效。患者和方法 在这里，我们描述了两名标准疗法难以治疗的晚期癌症患者。患者 1 患有肺腺癌，患者 2 患有胆管癌。对这些病例进行了全基因组和转录组测序，选择的结果通过荧光原位杂交验证。结果发现两个肿瘤都对NRG1基因融合呈阳性。在患者 1 中，检测到 SDC4-NRG1 基因融合，以前在肺癌中已经描述了类似的基因融合。在患者 2 中，检测到一种新的 ATP1B1-NRG1 基因融合。胆管癌不是以前描述过 NRG1 融合的疾病类型。综合基因组分析用于评估检测到的基因组事件（包括基因融合）的潜在功能意义，优先考虑针对 HER 生长因子受体家族的治疗策略。两名患者均接受了泛 HER 家族激酶抑制剂阿法替尼治疗，均对治疗表现出显着且持久的反应。对疾病进展部位进行测序。缺乏描述疾病进展的明显基因组事件表明，广泛的转录组学或表观遗传机制可归因于对阿法替尼缺乏长期反应。结临床方法，无论其起源部位如何。临床试验信息 不列颠哥伦比亚省的个性化肿瘤基因组学 (POG) 计划：利用基因组分析更好地了解肿瘤异质性和进化 (NCT02155621)。