We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors' institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors', revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology.
Key points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling.Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations.In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.
摘要
我们既往报道过一个有遗传性肺癌的家族, 其中鸟类成红细胞白血病病毒致癌基因同源物2（erb‐b2受体酪氨酸激酶2）[ERBB2；人表皮生长因子受体2（HER2）]跨膜结构域（G660D）中的种系突变似乎是造成癌症倾向的原因。虽然与治疗有关的数据非常少, 但抗ERBB2治疗剂可能对ERBB2突变型癌症有效。其中一位作者所在研究机构的家族性肺癌患者发生了骨转移, 并伴有肺肿瘤扩大, 接受了ERBB2抑制剂阿法替尼的治疗。在作者的另一个研究机构中, 我们还发现了一例经全面的基因组分析显示具ERBB2 G660D和S310F突变的壶腹部腺癌患者。该患者随后接受了阿法替尼治疗, 并实现了短暂的反应。我们还在PubMed、肿瘤基因图谱（TCGA）以及Memorial Sloan Kettering‐可操作肿瘤靶标综合突变分析序列（MSK‐IMPACT）数据库中搜索了ERBB2跨膜突变。除我们的两个病例外, 通过PubMed还发现了两例具V659E突变的患者。在TCGA中发现了三例潜在的患者。另外, 通过 MSK‐IMPACT 发现了三例具有G660D突变的泌尿道上皮癌和两例具有V659E突变的肺腺癌。我们的经验表明, 要实现肿瘤精准治疗, 必须建立一个综合信息数据库, 其中包括具有频发但不常见突变的患者的临床基因组和治疗结果信息。
要点：
• 罕见但可靶向的突变, 如鸟类成红细胞白血病病毒致癌基因同源物2（erb‐b2受体酪氨酸激酶2）[ERBB2；人表皮生长因子受体2（HER2）]跨膜结构域（TMD）突变可通过全面的基因组分析进行检测。
• 阿法替尼对具有ERBB2（HER2）跨膜结构域突变的癌症患者可能有效。
• 为了实现肿瘤精准治疗, 必须建立一个综合信息数据库, 其中包括具有频发但不常见突变的患者的临床基因组和治疗结果信息。
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