1Vall d'Hebron Institut d'Oncologia; 2Vall d'Hebron Institut de Recerca; 3Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona; 4Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; and 5Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
Cancer Discov. 2013 Nov;3(11):1238-44. doi: 10.1158/2159-8290.CD-13-0132. Epub 2013 Aug 15.
Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline TP53 mutation (Li-Fraumeni Syndrome) identified oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifications, an EGFR-exon 20 insertion, and the first-in-humans HER2V659E mutation showing a phenotypic convergent evolution toward HER2 and EGFR alterations. Following the identification of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A symptomatic and radiologic clinical response was achieved. HER2V659E sensitivity to lapatinib was confirmed in the laboratory.
The precise knowledge of the genomic alterations present in tumors is critical to selecting the optimal treatment for each patient. Here, we report the molecular characterization and clinical response to a lapatinib-based therapy for the tumors of a Li-Fraumeni patient showing prevalence of HER2 and EGFR genomic alterations.
目的：对一名 29 岁携有种系 TP53 突变（Li-Fraumeni 综合征）的患者在 10 年内发展的复发性乳腺和肺部肿瘤进行基因组特征分析，鉴定出所有肿瘤中 HER2 和 EGFR 基因的致癌改变，包括 HER2 扩增、EGFR 外显子 20 插入和首个在人体中发现的 HER2V659E 突变，这些改变显示出向 HER2 和 EGFR 改变的表型趋同进化。在最近的肺癌和循环肿瘤细胞中发现 HER2 激活事件后，我们用基于拉帕替尼的疗法治疗了具有代表性的转移性病变。达到了有症状和影像学临床反应。在实验室中证实了 HER2V659E 对拉帕替尼的敏感性。
结论：准确了解肿瘤中存在的基因组改变对于为每位患者选择最佳治疗方案至关重要。在这里，我们报告了一名 Li-Fraumeni 患者的肿瘤的分子特征和对基于拉帕替尼的治疗的临床反应，这些肿瘤表现出 HER2 和 EGFR 基因组改变的普遍性。
