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Abstract：
Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements, IDH1 mutations, and NTRK gene fusions. Also, several clinical studies involving molecular stratification have been performed in defined patient groups, for example, BRAF V600E and HER2. Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene. Targeting the MET signaling pathway is an effective strategy in numerous cancer types. However, the poor efficacy of MET inhibitors has been demonstrated in several phase II studies, but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC. In this article, we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy. After the patient had progressed and discontinued crizotinib, cabozantinib was introduced. Analysis of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) indicated a loss of MET amplification status. To our knowledge, this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.
摘要：
胆囊癌（GBC）是一种高侵袭性疾病，是胆道系统最常见的恶性肿瘤。GBC患者通常诊断为晚期，预后不良。在过去的几十年中，姑息化疗一直是复发性或转移性疾病的标准治疗方法。最近,已经在晚期胆道癌（BTC）中研究了几种靶向疗法，包括基因或途径的抑制剂，例如FGFR2融合或重排，IDH1突变,和NTRK基因融合。此外，已经在确定的患者组中进行了一些涉及分子分层的临床研究，例如,BRAFV600E和HER2。间充质上皮转化（MET）编码酪氨酸激酶受体，其配体肝细胞生长因子是原癌基因。靶向MET信号通路是许多癌症类型的有效策略。然而,在几个II期研究中已经证明了MET抑制剂的不良疗效，但目前尚无报道解释BTC对MET抑制剂耐药的潜在机制。在这篇文章中,我们报告一例转移性GBC伴MET扩增,在两行化疗失败后对克唑替尼表现出快速反应.在患者进展并停用克唑替尼后，介绍了卡博替尼。通过下一代测序(NGS)对循环肿瘤DNA(ctDNA)的分析指示MET扩增状态的丧失。据我们所知,这是首例证明ctDNA中使用NGS监测GBC抗MET治疗期间获得性耐药的发展的病例研究.
