Purpose: Biliary tract cancers (BTCs), which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant BTC models which recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in BTCs to create a resource for modeling precision oncology. Experimental Design: PDXs were derived from BTC collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole exome sequencing and RNASeq. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease=partial response; >20% increase in tumor volume=progressive disease, and any non-PR/PD was considered stable disease. Results: Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, IDH1, ERRB2, PIK3CA, PTEN and KRAS. RNAseq demonstrated fusions and expression of antibody drug conjugate targets including TROP2, HER2 and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically. Conclusions: Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

中文翻译：

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利用患者来源的异种移植物对胆道癌的精准肿瘤学进行建模


目的：胆道癌 （BTC） 是一种罕见的侵袭性恶性肿瘤，具有丰富的临床可操作分子改变。该领域的一个主要挑战是缺乏临床相关的 BTC 模型，这些模型概括了这些肿瘤的不同分子特征。本研究的目的是策划一系列患者来源的异种移植物 （PDX） 模型，这些模型反映了 BTC 中存在的基因组改变范围，从而为精准肿瘤学建模创建资源。实验设计：PDX 来源于从手术切除或转移活检中收集的 BTC。PDX 中存在的改变通过全外显子组测序和 RNASeq 鉴定。PDX 用批准的和研究性的药物治疗。通过肿瘤体积相对于基线的变化来评估疗效。无事件生存期定义为肿瘤从基线加倍的时间。反应在第 21 天分类：>30% 减少 = 部分反应;>肿瘤体积增加 20% = 疾病进展，任何非 PR/PD 都被认为是稳定的疾病。结果： 基因组测序显示了该队列中的关键可操作改变，包括 FGFR2 、 IDH1 、 ERRB2 、 PIK3CA 、 PTEN 和 KRAS 的改变。RNAseq 证明了抗体药物偶联靶标（包括 TROP2、HER2 和 Nectin4）的融合和表达。治疗匹配揭示了对临床上已被证明具有抗肿瘤活性的已批准和研究药物的客观反应。结论：在这里，我们开发了一个 BTC PDX 目录，该目录进行了全面的分子分析和治疗建模。迄今为止，这是最大的 BTC PDX 模型集合之一，将有助于为这些侵袭性恶性肿瘤患者开发个性化治疗。