Medical Oncology, Mayo Clinic, Phoenix, USA.
University College London Cancer Institute, London, UK.
Ann Oncol. 2021 Sep;32(9):1111-1126. doi: 10.1016/j.annonc.2021.04.012. Epub 2021 Apr 28.
Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and ∼10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the United States. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient's genetic signature.
胆管癌（CCA）包含多种上皮肿瘤，由于疾病进展迅速、诊断较晚以及晚期疾病标准化疗获益有限，其历史预后较差。全面的分子谱分析揭示了 CCA 中作为致癌驱动因素的基因组改变的多样性。TP53 突变、CDKN2A/B 缺失和 KRAS 突变是 CCA 中最常见的遗传改变。然而，肝内 CCA（iCCA）和肝外 CCA（eCCA）在许多改变的频率上有很大的不同。这包括可操作的改变，如异柠檬酸脱氢酶 1（IDH1）突变和多种 FGFR2 重排，分别在高达 29%和~10%的 iCCA 患者中发现，但在 eCCA 中很少见。FGFR2 重排是目前唯一在 CCA 中获得批准的靶向治疗药物，即成纤维细胞生长因子受体 1-3 抑制剂 pemigatinib。然而，IDH1 靶向治疗药物ivosidenib 在 iCCA 中进行的 III 期临床试验结果良好，许多其他改变也可通过在其他适应症中批准的靶向治疗药物进行治疗。下一代测序（NGS）的最新进展导致了能够在 2-3 周内对大型基因进行全面基因组分析的检测方法的发展，包括在美国获得批准的体外诊断检测方法。这些检测方法在可接受的来源材料（肿瘤组织或外周全血）、文库构建的遗传来源（DNA 或 RNA）、目标选择技术、基因面板大小和可检测基因组改变的类型方面有所不同。虽然一些大型商业实验室提供基于专有检测平台的快速和全面的基因组分析服务，但临床中心可能会使用专为临床研究设计的商业基因组分析试剂盒来开发自己的定制实验室开发测试。基于 NGS 的大规模基因组分析可实现 CCA 的详细和精确分子诊断，并为根据个体患者的遗传特征制定更优的靶向治疗计划提供重要机会。
