Practical considerations in screening for genetic alterations in cholangiocarcinoma

Abstract

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 w10% 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.

The Role of Conventional and Stereotactic Microwave Ablation for Intrahepatic Cholangiocarcinoma

“…A potential advantage is the fact that ablation can be carried out while chemotherapy is performed. Next generation sequencing (NGS) is currently changing the treatment regime for ICCA with new treatments for the recently detected mutations IDH1 and FGFR2 (Ivosidenib and Pemigatinib) showing promising results [44]. If these modern treatment approaches based on NGS continue to show their efficacy in ICCA patients [3] and if an additive treatment by ablation improves, the outcome still needs to be analyzed.…”

Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

“…Due to the limited efficacy of chemotherapy treatments in patients with BTC, major efforts have been necessary to better understand the complex molecular landscape of cholangiocarcinoma (CCA) to identify novel therapeutic targets [ 15 ]. Of note, alongside gastrointestinal stromal tumor, melanoma and non-small cell lung cancer, CCA is considered one of the cancers with the highest prevalence of oncogenic driver [ 2 , 16 ].…”

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

“…Cholangiocarcinoma is an aggressive tumor type, which is poorly manageable by conventional cytotoxic therapy [70]. Intrahepatic biliary cancers carry FGFR2 gene fusions at a rate of 10-20%.…”