Abstract
The effective management of biliary tract cancers (BTCs) has been hampered by limited options for systemic therapy. In recent years, the focus on precision medicine has made technologies such as next-generation sequencing (NGS) accessible to clinicians to identify targetable mutations in BTCs in tumor tissue (primarily) as well as blood, and to treat them with targeted therapies when possible. It has also expanded our understanding of functional pathways associated with genetic alterations and opened doors for identifying novel targets for treatment. Recent advances in the precision medicine approach allowed us to identify new molecular markers in BTCs, such as epigenetic changes (methylation and histone modification) and non-DNA markers such as messenger RNA, microRNA, and long non-coding RNA. It also made detecting these markers from non-traditional sources such as blood, urine, bile, and cytology (from fine-needle aspiration and biliary brushings) possible. As these tests become more accessible, we can see the integration of different molecular markers from all available sources to aid physicians in diagnosing, assessing prognosis, predicting tumor response, and screening BTCs. Currently, there are a handful of approved targeted therapies and only one class of immunotherapy agents (immune checkpoint inhibitors or ICIs) to treat BTCs. Early success with new targets, vascular endothelial growth factor receptor (VEGFR), HER2, protein kinase receptor, and Dickkopf-1 (DKK1); new drugs for known targets, fibroblast growth factor receptors (FGFRs) such as futabatinib, derazantinib, and erdafitinib; and ICIs such as durvalumab and tremelimumab is encouraging. Novel immunotherapy agents such as bispecific antibodies (bintrafusp alfa), arginase inhibitors, vaccines, and cellular therapy (chimeric antigen receptor—T cell or CAR-T, natural killer cells, tumor-infiltrating lymphocytes) have the potential to improve outcomes of BTCs in the coming years.
Highlights
Biliary tract cancers (BTCs) are a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract, which includes the bile ducts and gallbladder [1]
It is important to recognize the significant differences in the genomic landscape of intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), and gallbladder cancers (GBC)
We need to start investing in DNA markers other than somatic mutations such as methylation markers and nonDNA markers to help diagnose, screen, and predict the treatment response in biliary tract cancers (BTCs)
Summary
Biliary tract cancers (BTCs) are a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract, which includes the bile ducts and gallbladder [1]. The fruits of precision medicine were extended to other sources of tumor genetic material (DNA and RNA) such as blood, bile, urine, and cytology (biliary brushings), which is exciting CNVs in CDKN2A, TP53, MDM2 proto-oncogene, and CCD1 genes and HER2 amplifications increased with the development GBC from its precursor lesions (gallstones, low-grade/high-grade dysplasia) [37] These distinct mutational profiles among BTCs can help localize the origin of the tumor and tailor therapy for individual patients. Mutation detection in tumor tissue or blood helps identify the cell signaling pathways that play a pivotal role in carcinogenesis, drug resistance, and prognosis Tools such as Ingenuity Pathway Analysis (IPA) were used in previous studies to correlate the genomic variations with specific signaling pathways [27]. The major pathways and associated gene alterations in BTCs are as follows: i) FGF pathway with FGFR mutations; ii) mTOR with
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