Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology

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.

Changing Epidemiological Trends of Hepatobiliary Carcinomas in Austria 2010–2018

“…Recently, the principle of targeted therapy has gained traction for cholangiocarcinoma. Based on specific targetable mutations (e.g., IDH1, FGFR2, VEGF, and NTRK) several (second-line) therapies have shown promising prolonged OS and have been approved, mainly for iCC [44,45]. Together with immunotherapy [44], survival rates are expected to further improve in the future.…”

“…Based on specific targetable mutations (e.g., IDH1, FGFR2, VEGF, and NTRK) several (second-line) therapies have shown promising prolonged OS and have been approved, mainly for iCC [44,45]. Together with immunotherapy [44], survival rates are expected to further improve in the future. Recently, the TOPAZ-1 phase III study showed that combining cisplatin/gemcitabine with the PD-L1 inhibitor durvalumab further improved overall response rate (ORR), progression free survival (PFS), and median [46].…”

“…Therapeutic options at advanced stages are similar to those of cholangiocarcinoma and the standardization of cisplatin plus gemcitabine as first-line chemotherapy [43,45] has influenced the OS in GBC as well. Molecular-targeted therapies and immunotherapies are expected to further ameliorate the OS in the future [44].…”

Precision Medicine in Cholangiocarcinoma: Past, Present, and Future

“…FGFR2 gene fusions, such as FGFR2 – BICCI , FGFR2 – AHCYL1 , FGFR2 – TACC3 , and FGFR2 – KIAA1598 , are closely associated with tumor progression in iCCA [ 7 ]. The outcomes of clinical trials of small-molecule targeted therapies for these genetic alterations are presented in Table 3 [ 7 , 13 ]. Previous results indicated a maximum disease control rate (DCR) of 80% and progression-free survival (PFS) of approximately 6 months [ 14 , 20 , 21 ]; therefore, FGFR inhibitors are promising drugs for targeted therapies for CCA with FGFR2 fusions.…”

“…In recent years, the application of next-generation sequencing (NGS) technology has improved our knowledge of the molecular biology of cancer, as well as genetic alterations, and has expedited developments in targeted therapy for these alterations. Precision medicine involves the selection of suitable drugs, therapies, or preventive strategies based on an individual’s genotype or gene expression profile and clinical data, thereby achieving maximum therapeutic efficacy and minimal side effects [ 12 , 13 , 14 ]. This study describes the current state of precision medicine for CCA treatment.…”