Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options

Abstract

Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.

Prognostic Value of Lymph Node Dissection for Intrahepatic Cholangiocarcinoma Patients With Clinically Negative Lymph Node Metastasis: A Multi-Center Study From China

“…In our previous multi-center study ( 23 ), a total of 77 patients received postoperative adjuvant treatment, including 32 (41.6%) patients received TACE, 21 (27.3%) received chemotherapy, 10 (13.0%) received radiotherapy, and 14 (18.2%) received chemoradiotherapy, but only postoperative chemotherapy and TACE were found to benefit ICC patients (both P < 0.05). However, in the era of novel chemotherapy, targeted drug like apatinib, immune checkpoint inhibitors like pembrolizumab, and intensity modulated radiation therapy ( 35 , 36 ), the postoperative management of ICC with positive pLNM is very promising.…”

Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs

“…In the last years, genomic analysis of tumors has allowed an essential advance in the understanding of the mutational landscape of CCAs, demonstrating that they are among the tumors with the greatest variety of mutations, which contributes to their high resistance to pharmacotherapy. These studies have provided valuable information since there are many mutations with the potential to develop strategies directly targeting essential tumor machinery [8].…”

Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

“…IDH1 and IDH2 encode for metabolic enzymes, and mutations lead to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), particularly inducing epigenetic changes in the tumors, such as DNA hypermethylation and altered expression of chromatin remodelers [47,48]. Comparing the prognosis of the molecular subtypes suggested a favorable prognosis for patients with IDH mutations in comparison to fluke-related iCCA [18] and in comparison to patients with KRAS and TP53 mutations [12,49].…”