New Horizons for Precision Medicine in Biliary Tract Cancers

Abstract

Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients presents with resectable disease; however, relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been suggested. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g. radioembolization or external beam radiation); pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next generation sequencing analyses have identified actionable mutations (e.g. FGFR fusion rearrangements and IDH-1 and -2 mutations) with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC is rapidly evolving and the subject of this review.

A phase 2 trial of regorafenib as a single agent in patients with chemotherapy‐refractory, advanced, and metastatic biliary tract adenocarcinoma

“…13 promoter mutations are more prevalent in GBC). 16,17 Regorafenib is a diphenylurea oral multikinase inhibitor that potently inhibits angiogenic factors (VEGF receptors 1-3 [VEGFR1-VEGFR3], tyrosine-protein kinase receptor Tie-2 [TIE2]), and stromal factors (platelet-derived growth factor receptor β [PDGFR-β] and fibroblast growth factor receptor 1 [FGFR1]) that promote tumor neovascularization, vessel stabilization, and lymphatic vessel formation, which, in turn, play significant roles in the tumor microenvironment and metastases development. Among these significantly altered genes, Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), tumor protein 53 (TP53), ARID2 mutations are high in BTCs, and their mutation status was significantly associated with a poorer prognosis.…”

Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink

“…BTCs are rare but highly fatal diseases, with a median overall survival of ~12 months 1. Although the aetiology of BTCs is largely unknown, the epidemiological and molecular characteristics suggest that they are distinct disease entities 1 2.…”

“…Hyperlipidaemia is thought to interact with inflammation and proinflammatory immune response to influence the risk of BTCs 6 7. For GBC, local inflammation due to gallstones plays a central role,8 while for cholangiocarcinoma, both intrahepatic and extrahepatic sclerosing cholangitis play a major role 1. Inflammation from biliary adenomas, which are seen in patients with familial adenomatous polyposis,9 is thought to contribute to the 100-fold higher risk of AVC in that population 10.…”

A Molecular Diagnosis of Cholangiocarcinoma suggested using Cell-free DNA following Multiple Unsuccessful Attempts at Obtaining a Tissue Diagnosis.

“…As with other malignancies, a tissue diagnosis is highly recommended once cholangiocarcinoma is part of the differential diagnosis based on the clinical presentation, radiographic or biochemical findings [2].…”

“…Molecular profiling studies of tumor tissue or cfDNA from patients with cholangiocarcinoma have reported a variety of molecular alterations (2,6,7), including somatic KRAS driver mutations. Other frequently mutated genes in cholangiocarcinomas were also studied (see above), although BAP1 (which is commonly mutated in cholangiocarcinoma) was not (8,9,10,11).In this case, the TP53 (C141fs), IDH2 (R140Q), NF1 (Q83*) and ATM (R3008) alterations were detected using cfDNA NGS testing.…”