Precision Oncology Targets in Biliary Tract Cancer

Abstract

Targeted therapies in biliary tract cancer (BTC) are emerging as options for patients not who do not respond to first-line treatment. Agents acting on tumor-specific oncogenes in BTC may target fibroblast growth factor receptor 2 (FGFR2), isocitrate dehydrogenase (IDH), B-raf kinase (BRAF), and human epidermal growth factor receptor 2 (HER-2). Additionally, given the heterogeneous genetic landscape of advanced BTCs, many harbor genetic aberrations that are common among solid tumors, including RET fusions, tropomyosin receptor kinase (TRK) fusions, and high tumor mutational burden (TMB). This review aims to provide updates on the evolving array of therapeutics available, and to summarize promising works on the horizon.

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

“…Extrahepatic CCA makes up 20-30% of all BTC in the USA and globally and is associated with certain conditions that significantly increase risk of eCCA including non-alcoholic fatty liver disease (odds ratio [OR] 2.9), cirrhosis (OR 3.8), alcohol-related liver disease (OR 2.6), and primary sclerosing cholangitis (PSC; OR 40.8), with the latter carrying up to a 36% lifetime risk of developing CCA [3][4][5]. Hepatitis B (HBV) and C (HCV) are associated with iCCA (predominantly) and eCCA (HBV OR 2.38; HCV OR 3.18) [4][5][6][7]. Conditions predisposing to eCCA include chronic pancreatitis, cholangitis, and choledocholithiasis [5,8] with the estimated incidence of around 1.02 cases per 100,000 annually [9].…”

“…For patients who present with localized disease, definitive treatment with surgical resection can offer cure. Unfortunately, only 20% of patients have resectable disease at presentation, and recurrence rates up to 75% have been reported [6,36].…”

“…Figure 1 illustrates the most frequent actionable mutations found in BTC and Table 2 summarizes key clinical trials in target-selected populations. Herein, we will address the most frequently found mutations in eCCA, acknowledging that rare genetic alternations found in eCCA such as IDH1/2 mutations and FGFR2, NTRK, and RET fusions have targetable therapeutic options but are found almost exclusively in iCCA and will not be discussed in depth below but are included as part of Table 2 [6].…”

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

“…Alterations in genes that are related to the control of DNA damage response (DDR) and cell cycle regulation are also frequent in all CCA subtypes. Mutations of BAP1, PTEN, and PBRM1 are predominantly found in iCCA, whereas mutations of TP53, ARID1A, CDKN2A, CHK1/2, ATM, ATR, and BRCA occur in all CCA subtypes [103][104][105]. DDR pathways encompass a network of signaling cascades and effector mechanisms that maintain genomic integrity and ensure proper cellular responses to DNA damage.…”

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review

“…The RET proto-oncogene is a protein receptor tyrosine kinase that, when constituently activated, can lead to the development of cancer. RET is a rare mutation, occurring in only 1.8% of all solid tumors as either a fusion, amplification, or gene mutation [ 52 ]. RET alterations have been shown to occur in only 1.6% of hepatobiliary tract cancers [ 53 ].…”