Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies

Abstract

Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy.

Keywords: biomarkers; cholangiocarcinoma; intrahepatic; outcomes; trials.

Figure 1

ICC Molecular Subclasses, reproduced from Sia et al. [32]. Summary of characteristics of ICC classes. Specific molecular and clinical characteristics differ between ICC classes. Molecular characteristics such as signatures of poor prognosis (i.e., cluster A, CC-like, G3, S1, S2, and stem-cell like ICC), oncogenic pathways (i.e., IGF1R, MET, EGFR), gene expression (i.e., EGFR, ILs), copy number variations, and oncogenes mutations (KRAS and EGFR) are differentially enriched in the proliferation and inflammation classes. Clinical characteristics such as moderate/poorly differentiated tumors and intraneural invasion are more frequent in the proliferation class. Differences in survival and recurrence were observed.

Figure 2

Tile plot of genomic alterations in 28 cases of ICC, reproduced from Ross et al. [41].

Figure 3

Schematic representation of therapeutically relevant signaling pathways and selected targeted therapies currently under evaluation in biliary tract cancer, reproduced from Rizzo et al. [47]. AKT: protein kinase B; EGFR: epidermal growth factor receptor; FGF: fibroblast growth factor; HER2: epidermal growth factor receptor 2; HGF: hepatocyte growth factor; IL-6: interleukin 6; IDH: isocitrate dehydrogenase; JAK: Janus kinase; mTOR: mammalian target of rapamycin; PDGFR: platelet derived growth factor receptor; PDK1: phosphoinositide-dependent kinase-1; PI3K: phosphoinositide 3-kinase.