Page 150 - Read Online

Page 2 of 21 Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68

INTRODUCTION

iCCA is a highly aggressive primary liver cancer, representing approximately 20% of all malignant liver
[1]
tumors . Due to the distinctive biological characteristics, iCCA presents a hidden onset, elevated
malignancy degree, restricted treatment options, and dismal prognosis. Radical surgical resection, currently
the sole potential curative approach, is only executed in 30% of patients, and the median disease-specific
survival was about 36 months in these resected patients . Systemic therapy can delay progression for
[2]
approximately 70% of patients with advanced or metastatic disease; however, the median overall survival
[3]
(mOS) is still around one year . Multiple potential therapeutic targets and genomic alterations have been
discovered successively, with the advances of iCCA genomic profiling research and the progress of second-
generation sequencing technology, raising the hope for patients with advanced iCCA to achieve improved
oncologic outcomes .
[4]
Over the past decade, several promising therapeutic targets have been identified and will pave the way for a
new era of iCCA management, such as fibroblast growth FGFR2 fusions and IDH-1 and IDH-2
[5]
mutations . The FGFR2 inhibitor pemigatinib has been granted approval by the US Food and Drug
Administration (FDA) as the first targeted therapy for locally advanced or metastatic iCCA with FGFR2
[6]
fusions or rearrangements . Subsequently, a few FGFR inhibitors and IDH inhibitors have been approved,
[7]
with more agents undergoing evaluation as subsequent-line therapy for advanced cholangiocarcinoma .
Furthermore, increasing interest has been shown in patients with cholangiocarcinoma who possess BRAF
V600E mutation, amplifications or mutations of HER2 (ERBB2), fusions of NTRK, RET fusions, or KRAS
mutations.

In this paper, we provide a comprehensive review of recent significant literature on targeted therapy for
iCCA in recent years. Our focus is to summarize the latest advances in mutation-based targeted therapy and
offer a valuable reference for both experimental and clinical research.

CURRENT GENETIC LANDSCAPE AND ACTIONABLE ABERRATIONS
Given the genetic heterogeneity in iCCA, genomic profiling is crucial to inform targeted therapy. The
advancement of next-generation sequencing (NGS) technology has enabled the identification of actionable
alterations and facilitated the exploration of potential mechanisms underlying acquired resistance. Nearly
40% of iCCA patients carry targetable or potential actionable genetic alterations, including but not limited
to tumor protein p53 (TP53), IDH1/2, AT-rich interaction domain 1A (ARID1A), BRCA1 associated
protein 1 (BAP1), cyclin-dependent kinase inhibitor 2A (CDKN2A), KRAS, FGFR2, polybromo 1 (PBRM1),
SMAD4, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), MDM2, BRAF,
BRCA1/2, ERBB2 (HER2), and MET [8-14] . IDH1 mutations (incidence of 14%-29%) and FGFR2 fusions or
rearrangements (8%-13%) represent the most prevalent actionable alterations in iCCA. ERBB2 gene
(encoding HER2 protein) amplification and/or overexpression, as well as BRAF V600E, have also been
identified in 2%-5% of such patients [Figure 1 and 2 and Table 1]. Other alteration such as NRTK fusion,
RET fusion, KRAS G12C mutation, or microsatellite instability (MSI) has been detected in less than 2% of
iCCA patients. However, each of them has played an indispensable role in targeted therapy or
immunotherapy [8,12,15] .

Genetic mutation-based clinical and histopathological characterization
The genomic diversity and heterogeneity of cholangiocarcinoma are closely related to tumor origin, as well
as its epidemiological and clinicopathological features. In cholangiocarcinoma, iCCA is more likely to
exhibit FGFR2 fusion, IDH1/2 mutation, and BRAF V600E mutation, while extrahepatic