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Page 2 of 15 Allen et al. Hepatoma Res 2021;7:73 https://dx.doi.org/10.20517/2394-5079.2021.98

INTRODUCTION
Cancers of the biliary tract include intrahepatic, perihilar, and distal cholangiocarcinoma (CCA) and
gallbladder cancer (GBC). Intrahepatic CCA arises from epithelial cells distal to the second-order bile ducts,
hilar CCA arises from epithelial cells at either the right and/or left hepatic duct or their junction, while distal
[1,2]
CCA arises from epithelial cells within the common bile duct . CCA is the second most common primary
liver cancer after hepatocellular carcinoma accounting for 3% of all gastrointestinal cancers and 2% of all
[2,3]
yearly global cancer-related deaths . GBC is the most common biliary tract malignancy accounting for
1.2% of global cancer diagnoses .
[4-7]
The incidence of CCA and GBC varies between geographical regions owing to differences in genotype
predisposition, environmental and modifiable risk factors, with 85 cases per 100,000 in north-east Thailand,
3.6 per 100,000 in Western Europe, and 1.6 per 100,000 in the United States of America . However, the
[8,9]
[10]
incidence of biliary tract cancers is steadily increasing in most western countries .
Identified risk factors leading to the development of intrahepatic and perihilar/distal CCA differ, with a
Surveillance, Epidemiology, and End-Results-Medicare dataset suggesting an association between
intrahepatic CCA and hepatitis B and C infection, tobacco smoking, alcohol consumption, and non-
alcoholic fatty liver disease, while reporting that such associations do not exist with perihilar/distal
CCA [11,12] . Factors associated with GBC include obesity, female gender, chronic inflammation of the biliary
tracts as occurs in primary sclerosing cholangitis, cholelithiasis, cholecystitis, gallbladder polyps, smoking,
and Salmonella and Helicobacter infections . Alterations in up to 32 genes have been identified in
[13]
approximately 70% of biliary tract cancers, with TP53, KRAS, and SMAD4 the most common [14,15] , while
potentially targetable molecular mutations have been identified in approximately 39% of biliary tracts
cancers. These include ERBB2 amplification, BRAF substitution, PIK3CA substitution, FGFR1-3 fusions,
CDKN2A/B loss, IDH1/2 substitution, ARID1A alteration, MET and BAP1 mutations [16,17] . Molecular
heterogenicity exists with IDH1/2 mutations and FGFR2 fusions predominately identified in intrahepatic
CCA relative to perihilar and distal CCA and GBC . A reported 8.6% of all biliary tract cancers exhibit
[18]
high programmed death-ligand 1 (PD-L1) expression . Biomarker selection and precision treatments are
[19]
likely to play an increasingly important role in optimizing care for patients with biliary tract cancers, likely
validated first in advanced disease and then studied in the earlier disease settings.

Most patients are diagnosed with advanced (unresectable/metastatic) biliary tract cancer, with only 20%-
30% resectable at diagnosis [20-23] . The 5-year survival remains poor at approximately 10% for CCA and 19%
for GBC [3,24] . Chemotherapy is the standard of care treatment for advanced disease, with the median overall
survival (OS) of 11.7 months with first-line cisplatin and gemcitabine as demonstrated in phase III clinical
[25]
trial ABC-02 (NCT00262769) . This trial also reported an observed response rate (ORR) of 26.1% (CCA
19%; GBC 37.7%) with doublet chemotherapy. Comparable outcomes were observed in an Asian population
[26]
in the BT22 clinical trial, with both ABC-02 and BT22 then analyzed in a metanalysis by Valle et al. ,
which demonstrated consistent outcomes . Keynote-158 (NCT02628067) and Keynote-028
[27]
(NCT02054806) report an ORR with pembrolizumab of 6%-13%, with similar rates observed with
nivolumab (NCT02829918) in chemotherapy-refractory disease, while an ORR of 24% has been reported
with combination nivolumab and ipilimumab (NCT02923934) [28-32] . All of these were non-randomized trials.
For the smaller subset presenting with the localized disease, the median OS following curative surgical
resection is approximately 40 months . Criteria for resectability include no local vascular invasion (hepatic
[33]
artery, hepatic vein, or portal vein) or local vascular invasion amenable to reconstruction, an ability to
reconstruct the bile duct or achieve an R0 resection, sufficient liver volume, and no distant metastases [34,35] .
Outcomes are worse in lymph-node positive (N+) disease, while a negative resection margin (R0) achieves a