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Pedica et al. Hepatoma Res 2021;7:71 https://dx.doi.org/10.20517/2394-5079.2021.89 Page 9 of 12

[38]
BRCA mutations are found in around 3.6% of iCCAs without differences in terms of site, providing
rationale for targeted therapies. BRCA mutant biliary tract cancers are more frequently associated with MSI
[39]
and high mutational burden , but not with PD-L1 expression. Nevertheless, the clinical significance of
BRCA status in biliary tract cancer also needs further investigation.

Another rare mutation (1%) regards BRAF V600E[40] , which can be detectable with immunohistochemistry
[41]
and/or directly investigated with DNA-based methods .

Rarely, HER2 can be found overexpressed by immunohistochemistry in biliary tract cancer (around 1.4% in
[42]
a large study by Albrecht et al. ), more commonly in distal bile duct cancer , and its detection requires
[42]
screening with immunohistochemistry and confirmation with FISH, mainly because of the rare detections
and absence of guidelines for evaluation of immunostaining. In fact, the quantitative and qualitative
reporting of HER2 immunohistochemical expression still relies on the same system applied for gastric
[43]
cancer .

Concerning eCCAs, as mentioned above, they rarely show targetable alterations tending to be similar to
pancreatic adenocarcinoma, with mutations regarding TP53, KRAS and SMAD4 . ERBB2 amplification is
[44]
found only in around 1.3% of cases, mainly characterised by papillary architecture , which regards a small
[44]
percentage of whole eCCAs in the routine practice, since most of them are generally perihilar
adenocarcinomas with periductal pattern of growth. IDH1/2 mutations are found in 4.7% of cases of eCCA,
whilst other eventual targets to be evaluated for the future are found in other around 20% of cases . In the
[44]
[44]
important study by Montal et al. , 11.5% of cases were “inflamed” and overexpressing PD-L1, thus being
good candidates for immune checkpoint inhibitors therapy. Nevertheless, eCCAs is still a great orphan
concerning molecular targets and the available therapies for this poorly responsive cancer are scant .
[45]

Since patients present already in advanced stage of disease, another important issue regards the possible
application of liquid biopsy technology in biliary tract cancer. Importantly, a large recent study has
[20]
assessed the possibility to identify actionable alterations in primary, metastasis and liquid biopsy.
Israel et al. found that all three biopsy types are appropriate for genomic testing, although with
[20]
significantly different mutational rates. These results are fundamental considering the large number of
patients who can present in metastatic conditions or have comorbidities, leading the way for the liquid
biopsy application also in biliary tract cancer.

CONCLUSIONS
Biliary tract cancer is a large group of neoplasms including intrahepatic and extrahepatic biliary neoplasms
with a wide spectrum of morphological characteristics and recently discovered important molecular targets
for personalisation of therapies [Figure 12].

Future developments are urgently needed because, although the new molecular targets have allowed
important advancements in clinical practice, these chances regard only a part of our patients, variable from
[46]
15%-20%, as described in the literature, to around 40%-50% of the patients tested in our routine practice .
Moreover, another important issue regards the possibility to perform an early diagnosis or identify an early
[47]
relapse with new biomarkers, such as plasma N-glycoproteins with specific N-glycan compositions , or
change therapy according to molecular profiling performed through liquid biopsy as it happens for lung
[48]
cancer .