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Page 8 of 23 Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79

Integrative genomics studies have also unravelled the genomic characterisation of the most prevalent
oncogenic signalling pathways, including those involved in cell survival, angiogenesis, signal transduction
and transcriptional control [69,70] . Genetic and epigenetic changes in BTCs cooperate in complex oncogenic
networks, including NADPH metabolism, SWI-SNF complex, de-ubiquitination, and histone
(de-)methylation, kinase signalling, WNT-CTNNB1 network, cell cycle control, WNT/Notch signalling,
DNA damage repair, and many others [69,70] . This knowledge underlines the significant complexity of the
molecular biology of biliary malignancies and poses major challenges in translating the genomic discoveries
into the clinic. In particular, therapeutic inhibition of single gene activations is unlikely to achieve the
durable antitumour activity, while combinatorial approaches targeting different pathways may result in
more effectiveness. On the other hand, the identification of patient groups with shared molecular
aberrations beyond point mutations in coding genes could overcome the above-mentioned challenges, thus
facilitating the personalised drug development process.

In this context, distinct recurring molecular subgroups with different prognoses and responses to therapy
have been identified. Sia et al. described two subtypes of iCCA with different activated pathways and
[69]
prognosis: the inflammation class (38% of cases) associated with the activation of inflammatory pathways,
overexpression of cytokines, and STAT3 activation; and the proliferation class (62% of cases) associated with
KRAS and BRAF mutations and oncogenic pathways activation (i.e., RAS, MAPK, and MET).

Through integrated genomic analysis of iCCA (whole-exome sequencing, targeted exome sequencing) and
[71]
epigenomic data from 496 patients, Nepal et al. described unique mutational signatures, structural
variants and epigenomic alterations and proposed four different molecular subgroups with specific drug-
response profiles: IDH mutant (drug: metabolic modulators), KRAS mutant (drug: microtubule
modulators), TP53 mutant (drug: topoisomerase inhibitors), and “undetermined” (drug: mTOR inhibitors).

Another interesting classification that considers the tumour microenvironment (TME) characteristics of
iCCA has identified 4 TME-based subtypes related to distinct immune escape mechanisms and patient
outcomes . About 45% of iCCA displayed an immune desert phenotype, while the 11% presented a
[72]
massive T lymphocyte infiltration, activation of inflammatory and immune checkpoint pathways, and was
associated with the longest patient survival (inflamed subtype). The other two subtypes differed in nature
(lymphoid, myeloid, mesenchymal) and abundance of tumour-infiltrating cells . The inflamed subgroup
[72]
constitutes the most clinically relevant as it may potentially identify patients who are more likely to benefit
from ICIs.

Personalised therapeutic approaches in aBTCs
The above data indicate the potential for oncogenic network characterisation to enable efficient
stratification and therapy optimisation for patients with biliary cancers. A deeper understanding of the
molecular biology underlying biliary tract malignancies and the high genomic/anatomical heterogeneity
identified across histologically similar tumours may also partially explain the limited clinical advances
achieved in the past decades. The lack of therapeutic targets, along with the “all-comers” design of clinical
trials investigating targeted therapies in unselected patients (widely unsuccessful) may be an additional
explanation for disappointing results achieved in past years [15-24] .

On the other hand, promising results of personalised medicine for aBTCs have been demonstrated in
molecularly driven studies. Among 43 pre-treated patients with aBTCs included in the prospective clinical
trial MOSCATO-01, successful biopsy with multiple high-throughput molecular analysis was obtained in 34
patients. Orientation to an appropriate early clinical trial or administration of molecular-targeted agents was