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Page 18 of 23 Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79

trials are currently investigating the combination (or sequential approach) of AKT-mTOR inhibitors or
PI3K-mTOR inhibitors plus chemotherapy (NCT02465060, NCT02836847, NCT02631590).

Lastly, numerous chromatin-modifying enzymes are frequently mutated or altered by copy number
aberrations in BTCs. Blocking these targets when found dysregulated represent a compelling strategy to
explore in BTCs [54,127,128]

CONCLUSION
Overall, BTCs constitute a neglected disease for which novel therapeutic strategies are urgently needed.
After years of “one-size fits all” approach, characterised by a series of failures in improving patient outcomes
with only marginal progress made thanks to the allocation of first-line chemotherapy, we are now
witnessing the dawn of a new era based on molecularly driven decision making. The current standard
therapeutic portfolio includes chemotherapy in first-line (CisGem) and second-line for unselected patients
(FOLFOX); patients with molecular aberrations (IDH mutations, FGFR fusions, MSI high) can be treated
with targeted therapies or pembrolizumab following progression to frontline chemotherapy [Figure 1].

Despite currently being limited to small patient subgroups, “precision medicine” for BTCs is possible - and
desirable - given the numerosity of ongoing biomarker-based/enriched clinical trials and potential
therapeutic vulnerabilities recently identified, both in the tumour and in the immune-microenvironment.
To reach this ambitious goal, a revolution in patient management is much needed. Large-scale efforts to
implement tumour’s molecular characterisation at diagnoses with a rapid translation of information to
clinical research, in addition to expanding clinical trials (and trial enrolment), should be a health priority.
Implementing liquid biopsy studies will be a crucial step to facilitate sample collection for biomarker
discovery, treatment monitoring, and disease surveillance in BTCs. In parallel, enhanced preclinical
research will be essential to the identification of predictive biomarkers and to the elucidation of mechanisms
of primary and acquired resistance. Multi-omics studies and international collaborations are also
fundamental to accelerate the precision therapeutic development in this aggressive disease.

DECLARATIONS
Authors’ contributions
Conception and design of the study: Braconi C, Casolino R
Drafting the manuscript: Casolino R
Review of the manuscript: Braconi C
Approval of the final version of the manuscript: Casolino R, Braconi C

Availability of data and materials
Not applicable.

Financial support and sponsorship
Braconi C is a recipient of the Lord Kelvin Adam Smith Readership from the University of Glasgow.

Conflicts of interest
Braconi C (or spouse) received honoraria from Incyte, Bayer, Eli-Lilly, Pfizer, Merck-Serono.

Ethical approval and consent to participate
Not applicable.