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Page 8 of 10 Ruff et al. Hepatoma Res 2023;9:37 https://dx.doi.org/10.20517/2394-5079.2023.51

overcome acquired resistance, biopsies and genetic analysis of the tumor throughout IDH inhibitor therapy
may identify patients who have developed new mutations that will confer secondary resistance prior to
progression on clinical scans. This would allow clinicians to either add additional therapies or change the
treatment plan. These studies stress the complexity of primary and secondary resistance and that success
will likely require combination therapy.

CONCLUSION
ICCA is a rare malignancy that often presents at an advanced stage. Currently, the first-line therapy for
advanced CCA is gemcitabine and cisplatin. However, 5-year survival is still extremely low. It has become
abundantly clear that a “one size fits all” approach no longer applies to the treatment of individual cancers,
considering the large amount of tumor heterogeneity. As such, research in recent years has been motivated
to develop effective targeted therapies through genetic profiling of CCA tumors. IDH1 and IDH2 mutations
can be found in 16% and 4% of patients with ICCA, respectively. Currently, ivosidenib is approved as
second-line therapy for IDH1 mutated CCA. Ongoing clinical trials are currently evaluating the use of other
IDH inhibitors that are approved for gliomas or acute myeloid leukemia in patients with advanced CCA.

The main obstacle of targeted therapy is primary and secondary resistance. Overcoming this can only be
accomplished through strong translational work. Data from the lab should identify potential targeted
therapies, inform clinical trial design, and identify the underlying mechanisms of resistance to better select
patients that will benefit the most from specific therapy regimens. Biopsies and genetic analysis of the tumor
throughout therapy may identify acquired mutations that confer resistance and inform treatment timelines.
Combination therapy is likely the best way to tackle the complexity of the underlying biology of resistance.
Given the rarity of these tumors, it is imperative that patients are referred and treated on trial to expedite
accrual, increase tissue collection for post-trial genomic analysis, and identify successful therapies. Large
institutions and cooperative groups should continue a collaborative effort to test new therapies through
clinical trials to maintain forward progress over the next decade.

DECLARATIONS
Authors’ contributions
Contributed equally to the design, writing, and editing of this manuscript: Ruff SM, Dillhoff M

Availability of data and material
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.