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Page 16 of 21 Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68

[92]
To date, the most comprehensive study on ctDNA involved 2068 samples from 1671 BTC patients .
Genetic alterations were detected in 84% of patients, with targetable alterations identified in 44%. The
concordance of mutation detection between ctDNA and tissue DNA was high for IDH1 mutations (87%)
and BRAF V600E (100%), but low for FGFR2 fusions (18%). Additionally, ctDNA analysis did reveal novel
potential mechanisms of resistance to targeted therapies, including the mutation in cysteine residue (FGFR2
C492F) that interacts with covalent FGFR inhibitors. A high pre-treatment ctDNA variant allele fraction
was associated with unfavorable prognosis and reduced response duration to both chemotherapy and
targeted therapy.

However, liquid biopsy cannot serve as a substitute for tissue biopsy since the latter remains necessary for
tumor histological evaluation, staging, and diagnosis. Particularly in early lesions or low-burden tumors
with limited concentrations of ctDNA, crucial gene alterations may go undetected.

DILEMMA AND OUTLOOK

Targeted mutation-based therapy has shown higher response rates and more survival benefits in the
treatment of BTC/iCCA compared to contemporaneous standard therapy in subsequent-line settings. FGFR
inhibitors (pemigatinib and futibatinib), IDH inhibitors (ivosidenib), BRAF and MEK tyrosine kinase
inhibitors (dabrafenib and trametinib), RET inhibitors (selpercatinib and pralsetinib), NTRK inhibitors
(larotrectinib and entrectinib), and anti-HER2 monoclonal antibodies (trastuzumab plus pertuzumab) have
been approved by the FDA or recommended in Guidelines for the treatment of iCCA patients. Although
targeted therapies for CCA have achieved ORR usually more than 30% and mPFS commonly beyond 6
months, the use of targeted agents still faces challenges such as acquired drug resistance, precise patient
selection, and serious adverse events.

Acquired resistance to FGFR inhibitors (infigratinib and Debio1347) has been observed in small sample
studies. After disease progression, subsequent biopsy and ctDNA sequencing results showed the emergence
of secondary mutations within the FGFR2 kinase domain . In preclinical models of iCCA, various FGFR
[93]
inhibitors exhibited different sensitivities to FGFR2 kinase domain mutations. Planned adjustment of the
use order of different FGFR inhibitors may play an important role in overcoming resistance to
[94]
themselves . There are two potential solutions to acquired resistance: one is to develop covalent inhibitors,
anti-FGFR monoclonal antibodies, and FGF ligand traps; the other is therapy combination or the
development of biparatopic compounds or antibodies.

Resistance to targeted mutation-based therapy has also been reported in various other malignancies. For
instance, resistance to IDH inhibitors is associated with the accumulation of 2-HG and has been observed in
[95]
acute myeloid leukemia and glioma . One study suggests that certain mutations occur at the interface of
IDH heterodimers and thus affect the binding of inhibitors . “Isoform switching” between IDH1 and
[96]
IDH2 subtypes has been reported as another mechanism to restore the activity of mutated IDH and to
produce 2-HG . Due to the lack of clinically relevant IDH mutation cell or animal models, the resistance
[97]
mechanisms caused by 2-HG restoration remain incompletely understood. A study on BRAF inhibitor
resistance shows that the dominated resistance mechanism results in ERK signaling not sensitive to RAF
inhibitors by upregulating RAF dimers in melanoma, while other mechanisms detour the tumor's
dependence on BRAF mutation . Therefore, the combined use with other targeted or immunotherapy
[98]
regimens may help break through the limitations of targeted monotherapy.