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Page 10 of 13 Kwee et al. Hepatoma Res 2021;7:8 I http://dx.doi.org/10.20517/2394-5079.2020.124

disease, satisfaction of radiographic criteria based on contrast-enhanced CT or MRI (LIRADS-5) confers
a positive predictive value of > 98% for the diagnosis of HCC, effectively alleviating the need for liver
[75]
biopsies to secure a tissue diagnosis . Unfortunately, this non-histopathologic approach to diagnosis
can impede clinical and research efforts to advance precision medicine for HCC, as it makes tumor
tissue unavailable for genetic testing or molecular profiling. Non-invasive diagnostic tools such as liquid
biopsy and molecular imaging have the potential to address this lack of molecular information. Clinical
development of such non-invasive methods for HCC for molecular-subclassification, risk-stratification, and
treatment selection share the promise of preserving and extending the non-invasive clinical diagnosis and
management approach pioneered in HCC.

SUMMARY AND CONCLUSION
Presently, there is a critical yet unmet need for biomarkers to predict immunotherapeutic response in HCC,
since objective clinical responses to the existing approved ICI agents occur in only a fraction of patients.
There is now a large body of evidence that associates Wnt/b-catenin activation with tumor immune
evasion and immunotherapeutic resistance. Recent work has also shown that it is feasible to assess the
Wnt/b-catenin activation status of malignant tumors non-invasively through liquid biopsy and possibly
molecular imaging. Further efforts along these lines to develop non-invasive assays of tumor Wnt/b-catenin
activation may have the potential to be fruitful in producing much-needed biomarkers for predicting
immunotherapeutic response in HCC. However, as with therapeutic agents, these biomarker tools will
require rigorous and thorough clinical testing along a well-planned series of clinical trial phases that begins
with the assessment of biomarker classification performance and ends with the measurement of clinical
impact.

DECLARATIONS
Authors’ contributions
Contributions to the conception, design, data analysis, interpretation, and writing of this article: Kwee SA,
Tiirikainen M

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by U.S. National Institutes of Health grants (R01CA161209-06, U54MD007584-07,
5P30CA071789), and Hawaii Legislative Act (265(19) HB654HD1SD1CD1).

Conflicts of interest
Both authors declared that there are no conflicts of interest. This work does not necessarily reflect the views
of the Queen’s Medical Center or its affiliates.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.