Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide and its incidence is
rising in both men and women in the United States. Anti-PD1 and anti-PD-L1 immune checkpoint inhibitor (ICI)
antibodies are now FDA approved for advanced HCC, however, as few as 20% of patients receiving these agents
will show an objective response to therapy. Because immune-related adverse events are non-trivial, predictive
biomarkers that can explain the variability in immunotherapy response are needed to optimize patient selection.
Several lines of research have recently converged to associate oncogenic activation of the Wnt/beta-
catenin signaling pathway with tumor immune-evasion and poor clinical response to ICI therapy in HCC. In
previous research, we found that HCC exhibiting high uptake of the positron emission tomography / computed
tomography (PET/CT) imaging agent 18F- fluorocholine (FCH) often belonged to molecular tumor sub-types
associated with beta-catenin activation and immune avoidance. Liquid biopsy based on targeted sequencing of
cell-free DNA (cfDNA) has also made it possible to identify patients who have tumors that harbor mutations
associated with increased Wnt/beta-catenin signaling.
This project comprises a phase 2 biomarker clinical trial to prospectively evaluate these specific
embodiments of PET/CT and liquid biopsy as tools for detecting HCC recalcitrant to ICI therapy on the basis of
beta-catenin activation. In addition to characterizing and comparing the predictive capabilities of FCH PET/CT
and cfDNA mutation profiling based on phase 2 clinical endpoints, this project will utilize decision tree based
machine learning to estimate the predictive performance of an integrative imaging-genomic biomarker while also
further examining how tumor mutations are related to PET metabolic phenotype and immunotherapy response.
Furthermore, because tumor 18F-fluorodeoxyglucose (FDG) uptake is incongruent with FCH uptake in HCC, a
third aim will utilize the trial as a molecular screening process to create an enriched sub-cohort of patients with
FDG-avid tumors. These patients will undergo serial FDG PET/CT to evaluate FDG as a source of predictive
biomarkers of ICI response for an orthogonal molecular sub-type of HCC. If these diagnostic tests are found
reliable at predicting tumor resistance/response, they could significantly enhance the clinical precision and
overall benefit of immunotherapy for HCC and possibly other cancers.