The role of liquid biopsy in identifying circulating molecular predictors of response or resistance to systemic therapy in hepatocellular carcinoma

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Despite recent advantages regarding molecular knowledge of HCC and many novel systemic treatment options, the prognosis remains dismal. Specifically, druggable alterations are scarce and there are no biomarkers available to predict responsiveness or resistance to the many available systemic drugs (except serum alpha-fetoprotein (AFP) for ramucirumab). We have conducted a liquid biopsy study on patients with advanced HCC found that the mutation profile in circulating tumor DNA (ctDNA) of advanced HCC patients is similar to that in tissue of early stage patients undergoing resection. Our preliminary results suggest a primary resistance to sorafenib in patients with mutations in the PI3K-MTOR pathway resulting in shorter progression-free survival. Another study has suggested an association between Wnt pathway activation and resistance to PD-1 inhibitors in vivo. Therefore, we hypothesize that detection of specific pathway alterations, e.g. in the PI3K-MTOR pathway or Wnt/beta-catenin pathway, in ctDNA is capable to predict resistance to tyrosine kinase or checkpoint inhibitors, respectively.Ultimately, this translational research project aims to improve core problems in HCC management and disease monitoring by establishing the role of liquid biopsy in the clinical management of HCC patients, specifically by incorporating molecular findings derived from sequential sampling of circulating tumor DNA (ctDNA) with clinical endpoints of patients. Specifically, we will use state-of-the-art liquid biopsy technologies to tackle two crucial questions in the clinical management of HCC: How can patients who respond to or resist systemic therapies be identified and what are the drivers of primary and acquired resistance. The successful execution of this project will yield a comprehensive set of liquid biopsy biomarkers to be tested in prospective registration clinical trials for the prediction of response to systemic therapy. The project has the potential to redefine the model that guides decision-making in HCC, particularly in the area of allocation to systemic therapies, which currently relies on cross-sectional imaging and serum levels of AFP and lacks molecular biomarkers for effective treatment allocation. Furthermore, this project will provide novel molecular findings at the time of resistance that are useful for the development of future therapeutic approaches. The obvious advantage of using liquid biopsy over conventional tissue biopsies to address these questions are manifold (minimally invasive blood draw, sequential applications and longitudinal sampling, capture of tumor heterogeneity). This facilitates the implementation of biomarker-based clinical trials and overcome limited accessibility to tissue of advanced patients, a clear unmet need in HCC research. Overcoming tumor heterogeneity is of particular interest in advanced stages with large tumor burden, multiple nodules and metastatic spread.