"Liquid Biopsy" in Liver Cancer

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Liver cancer is the second cause of cancer-related death worldwide. Regarding decision-making and staging, Clinical Practice Guidelines (CPG) only rely on clinical and / or pathological parameters encapsulated in the Barcelona Clinic for Liver Cancer (BCLC) algorithm, but do not incorporate any biological, e.g. molecular, readout of the tumor. There are still clinical situations where prognosis is not accurately captured by current algorithms such as preoperative identification of tumor recurrence after surgery, and prediction of treatment response to systemic therapy. The genetic landscape of hepatocellular carcinoma (HCC) has been uncovered over the last decade, including point somatic mutations, chromosomal rearrangements and gene expression de-regulation. In addition, recent evidence suggests a significant molecular heterogeneity within HCC, which may limit molecular information derived from a single tissue biopsy. The concept of “liquid biopsy” was developed to facilitate the collection of molecular information from the tumor, and to capture the entire landscape of alterations present in heterogeneous samples. Liquid biopsy comprise the isolation and analysis of tumor by-products, mainly cell-free nucleic acids and circulating tumor cells (CTC), released to the bloodstream and easily accessible in peripheral blood. Even more interesting than a baseline snapshot of the molecular landscape of cancer, circulating biomarkers allow for a sequential evaluation of tumor genetics as the disease evolves and when the patient is exposed to different medical interventions. Coupled with the analysis of baseline genome aberrations, circulating nucleic acids will be an unparalleled tool to easily and non-invasively monitor the course of cancer in clinical practice.The overall objective of this two-year translational research initiative is to solve core problems in liver cancer management by defining the prognostic / predictive role of circulating molecular biomarkers. Blood samples have already been collected from 165 HCC patients (25 with paired tissue) at different stages of disease and treatment, including sequential collection in the same patient. Using latest genomic methodologies (e.g. deep-sequencing, coupled FACS sorting and single-cell sequencing), we will assess a) somatic mutations in a subset of high-frequency mutated genes in plasmatic DNA, b) RNA expression profiles and c) CTC in HCC patients. We will also correlate molecular plasmatic data with paired tissue in those patients with both components available. Circulating markers will be assessed along other clinical variables to maximize the accuracy of outcome prediction in HCC (i.e., tumor recurrence and overall survival). Ultimately, our aim is to provide the scientific ground to implement molecular monitoring in decision-making for liver cancer patients.