Molecularly Guided Therapy in HCC: Journal of Hepatology | March 2026

Introduction

Advanced primary liver cancers, including hepatocellular carcinoma and cholangiocarcinoma, remain difficult to treat once they become refractory to standard systemic therapies. Survival outcomes are poor, and therapeutic options are limited, particularly in heavily pretreated patients. With the growing understanding of tumor biology, comprehensive genomic profiling has emerged as a promising strategy to identify actionable molecular targets and guide personalized therapy, but its real-world clinical utility in liver cancers has remained uncertain.

Problem Statement

Although next-generation sequencing is increasingly used, standard panels often fail to detect a significant proportion of actionable alterations. Moreover, it is unclear whether identifying such alterations truly translates into meaningful clinical benefit, especially in patients who have already failed multiple lines of therapy.

Summary

This multicenter French initiative demonstrates that comprehensive genomic profiling using whole-genome, whole-exome, and RNA sequencing is feasible in advanced liver cancers and identifies actionable alterations in nearly two-thirds of patients. Importantly, this approach detects more targets than conventional sequencing panels. Matched targeted therapies based on ESCAT I–III alterations led to meaningful disease control in a subset of patients, particularly in cholangiocarcinoma and combined tumors, with significantly improved progression-free survival. In contrast, no benefit was observed when therapies were guided by lower-evidence ESCAT IV alterations. These findings highlight that the clinical value of precision oncology depends not only on identifying mutations but also on the level of evidence supporting their actionability. Early genomic profiling may allow better patient selection, preserve liver function, and expand access to effective targeted therapies in advanced hepatobiliary cancers.