Precision Genomics in Refractory PLC : J Hepatol | May 2026

Introduction

Advanced Hepatocellular Carcinoma, Cholangiocarcinoma and rare primary liver cancers remain therapeutically challenging after progression on standard systemic therapy. Conventional targeted next-generation sequencing panels identify actionable alterations in only a minority of patients, particularly outside biliary tract cancers. This multicenter French Genomic Medicine 2025 (FMG2025) initiative evaluated whether comprehensive molecular profiling using whole-genome sequencing (WGS), whole-exome sequencing (WES) and RNA sequencing could expand precision oncology opportunities in advanced primary liver cancers.

Problem Statement

Precision medicine approaches in primary liver cancers are limited by inadequate genomic characterization, delayed profiling and restricted access to actionable biomarkers beyond standard panels. The clinical utility of broad genomic sequencing in refractory liver cancers, especially HCC and rare histologies, remains insufficiently defined.

Summary

This nationwide French initiative enrolled 120 patients with advanced or refractory primary liver cancers across eight tertiary centers. The cohort included HCC, cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and rare tumors such as fibrolamellar carcinoma and hepatic epithelioid hemangioendothelioma. Comprehensive genomic profiling was successfully completed in 86% of tumors using integrated WGS, WES and RNA sequencing.

Actionable molecular alterations were identified in 65% of patients, substantially exceeding the yield achievable with standard targeted sequencing panels. Common alterations included TP53, TERT and CTNNB1 in HCC, while cholangiocarcinoma demonstrated frequent TP53, ARID1A, BAP1 and FGFR2 alterations. cHCC-CCA displayed hybrid genomic signatures involving TP53 and PI3K pathway abnormalities. RNA sequencing added clinically meaningful information through identification of oncogenic pathway activation, immune-related transcriptomic signatures and fusion transcripts.

Among 67 patients with actionable alterations, 31 ultimately received genomically matched therapies, predominantly directed against ESCAT II–III targets involving FGFR, MET, ERBB2, PI3K–AKT–mTOR, homologous recombination deficiency and cell-cycle pathways. Disease control was achieved in 32.3% overall and exclusively occurred in patients treated for ESCAT I–III alterations, while ESCAT IV-directed therapies failed to demonstrate clinical benefit. Disease control rates were particularly notable in cholangiocarcinoma and cHCC-CCA. Median progression-free survival was significantly longer in responders compared with non-responders (11.8 vs 2.4 months).

The study also highlighted important translational insights. Whole-genome analysis identified mutational signatures linked to aflatoxin exposure and aristolochic acid carcinogenesis, while germline cancer-predisposition variants were detected in 5% of patients. Importantly, many patients could not receive matched therapies because of progressive liver failure or clinical deterioration before genomic results became available, emphasizing the need for earlier molecular profiling in liver cancers.

Overall, this landmark real-world study demonstrates that broad genomic profiling in advanced primary liver cancers is feasible and clinically relevant, particularly for identifying therapeutically actionable ESCAT II–III alterations beyond standard sequencing panels. The findings support earlier integration of comprehensive molecular profiling into hepatobiliary oncology workflows and reinforce the emerging role of precision oncology in advanced liver cancers.