Molecularly guided therapies for advanced primary liver cancers refractory to systemic treatment: Results from the 2025 French genomic medicine initiative.

Advanced primary liver cancers remain difficult to treat after failure of first-line therapy. The 2025 French Genomic Medicine Initiative aimed to identify actionable targets for personalized treatment. Patients with PLC progressing on systemic therapy were enrolled across eight centers. Tumor and blood samples were analyzed using whole-genome, whole-exome, and RNA sequencing to identify targetable alterations classified according to the ESCAT scale. Genomic results and potential therapies were reviewed by a molecular tumor board. A total of 120 patients were enrolled: 80 with hepatocellular carcinoma (HCC), 25 with cholangiocarcinoma (CCA), 9 with combined hepatocellular-cholagiocarcinoma (cHCC-CCA), 4 with fibrolamellar carcinoma, 1 with hepatic sarcoma, and 1 with hepatic epithelioid hemangioendothelioma (HEHE). Recurrent genomic alterations included TP53 (46%), TERT (44%), and CTNNB1 (20%) in HCC; TP53 (55%), ARID1A (20%), and BAP1 in CCA; and TP53 (67%), PIK3CA (22%), and ARID2 (11%) in cHCC-CCA. Among 103 interpretable genomes, 67 patients harbored at least one actionable alteration (HCC: 59%, CCA: 80%, cHCC-CCA: 78%). Thirty-one patients (22 HCC, 5 CCA, 3 cHCC-CCA, 1 HEHE, 1 hepatic sarcoma) received matched therapies: 1 ESCAT I, 2 ESCAT II, 21 ESCAT III, and 7 ESCAT IV. These patients had received prior systemic therapy, including ≥2 lines in 69% of cases. Disease control (DC; radiological response/stable disease) was achieved in 10 of 31 patients (32.3%), including 23% of HCC, 75% of CCA, and 67% of cHCC-CCA cases. DC was observed exclusively in patients treated for ESCAT I-III alterations (41.7%), with no clinical benefit in those treated for ESCAT IV alterations. Median progression-free survival was significantly longer in patients achieving DC compared with those with progressive disease (11.8 vs. 2.4 months; p = 0.009). Comprehensive genomic profiling in advanced PLC refractory to systemic treatment is feasible and associated with DC in a subset of pretreated patients with ESCAT I/II/III alterations. Our research demonstrates that comprehensive genomic profiling through the French Genomic Medicine 2025 (FGM2025) initiative is feasible and clinically impactful in advanced primary liver cancers, including rare subtypes. By integrating whole-genome, whole-exome, and RNA sequencing, actionable genomic alterations were identified in nearly two-thirds of patients - well beyond the reach of standard next-generation sequencing panels. These findings provide a strong rationale for implementing early, broad molecular profiling to optimize therapeutic matching, preserve liver function, and expand access to precision medicine. Ultimately, our work highlights the transformative potential of genomics-guided strategies in improving clinical outcomes and advancing personalized care for patients with hepatobiliary malignancies.