《法国医药基因组计划2025》允许对于对系统治疗无效的癌症进行基因组分析，以获得适合基因改变的非标签治疗方案。我们在晚期肝细胞癌（HCC）和肝胆管癌（H-CCK）中报告了结果。在一个中心，所有在阿替珠单抗/贝伐珠单抗治疗下疾病进展的HCC或H-CCK患者，如果有可用的肿瘤冷冻样本，就会接受全基因组/外显子/RNA测序。根据分子肿瘤委员会的建议，将靶向治疗与基因改变相匹配，并评估放射学反应和总生存情况。在接受阿替珠单抗/贝伐珠单抗治疗的135名HCC和H-CCK患者中，20名患者在进展后受益于基因组分析（16例HCC；4例H-CCK）。有19名患者有可分析的数据，70％为男性，中位年龄57岁，65％有转移性疾病，45％有血管侵犯。在这19名患者中，14名患者（76％）至少携带一种可操作基因改变，其中9/14接受了适应的靶向治疗（45％）。一名H-CCK患者发现有CDK4扩增，在接受帕博西尼治疗期间出现了部分放射学反应，持续16个月。另一名H-CCK患者发现高HER2过表达和高同源重组得分，在接受曲妥珠单抗/奥拉帕尼治疗期间病情稳定。一名患有HCC的患者发现TSC2基因双等位基因失活，导致基因表达受到抑制，接受依维莫司治疗后出现完全放射学反应。剩下的六名接受治疗的患者（6例HCC）病情进展，其中三例接受曲美替尼治疗，两例接受依维莫司治疗，一例接受奥拉帕尼治疗。分子引导治疗在阿替珠单抗/贝伐珠单抗治疗下进展的HCC/H-CCK患者中是可行的，并可能在少数患者中有用。全基因组/外显子和RNA测序在HCC和H-CCK患者的临床实践中尚未有报告。在此，我们提供了一项初步研究，表明全基因组/外显子RNA测序可行于对阿替珠单抗/贝伐珠单抗无效的肿瘤活检样本中，少数患者中发现至少一种可操作的基因改变，并接受了适应的靶向治疗。这是一项概念验证研究，表明少数患者可以从这种策略中获得临床益处。最后，这种方法需要在一个更大的患者群中进行验证。版权所有©2023年欧洲肝脏研究学会。由Elsevier B.V.出版。保留所有权利。

The "French Medicine Genomic program 2025" allows to genomic analysis in cancer refractory to systemic treatments to give access to off-labeled therapies adapted to genomic alterations. We reported results in advanced hepatocellular carcinoma (HCC) and hepato-cholangiocarcinoma (H-CCK).In one center, all patients with HCC or H-CCK who progressed under atezolizumab/bevacizumab with available tumor frozen samples benefited from whole-genome/exome/RNA sequencing. Targeted therapies were matched to the genomic alterations following recommendation of a molecular tumor board and radiological response and overall survival were assessed.Among 135 patients with HCC and H-CCK treated by atezolizumab/bevacizumab, twenty patients benefited from genomic analysis after progression (16 HCC; 4 H-CCK). 19 patients had analyzable data, 70% were male, median age was 57 years, 65% had metastatic disease and 45% had vascular invasion. Among these 19 patients, 14 patients (76%) harbored at least one actionable genomic alteration and 9/14 received an adapted targeted therapy (45%). One patient with H-CCK showing CDK4 amplification was treated by palbociclib with a partial radiological response during 16 months. Another patient with H-CCK, a high HER2 overexpression and a high homologous recombination score was treated by trastuzumab/olaparib and had a stable disease. One patient with an HCC and biallelic inactivation of TSC2 silencing its gene expression, harbored a complete radiological response under everolimus. The remaining six treated patients (6 HCC) harbored a progressive disease including three patients treated by trametinib, two by everolimus and one by olaparib.Molecular-based guided therapy is feasible in patients with HCC/H-CCK progressing under atezolizumab/bevacizumab and may be useful in a small subset of patients.Whole genome/exome and RNA sequencing in clinical practice have never been previously reported in patients with HCC and H-CCK. Herein, we provided a pilot study suggesting that Whole genome/exome RNA sequencing is feasible on tumor biopsy in patients refractory to atezolizumab/bevacizumab with a small subset of the patients with at least one actionable genomic alteration and who received an adapted targeted therapy. This is a proof-of-concept study suggesting that a small subset of patients have a clinical benefit from this strategy. Finally, validation of this approach will be required in a larger cohort of patients.Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.