Hwang Sohyun, Woo Seonjeong, Kang Beodeul, Kang Haeyoun, Kim Jung Sun, Lee Sung Hwan, Kwon Chang Il, Kyung Dong Soo, Kim Hwang-Phill, Kim Gwangil, Kim Chan, Chon Hong Jae
Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.
Department of Biomedical Science, CHA University, Seongnam, Republic of Korea.
J Hepatol. 2025 Apr;82(4):649-657. doi: 10.1016/j.jhep.2024.10.020. Epub 2024 Oct 21.
BACKGROUND & AIMS: Recent advances in molecular profiling have enabled the identification of potential therapeutic targets for biliary tract cancer (BTC). However, in patients with BTC, molecular profiling is hindered by challenges in obtaining adequate tissue samples. Circulating tumor DNA (ctDNA) may offer an alternative to tissue-based analysis. Herein, we aimed to assess the concordance between ctDNA and tissue genomic profiling in a large cohort of Asian patients with advanced BTC, and to evaluate the feasibility of liquid biopsy in BTC treatment.
This study included patients with systemic treatment-naive advanced BTC, treated at CHA Bundang Medical Center between January 2019 and December 2022. We enrolled patients with available baseline tissue-based next-generation sequencing, and sufficient plasma samples for ctDNA analysis (AlphaLiquid®100 from IMBdx).
Among 102 enrolled patients, 49.0% had intrahepatic cholangiocarcinoma, 26.5% extrahepatic cholangiocarcinoma, and 24.5% gallbladder cancer. The concordance between intra-patient ctDNA and tumor tissue mutations revealed a sensitivity of 84.8%, and positive predictive value of 79.4%. ctDNA revealed targetable alterations in 34.3% of patients - including FGFR2 fusions, IDH1 mutations, microsatellite instability-high, ERBB2 amplifications, PIK3CA mutations, BRCA1/2 mutations, and MET amplifications. Notably, a novel FGFR2-TNS1 fusion was identified in ctDNA, which was not targeted in the tissue NGS panel. A high maximum somatic variant allele frequency in ctDNA was associated with poor prognosis after gemcitabine/cisplatin-based chemotherapy, in terms of both overall survival (p = 6.9 × 10) and progression-free survival (p = 3.8 × 10).
Among patients with advanced BTC, ctDNA-based genotyping showed acceptable concordance with tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable complement to tissue-based genomic analysis in BTC.
Our study is the first large-scale investigation of the clinical utility of liquid biopsy, focusing on circulating tumor DNA (ctDNA), as an alternative to conventional tumor tissue analysis, among Asian patients with advanced biliary tract cancer. The results demonstrated acceptable concordance between analysis of ctDNA vs. tissue for identifying therapeutic targets and potentially actionable genetic alterations. This indicates that ctDNA analysis can provide critical insights regarding advanced biliary tract cancer treatment, particularly in cases where it is challenging to obtain or analyze tumor tissue.
分子谱分析的最新进展使得能够识别胆管癌（BTC）的潜在治疗靶点。然而，对于BTC患者，获取足够的组织样本存在挑战，这阻碍了分子谱分析。循环肿瘤DNA（ctDNA）可能为基于组织的分析提供一种替代方法。在此，我们旨在评估一大群亚洲晚期BTC患者中ctDNA与组织基因组谱分析之间的一致性，并评估液体活检在BTC治疗中的可行性。
本研究纳入了2019年1月至2022年12月期间在CHA盆唐医疗中心接受治疗、未接受过全身治疗的晚期BTC患者。我们纳入了有可用的基于基线组织的下一代测序数据，以及足够用于ctDNA分析的血浆样本（来自IMBdx的AlphaLiquid®100）的患者。
在102名纳入的患者中，49.0%患有肝内胆管癌，26.5%患有肝外胆管癌，24.5%患有胆囊癌。患者体内ctDNA与肿瘤组织突变之间的一致性显示敏感性为84.8%，阳性预测值为79.4%。ctDNA在34.3%的患者中显示出可靶向改变，包括FGFR2融合、IDH1突变、微卫星高度不稳定、ERBB2扩增、PIK3CA突变、BRCA1/2突变和MET扩增。值得注意的是，在ctDNA中鉴定出一种新的FGFR2 - TNS1融合，其在组织NGS检测板中未被靶向。就总生存期（p = 6.9×10）和无进展生存期（p = 3.8×10）而言，ctDNA中高的最大体细胞变异等位基因频率与基于吉西他滨/顺铂的化疗后的不良预后相关。
在晚期BTC患者中，基于ctDNA的基因分型与组织基因组谱分析显示出可接受的一致性。使用ctDNA进行液体活检可能是BTC中基于组织的基因组分析的有价值补充。
我们的研究是首次大规模调查液体活检（聚焦于循环肿瘤DNA（ctDNA））作为亚洲晚期胆管癌患者传统肿瘤组织分析替代方法的临床实用性。结果表明，在识别治疗靶点和潜在可操作的基因改变方面，ctDNA分析与组织分析之间具有可接受的一致性。这表明ctDNA分析可为晚期胆管癌治疗提供关键见解，特别是在获取或分析肿瘤组织具有挑战性的情况下。
