Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize its use.Methods: We retrospectively analyzed BTC cases in Japan’s C-CAT (June 2019–January 2025), restricting panel comparisons to FoundationOne®CDx (F1; n = 5019) and FoundationOne®Liquid CDx (F1L; n = 1550). Missing covariates were handled by multiple imputations (m = 20). Between-panel balance used 1:1 propensity-score matching (caliper 0.2). Outcomes were modeled with logistic regression. Targets included MSI-H, TMB-H,FGFR2/RET/NTRKfusions,BRAFV600E,KRASG12C,IDH1mutations, andERBB2amplification. An exploratory analysis stratified results by the number of prespecified enrichment factors (0–4). Liquid biopsy was performed using plasma-based comprehensive genomic profiling assays (FoundationOne®Liquid).Results: Missingness was low; after matching (n = 1549 per group) covariates were well balanced (all|SMD|≤0.05). Detection of any actionable alteration was lower with F1L than F1 (16.8% vs. 24.8%; OR 0.61, 95% CI 0.49–0.75;p< 0.001). F1L also had lower TMB-H (OR 0.62, 0.43–0.90;p= 0.01) andERBB2amplification (OR 0.42, 0.31–0.57;p< 0.001), with no significant differences for MSI-H,IDH1,KRASG12C, orBRAFV600E. Within F1L, non-perihilar location (OR 2.05), liver (1.90), lymph-node (1.41), and lung metastases (1.52) predicted detection of actionable genomic alterations. F1L detection increased from 5.8% (zero factors) to 32.8% (four factors), approximating tissue at three factors.Conclusions: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate.
背景：基于血液的综合基因组分析（液体活检）在无法获取组织样本时，常被用于胆道癌的基因检测，但其检出率较低。本研究旨在探讨影响可操作基因组变异检出的相关因素，以优化其临床应用。 方法：我们回顾性分析了日本C-CAT数据库中（2019年6月至2025年1月）的胆道癌病例，将检测平台限定为FoundationOne®CDx（F1；n=5019）和FoundationOne®Liquid CDx（F1L；n=1550）。采用多重插补法（m=20）处理缺失协变量，通过1:1倾向评分匹配（卡钳值0.2）实现组间平衡，并使用逻辑回归模型分析结果。检测目标包括MSI-H、TMB-H、FGFR2/RET/NTRK融合、BRAF V600E、KRAS G12C、IDH1突变及ERBB2扩增。探索性分析根据预设富集因素数量（0-4个）进行分层。液体活检采用基于血浆的综合基因组分析检测（FoundationOne®Liquid）。 结果：数据缺失率较低；匹配后（每组n=1549）协变量平衡良好（所有|SMD|≤0.05）。F1L检测到任何可操作变异的比例低于F1（16.8% vs. 24.8%；OR 0.61，95% CI 0.49–0.75；p<0.001）。F1L在TMB-H（OR 0.62，0.43–0.90；p=0.01）和ERBB2扩增（OR 0.42，0.31–0.57；p<0.001）检出率更低，而在MSI-H、IDH1、KRAS G12C或BRAF V600E方面无显著差异。在F1L组内，非肝门部肿瘤位置（OR 2.05）、肝转移（1.90）、淋巴结转移（1.41）和肺转移（1.52）可预测可操作基因组变异的检出。F1L检出率从零因素时的5.8%提升至四因素时的32.8%，当存在三个富集因素时接近组织检测水平。 结论：通过基于提高检出率的条件审慎选择样本，可最大化液体活检的临床应用价值。
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