Factors Associated with the Detection of Actionable Genomic Alterations Using Liquid Biopsy in Biliary Tract Cancer

<b>Background</b>: 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. <b>Methods</b>: 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, <i>FGFR2</i>/<i>RET</i>/<i>NTRK</i> fusions, <i>BRAF</i> V600E, <i>KRAS</i> G12C, <i>IDH1</i> mutations, and <i>ERBB2</i> amplification. 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). <b>Results</b>: 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; <i>p</i> < 0.001). F1L also had lower TMB-H (OR 0.62, 0.43-0.90; <i>p</i> = 0.01) and <i>ERBB2</i> amplification (OR 0.42, 0.31-0.57; <i>p</i> < 0.001), with no significant differences for MSI-H, <i>IDH1</i>, <i>KRAS</i> G12C, or <i>BRAF</i> V600E. 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. <b>Conclusions</b>: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate.