Biliary tract cancer (BTC) represents a formidable clinical challenge characterized by extensive genomic heterogeneity and a poor prognosis, primarily due to advanced stage diagnosis. Although systemic therapies, including chemotherapy, targeted therapies, and immune checkpoint inhibitors, have become the standard of care, their efficacy remains modest, and subsequent treatment options are limited. BTC management is further complicated by the inherent difficulty of obtaining high-quality tissue biopsies, impeding timely genomic profiling and subsequent therapeutic decision-making. Liquid biopsy has emerged as a minimally invasive alternative, facilitating comprehensive tumor characterization through circulating tumor cells, cell-free DNA, RNA, and proteins. These approaches hold promise for early detection, assessment of minimal residual disease, identification of actionable targets, and real-time monitoring of treatment response and resistance, thereby supporting precision oncology. Despite technical challenges such as limited sensitivity for structural variations, variability across platforms, and the need for standardized validation, liquid biopsy offers transformative potential in BTC. This review discusses current strategies, clinical applications, and future directions for integrating liquid biopsy into routine practice to improve survival and quality of life in patients with BTC.
Daeseong Kim, Nam Suk Sim, Seonjeong Woo, Min Hwan Kim, Choong-kun Lee, Seung Soo Hong, Sung Hyun Kim, Ho Kyoung Hwang, Chang Moo Kang, Woo Jung Lee, Jung Hyun Jo, Taek Chung, Sohyun Hwang, Beodeul Kang, Jung Sun Kim, Chang-Il Kwon, Sangwoo Kim, Hong Jae Chon, Chang Gon Kim, Young Nyun Park, Hye Jin Choi
Clin Mol Hepatol 2026;32(2):721-736. Published online December 26, 2025
Background/Aims Biliary tract cancer (BTC) is a rare malignancy with poor prognosis. We investigated genomic determinants of clinical benefit from gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC) in advanced BTC.
Methods Clinical and genomic data using TruSight Oncology 500 were analyzed from patients treated with GAP (N=198) or GC (N=89) as first-line therapy.
Results With a median follow-up of 33.0 months, GAP modestly improved progression-free survival (PFS) (hazard ratio [HR] 0.764; 95% confidence interval [CI] 0.591–0.989) without significant overall survival (OS) difference compared to GC. Genomic profiling revealed frequent alterations in TP53 (35.2%), KRAS (16.4%), SMAD4 (10.5%), and TNFRSF14 (10.5%), involving RTK/RAS (44.3%), TP53 (41.8%), and PI3K (20.2%) pathways. Single-gene mutations did not predict treatment benefit. However, pathway-level analysis identified PI3K pathway activation as significantly associated with inferior PFS (HR 2.148; 95% CI 1.478–3.124) and OS (HR 2.096; 95% CI 1.413–3.109) in patients receiving GAP, an effect not observed with GC. Importantly, GAP conferred clinical benefit only in patients without PI3K pathway activation, while no survival advantage was seen in those with such alterations (Pinteraction=0.023 for PFS, Pinteraction=0.003 for OS). Similar results were obtained in the independent validation cohort treated with GAP (N=103) or GC (N=64) for BTC.
Conclusions Genomic profiling using next-generation sequencing identified PI3K pathway activation as key molecular determinant that differentiates patient outcomes between GAP and GC treatments in advanced BTC.
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Systematic review and first meta-analysis of the efficacy and safety of gemcitabine-cisplatin combined with paclitaxel in patients with advanced biliary tract cancer Gang Zhu, Shenglan Li, Yan Zhang, Guoying Feng, Guangnian Zhang, Huanli Cheng, Bo Jiang, Benjian Gao, Xiaoli Yang, Bo Li European Journal of Clinical Pharmacology.2026;[Epub] CrossRef
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Clin Mol Hepatol 2026;32(1):258-275. Published online October 27, 2025
Background/Aims Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).
Methods We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.
Results Infiltrative morphology, encompassing pure and mixed forms, was present in 42.7% of advanced HCC and associated with advanced disease features and compromised liver function. Patients with type IV infiltrative HCC showed lowest objective response rate (14.6%) and worst progression-free (median, 2.8 months) and overall survival (median, 7.1 months). Infiltrative morphology remained an independent predictor of poor outcomes after multivariable adjustment for confounders, including intrahepatic tumor extent. Genomic profiling revealed enriched TP53 and ATM loss-of-function mutations in type IV infiltrative HCC. Transcriptomic and proteomic analyses identified consistent activation of tumor proliferation, epithelial-mesenchymal transition, TGF-β signaling, and immunosuppressive pathways in type IV infiltrative HCC. Type IV infiltrative signature was significantly associated with poor survival across external datasets and retained independent prognostic value.
Conclusions Infiltrative HCC is a clinically aggressive and molecularly distinct subtype of advanced HCC. Morphological classification and type IV infiltrative signatures may guide risk stratification and therapeutic decision-making in advanced HCC treated with immunotherapy.
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