Liquid biopsy in hepatobiliary and pancreatic cancers: A paradigm shift in early detection, prognostic stratification, and perioperative monitoring

Table 1 Role of liquid biopsy in early detection of cancers

No.	Title of study	Ref.	Conclusion of study
1	A preliminary study of the clinical significance of folate receptor-positive CTC in the management of hepatobiliary-pancreatic cancers	He et al[2], 2020	Suggests that folate receptor-positive CTCs could serve as a potential biomarker for diagnosing and monitoring hepatobiliary-pancreatic cancers
2	Profiling tumor heterogeneity through circulating tumor DNA in patients with pancreatic cancer	Adamo et al[11], 2017	Suggests that circulating tumor DNA (ctDNA) analysis can reveal tumor heterogeneity in pancreatic cancer, aiding in personalized treatment strategies
3	A noninvasive urinary microRNA-based assay for the detection of pancreatic cancer from early to late stages: A case control study	Baba et al[12], 2024	Demonstrates that a urinary microRNA-based assay can detect pancreatic cancer across different stages, offering a noninvasive diagnostic tool
4	Cell-free DNA testing for early HCC surveillance	Chen et al[13], 2024	Highlights the potential of cell-free DNA testing for early HCC detection, suggesting its role in surveillance programs
5	Cancer type classification using plasma cell-free RNAs derived from human and microbes	Chen et al[14], 2022	Shows that plasma-derived cell-free RNAs from both human and microbial sources can aid in cancer type classification
6	Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers	Cohen et al[15], 2017	Suggests that integrating ctDNA and protein biomarkers improves early detection of pancreatic cancer
7	CTCs in HCC: A comprehensive review and critical appraisal	Espejo-Cruz et al[1], 2021	Discusses the role of CTCs in HCC diagnosis, prognosis, and therapy. Highlights the need for further research on CTC detection techniques
8	Multi-omics analysis revealed the role of extracellular vesicles in hepatobiliary & pancreatic tumor	Gongye et al[16], 2022	Identifies extracellular vesicles as key players in hepatobiliary and pancreatic cancer progression using multi-omics analysis
9	Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumor DNA methylation: A multicenter cohort study	Guo et al[17], 2024	Supports ctDNA methylation analysis as a promising tool for early HCC detection and prognosis evaluation
10	Liquid biopsy from bile-circulating tumor DNA in patients with biliary tract cancer	Han et al[18], 2021	Suggests that bile-based liquid biopsy can help in diagnosing and monitoring biliary tract cancer
11	Application of liquid biopsy in early screening and recurrence prediction of HCC	Hao et al[19], 2022	Discusses the role of liquid biopsy in early detection and recurrence prediction in HCC patients
12	Molecular diagnosis of pancreatobiliary tract cancer by detecting mutations and methylation changes in bile samples	He et al[3], 2023	Demonstrates the utility of bile-based molecular diagnosis for pancreatobiliary cancers, suggesting it could improve early detection and treatment
13	Deciphering extracellular vesicles protein cargo in pancreatic cancer	Hong et al[20], 2024	Highlights the role of extracellular vesicle proteins in pancreatic cancer progression and their potential as biomarkers
14	Emerging biomolecules for practical theranostics of liver HCC	Hu et al[21], 2023	Reviews novel biomolecules for theranostics in HCC, emphasizing their potential for diagnosis and targeted therapy
15	Liquid biopsy using cell-free DNA in the early diagnosis of HCC	Hu et al[22], 2023	Supports cfDNA as a noninvasive approach for early HCC detection, highlighting its diagnostic accuracy
16	Tumor-Specific miRNA signatures in combination with CA19-9 for liquid biopsy-based detection of PDAC	Kim et al[23], 2021	Suggests that miRNA signatures combined with CA19-9 improve PDAC detection using liquid biopsy
17	A biocomposite-based rapid sampling assay for circulating cell-free DNA in liquid biopsy samples from human cancers	Koo et al[24], 2020	Introduces a novel biocomposite assay for efficient cfDNA isolation, enhancing liquid biopsy applications
18	Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma	Lapitz et al[25], 2023	Identifies protein biomarkers from liquid biopsy for early detection and prognosis of cholangiocarcinoma
19	Clinical applications of liquid biopsy as prognostic and predictive biomarkers in HCC: CTC and circulating tumor DNA	Li et al[26], 2018	Reviews the prognostic value of CTCs and ctDNA in HCC, highlighting their clinical applications
20	A novel PiRNA enhances CA19-9 sensitivity for pancreatic cancer identification by liquid biopsy	Li et al[27], 2022	Suggests a novel piRNA that enhances CA19-9 sensitivity, improving pancreatic cancer detection via liquid biopsy
21	Enrichment of short mutant cell-free DNA fragments enhanced detection of pancreatic cancer	Liu et al[28], 2019	Demonstrates that short mutant cfDNA fragments improve pancreatic cancer detection accuracy
22	The value of CTC in the prognosis and treatment of pancreatic cancer	Luo et al[29], 2022	Highlights CTCs as potential prognostic and treatment monitoring biomarkers in pancreatic cancer
23	The efficacy of bile liquid biopsy in the diagnosis and treatment of biliary tract cancer	Miura et al[30], 2024	Supports bile liquid biopsy as a promising tool for diagnosing and managing biliary tract cancer
24	An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study	Nakamura et al[31], 2022	Identifies an exosome-derived transcriptomic signature for noninvasive early detection of PDAC
25	A comprehensive evaluation of full-spectrum cell-free RNAs highlights cell-free RNA fragments for early-stage hepatocellular carcinoma detection	Ning et al[32], 2023	Demonstrates that cfRNA fragments can improve early HCC detection, expanding the utility of liquid biopsy
26	Detection of early-stage HCC in asymptomatic HBsAg-seropositive individuals by liquid biopsy	Qu et al[33], 2019	Supports liquid biopsy for early HCC detection in high-risk asymptomatic HBV-infected individuals
27	Molecular pathology and protein markers for pancreatic cancer: Relevance in staging, in adjuvant therapy, in determination of minimal residual disease, and follow-up	Sok et al[34], 2024	Discusses molecular pathology and protein markers as key tools for pancreatic cancer staging and monitoring
28	Synergistic effects of extracellular vesicle phenotyping and AFP in hepatobiliary cancer differentiation	Urban et al[35], 2020	Suggests that extracellular vesicle profiling combined with AFP improves hepatobiliary cancer differentiation
29	Proteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of HCC	Xing et al[36], 2023	Identifies serum protein panels as potential noninvasive biomarkers for early HCC diagnosis
30	Detection of a novel panel of somatic mutations in plasma cell-free DNA and its diagnostic value in HCC	Xiong et al[37], 2019	Proposes a novel somatic mutation panel in cfDNA for improving HCC diagnosis
31	A Circulating panel of circRNA biomarkers for the noninvasive and early detection of pancreatic ductal adenocarcinoma	Xu et al[38], 2024	Suggests circRNA panels as potential noninvasive biomarkers for early detection of PDAC
32	Liquid biopsy in pancreatic cancer: The beginning of a new era	Yadav et al[39], 2018	Reviews the role of liquid biopsy in pancreatic cancer management, emphasizing its growing clinical significance
33	Advances in the detection of pancreatic cancer through liquid biopsy	Yan et al[40], 2021	Summarizes advances in pancreatic cancer detection using liquid biopsy, highlighting key biomarkers and techniques
34	Liquid biopsy in HCC: CTC and circulating tumor DNA	Ye et al[41], 2019	Reviews the roles of CTCs and ctDNA in HCC, emphasizing their diagnostic and prognostic potential
35	Transcriptomic signature of 3D hierarchical porous chip enriched exosomes for early detection and progression monitoring of HCC	Yi et al[42], 2024	Suggests that exosome-based transcriptomic signatures can enable early detection and monitoring of HCC
36	Tidal microfluidic chip-based isolation and transcriptomic profiling of plasma extracellular vesicles for clinical monitoring of high-risk patients with hepatocellular carcinoma-associated precursors	Yi et al[43], 2025	Introduces a novel microfluidic chip-based method for isolating extracellular vesicles, improving HCC monitoring
37	O-Glycan-Altered extracellular vesicles: A specific serum marker elevated in pancreatic cancer	Yokose et al[44], 2020	Identifies O-glycan-altered extracellular vesicles as a specific serum biomarker for pancreatic cancer detection
38	Circulating cell-free DNA methylation-based multi-omics analysis allows early diagnosis of pancreatic ductal adenocarcinoma	Zhao et al[45], 2024	Supports cfDNA methylation analysis as an effective early diagnostic tool for PDAC
39	Biomarkers in liquid biopsies for prediction of early liver metastases in pancreatic cancer	Mehdorn et al[46], 2022	Suggests liquid biopsy biomarkers as predictors of early liver metastases in pancreatic cancer patients
40	Cell-free DNA from metastatic pancreatic neuroendocrine tumor patients contains tumor-specific mutations and copy number variations	Boons et al[47], 2018	Finds tumor-specific mutations and CNVs in cfDNA of metastatic pancreatic neuroendocrine tumor patients, supporting its use in diagnosis and monitoring
41	Circulating tumor DNA as a predictive marker for occult metastases in pancreatic cancer patients with radiographically non-metastatic disease	Hata et al[48], 2021	Suggests that ctDNA can serve as a predictive marker for occult metastases in pancreatic cancer
42	Tumor-educated platelet RNA and circulating free RNA: Emerging liquid biopsy markers for different tumor types	Hu et al[49], 2024	Reviews tumor-educated platelet RNA and cfRNA as emerging biomarkers for various cancer types
43	Clinical significance of circulating-tumor DNA analysis by metastatic sites in pancreatic cancer	Umemoto et al[50], 2023	Demonstrates that ctDNA analysis varies by metastatic site, offering insights into pancreatic cancer progression

CTC: Circulating tumor cells; ctDNA: Circulating tumor DNA; HCC: Hepatocellular carcinoma; RNA: Ribonucleic acid; DNA: Deoxyribonucleic acid; cfDNA: Cell free DNA; cfRNA: Cell free RNA; piRNA: Piwi-interacting RNAs; CA19-9: Carbohydrate antigen 19-9; PDAC: Pancreatic duct adenocarcinoma; CNV: Copy number variation.

Table 2 Role of liquid biopsy in tumor profiling

No.	Title of study	Ref.	Conclusion of study
1	The growing role of precision and personalized medicine for cancer treatment	Krzyszczyk et al[51], 2018	Highlights advancements in precision medicine and its role in tailoring cancer treatments based on genetic and molecular markers
2	CTC as liquid biomarker for high HCC recurrence risk after curative liver resection	von Felden et al[52], 2017	Suggests that CTCs can serve as a prognostic biomarker for high recurrence risk in HCC patients after liver resection
3	Precision medicine of hepatobiliary and pancreatic cancers: Focusing on clinical trial outcomes	Tsumura et al[53], 2022	Reviews the role of precision medicine in hepatobiliary and pancreatic cancers, emphasizing clinical trial findings
4	Bile liquid biopsy in biliary tract cancer	Liu et al[54], 2023	Supports the use of bile liquid biopsy for diagnosing and monitoring biliary tract cancer
5	Bile cellfree DNA as a novel and powerful liquid biopsy for detecting somatic variants in biliary tract cancer	Shen et al[55], 2019	Demonstrates that bile cfDNA can detect somatic mutations, aiding in the diagnosis of biliary tract cancer

CTC: Circulating Tumor Cells; HCC – Hepatocellular carcinoma; cfDNA: Cell free DNA.

Table 3 Role of liquid biopsy in risk stratification

No.	Title of study	Ref.	Conclusion of study
1	TP53 mutation detected in circulating exosomal DNA is associated with prognosis of patients with hepatocellular carcinoma	Li et al[56], 2022	Identifies TP53 mutation in exosomal DNA as a prognostic marker for HCC
2	Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now?	Pelizzaro et al[57], 2021	Reviews current advancements and challenges in liquid biopsy for HCC
3	Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients with Hepatocellular Carcinoma	Qi et al[58], 2018	Shows that EMT markers in CTCs can aid in HCC diagnosis and prognosis
4	Diagnostic and prognostic value of circulating exosomal glypican-1 in pancreatic cancer: A meta-analysis	Qiao et al[59], 2024	Supports exosomal glypican-1 as a valuable biomarker for pancreatic cancer detection and prognosis
5	Clinical significance of small extracellular vesicles in cholangiocarcinoma	Wang et al[60], 2024	Highlights the role of small extracellular vesicles as potential biomarkers for cholangiocarcinoma
6	Liquid biopsy techniques and pancreatic cancer: Diagnosis, monitoring, and evaluation	Wang et al[61], 2023	Reviews liquid biopsy techniques for pancreatic cancer diagnosis, treatment monitoring, and prognosis evaluation
7	Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma	Zhang et al[62], 2024	Identifies biomarkers and prognostic factors influencing response to PD-1/PD-L1 inhibitors in advanced HCC
8	Tumor-derived proliferative CTCs and CTC clusters predict aggressiveness and early recurrence in hepatocellular carcinoma patients	Zhao et al[63], 2023	Suggests that proliferative CTCs and CTC clusters are predictive markers for aggressive HCC and early recurrence

Tp53: Tumor protein 53; HCC: Hepatocellular carcinoma; EMT: Epithelial mesenchymal transition; CTC: Circulating tumor cells; PD-1/PD-L1: Programmed death 1/programmed death ligand 1.

Table 4 Role of liquid biopsy in target therapies

No.	Title of study	Ref.	Conclusion of study
1	The role and potential application of extracellular vesicles in liver cancer	Qi et al[64], 2021	Highlights extracellular vesicles as potential biomarkers and therapeutic targets in liver cancer
2	Bile exosomal miR-182/183-5p increases cholangiocarcinoma stemness and progression by targeting HPGD and increasing PGE2 generation	Shu et al[65], 2024	Demonstrates that bile exosomal miR-182/183-5p contributes to cholangiocarcinoma progression and stemness, making it a potential therapeutic target
3	Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection	Wang et al[66], 2022	Shows that simultaneous mutation and methylation analysis of cfDNA improves HCC detection
4	Identification of whole-genome mutations and structural variations of bile cell-free DNA in cholangiocarcinoma	Yin et al[67], 2024	Suggests that whole-genome analysis of bile cfDNA can identify mutations and structural variations in cholangiocarcinoma

HPGD: 15-hydroxyprostaglandin dehydrogenase; PGE: Prostaglandin; cfDNA: Cell free DNA; HCC: Hepatocellular carcinoma.

Table 5 Role of liquid biopsy in intra-operative period

No.	Title of study	Ref.	Conclusion of study
1	Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection	Wang et al[66], 2022	Shows that simultaneous mutation and methylation analysis of cfDNA improves HCC detection
2	Liquid biopsy for monitoring minimal residual disease in localized and locally-advanced non-small cell lung cancer after radical-intent treatment	Aguilar et al[6], 2024	Evaluates liquid biopsy for detecting minimal residual disease in lung cancer, supporting its role in post-treatment monitoring
3	Current role and future perspectives of immunotherapy and circulating factors in treatment of biliary tract cancers	Conci et al[68], 2023	Reviews the role of immunotherapy and circulating biomarkers in the treatment of biliary tract cancers

cfDNA: Cell free DNA; HCC: Hepatocellular carcinoma.

Table 6 Role of liquid biopsy in postoperative period

No.	Title of study	Ref.	Conclusion of study
1	Clearance of circulating tumor cells in patients with hepatocellular carcinoma undergoing surgical resection or liver transplantation	Amado et al[69], 2021	Investigates CTC clearance post-surgery or liver transplantation, indicating its potential as a prognostic factor in HCC
2	Prognostic impact of postoperative circulating tumor DNA as a molecular minimal residual disease marker in patients with pancreatic cancer undergoing surgical resection	Hata et al[70], 2023	Suggests that postoperative ctDNA can be used as a MRD marker to predict pancreatic cancer recurrence
3	Current progress in the clinical use of circulating tumor cells as prognostic biomarkers	Jin et al[71], 2019	Reviews the clinical applications of CTCs as prognostic biomarkers across various cancers
4	CTCs: A unique model of cancer metastases and non-invasive biomarkers of therapeutic response	Liu et al[72], 2021	Highlights the role of CTCs as biomarkers for monitoring treatment response and cancer metastasis
5	Exosome-derived differentiation antagonizing non-protein coding RNA with risk of HCV-related hepatocellular carcinoma recurrence	Wang et al[73], 2021	Suggests that exosomal non-protein coding RNA is associated with HCV-related HCC recurrence risk
6	Exosomal circ-PTPN22 and circ-ADAMTS6 mark T cell exhaustion and neutrophil extracellular traps in Asian intrahepatic cholangiocarcinoma	Wang et al[74], 2023	Identifies exosomal circ-PTPN22 and circ-ADAMTS6 as markers of immune exhaustion in intrahepatic cholangiocarcinoma

CTC: Circulating tumor cells; ctDNA: Circulating tumor DNA; cfDNA: Cell free DNA; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus.