{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:19:26Z","timestamp":1791580766277,"version":"4.3.4"},"reference-count":70,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["24K11058"],"award-info":[{"award-number":["24K11058"]}]},{"DOI":"10.13039\/100007434","name":"Suzuken Memorial Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007434","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite extensive technological advances and an ever-growing body of literature, liquid biopsy has yet to achieve reliable early detection of pancreatic ductal adenocarcinoma (PDA). Numerous studies have investigated circulating tumor-derived components, including cell-free DNA (cfDNA), cell-free RNA (cfRNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs), primarily using peripheral blood samples; however, their clinical utility for early-stage disease remains limited. The fundamental obstacles are biological rather than purely technical: early PDA and its precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN), are characterized by minimal tumor burden, low levels of nucleic acid shedding, and substantial background signals from non-neoplastic tissues. Increasing analytical complexity through multilayered liquid biopsy approaches, including analyses from pancreas-associated fluid, has not consistently translated into improved diagnostic performance and, in some cases, has amplified issues related to specificity, reproducibility, and interpretability. Moreover, molecular alterations detected in body fluids may reflect clonal expansion without inevitable malignant progression, raising concerns regarding overdiagnosis and clinical decision-making. Pre-analytical variability, lack of standardization, and limited access to tumor-adjacent fluids further hinder clinical implementation. Liquid biopsy should therefore be regarded as a complementary modality rather than a substitute for histopathological diagnosis, with its precise clinical role in early detection still ill-defined. In this review, we critically examine why liquid biopsy has not yet succeeded in early PDA detection, highlighting the key biological, technical, and clinical barriers that must be addressed to move the field beyond exploratory research toward meaningful clinical application.<\/jats:p>","DOI":"10.3390\/cancers18030525","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T15:24:19Z","timestamp":1770305059000},"page":"525","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Liquid Biopsy for Early Pancreatic Cancer Detection: Why Has It Not Yet Worked?"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6166-6848","authenticated-orcid":false,"given":"Kenji","family":"Takahashi","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan"},{"name":"Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-5386","authenticated-orcid":false,"given":"Yusuke","family":"Ono","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan"},{"name":"Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan"},{"name":"Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo 065-0033, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-3009","authenticated-orcid":false,"given":"Kenzui","family":"Taniue","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan"},{"name":"Isotope Science Center, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krushna C.","family":"Patra","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3753-1211","authenticated-orcid":false,"given":"Takuya","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan"},{"name":"Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan"},{"name":"Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo 065-0033, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikihiro","family":"Fujiya","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1068-7024","authenticated-orcid":false,"given":"Yusuke","family":"Mizukami","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan"},{"name":"Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan"},{"name":"Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo 065-0033, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1093\/jnci\/djt316","article-title":"Pancreas cancer on the rise: Are we up to the challenge?","volume":"105","author":"Cardin","year":"2013","journal-title":"J. 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