{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:19:42Z","timestamp":1788175182188,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background and Objective: Liquid biopsy has transformed the management of advanced prostate cancer, yet its clinical role in non-metastatic disease remains uncertain. Conventional biomarkers such as PSA, imaging, and pathology have limited ability to capture minimal residual disease and biological aggressiveness. The objective of this review was to critically evaluate the current evidence on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in non-metastatic prostate cancer, focusing on feasibility, prognostic value, and potential clinical applications. Methods: A narrative review of PubMed-indexed original studies evaluating liquid biopsy in clinically localized or non-metastatic prostate cancer was performed. Eligible studies included patients treated with curative-intent local therapy or experiencing biochemical recurrence without radiologic metastases. Study designs were predominantly prospective or retrospective observational cohorts. Liquid biopsy analytes included CTCs and ctDNA assessed from peripheral blood plasma using EpCAM-based enrichment, targeted next-generation sequencing, whole-genome sequencing, or ultra-sensitive tumor-informed assays. Primary outcomes included detection rates, associations with clinicopathologic features, biochemical recurrence, metastasis-free survival, and overall survival. Key Findings and Limitations: Across 11 studies, CTC detection using EpCAM-based platforms was infrequent in localized disease and biochemical recurrence and showed limited prognostic value (10\u201311% in preoperative settings). In contrast, ctDNA was detectable in a minority of patients but consistently identified biologically aggressive disease and a higher risk of recurrence when present, particularly using tumor-informed ultra-sensitive assays. Limitations include low detection rates, heterogeneous methodologies, small sample sizes, and predominantly exploratory study designs. Conclusions and Clinical Implications: Currently, its most promising application is not broad screening, but as a selective, biology-driven tool for detecting minimal residual disease and refining risk assessment. CtDNA acts as a biological risk modifier, potentially guiding the escalation or de-escalation of adjuvant therapy. However, prospective biomarker-driven trials are required to validate these strategies before routine clinical implementation.<\/jats:p>","DOI":"10.3390\/cancers18050800","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T16:18:45Z","timestamp":1772554725000},"page":"800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Liquid Biopsy in Non-Metastatic Prostate Cancer: Clinical Evidence and Future Directions"],"prefix":"10.3390","volume":"18","author":[{"given":"Maria Chiara","family":"Sighinolfi","sequence":"first","affiliation":[{"name":"Fondazione Policlinico Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9963-3499","authenticated-orcid":false,"given":"Giuseppe","family":"Pallotta","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Agostino Gemelli IRCCS, 00168 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(2022). Liquid biopsy in diagnosis and prognosis of non-metastatic prostate cancer. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123115"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dathathri, E., Isebia, K.T., Abali, F., Lolkema, M.P., Martens, J.W.M., Terstappen, L.W.M.M., and Bansal, R. (2022). Liquid biopsy based circulating biomarkers in metastatic prostate cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.863472"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.molonc.2015.12.002","article-title":"Challenges in circulating tumor cell detection by the CellSearch system","volume":"10","author":"Andree","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5271","DOI":"10.2147\/CMAR.S170380","article-title":"Current status of liquid biopsies for the detection and management of prostate cancer","volume":"11","author":"Lu","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/s41416-022-01881-9","article-title":"Blood-based liquid biopsies for prostate cancer: Clinical opportunities and challenges","volume":"127","author":"Trujillo","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/978-3-319-93339-9_4","article-title":"Liquid biopsy in prostate cancer: Circulating tumor cells and beyond","volume":"175","author":"Zainfeld","year":"2018","journal-title":"Cancer Treat. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.eururo.2020.12.037","article-title":"Quantitative and qualitative analysis of blood-based liquid biopsies to inform clinical decision-making in prostate cancer","volume":"79","author":"Boutros","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.eururo.2025.07.016","article-title":"The role of liquid biopsy in the management of patients with genitourinary malignancies","volume":"88","author":"Maughan","year":"2025","journal-title":"Eur. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chanhih, N., Laraqui, A., Hassine, S., Ameur, A., Hamedoun, L., El Annaz, H., Abi, R., Tagajdid, M.R., Amine, I.L., and Ennibi, K. (2025). Circulating tumor DNA as a biomarker for precision medicine in prostate cancer: A systematic review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262211049"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.eururo.2024.11.011","article-title":"Novel methods to assess tumor burden and minimal residual disease in genitourinary cancers","volume":"87","author":"Barata","year":"2025","journal-title":"Eur. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1159\/000356251","article-title":"Prevalence of circulating tumor cells in localized prostate cancer","volume":"7","author":"Khurana","year":"2013","journal-title":"Curr. Urol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.clgc.2014.08.014","article-title":"Detection and phenotyping of circulating tumor cells in high-risk localized prostate cancer","volume":"13","author":"Pal","year":"2015","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e341","DOI":"10.1016\/j.clgc.2015.04.003","article-title":"Circulating tumor cells in biochemical recurrence of prostate cancer","volume":"13","author":"Siegel","year":"2015","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235.e11","DOI":"10.1016\/j.urolonc.2015.12.003","article-title":"Limited prognostic value of preoperative circulating tumor cells for early biochemical recurrence in patients with localized prostate cancer","volume":"34","author":"Meyer","year":"2016","journal-title":"Urol. Oncol."},{"key":"ref_16","first-page":"2975","article-title":"Analysis of circulating tumor cells in prostate cancer patients at PSA recurrence and review of the literature","volume":"36","author":"Grisanti","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.19.00176","article-title":"Low abundance of circulating tumor DNA in localized prostate cancer","volume":"3","author":"Hennigan","year":"2019","journal-title":"JCO Precis. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13073-020-00770-1","article-title":"Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression","volume":"12","author":"Lau","year":"2020","journal-title":"Genome Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.eururo.2024.01.002","article-title":"Ultrasensitive detection of circulating tumour DNA enriches for patients with a greater risk of recurrence of clinically localised prostate cancer","volume":"85","author":"Pope","year":"2024","journal-title":"Eur. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"969","DOI":"10.4143\/crt.2022.1557","article-title":"Early plasma circulating tumor DNA as a potential biomarker of disease recurrence in non-metastatic prostate cancer","volume":"55","author":"Fei","year":"2023","journal-title":"Cancer Res. Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1200\/JCO.2025.43.5_suppl.402","article-title":"Feasibility of enriched amplicon circulating tumor DNA sequencing to detect minimal residual disease after prostatectomy in localized prostate cancer","volume":"42","author":"Zang","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1007\/s00259-024-06698-7","article-title":"Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET\/CT and circulating tumor DNA in prostate cancer\u2014A cross-sectional study","volume":"51","author":"Kluge","year":"2024","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000512819","article-title":"Detection of Microsatellite Instability via Circulating Tumor DNA and Response to Immunotherapy in Metastatic Castration-Resistant Prostate Cancer: A Case Series","volume":"14","author":"Ravindranathan","year":"2021","journal-title":"Case Rep. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.eururo.2019.09.036","article-title":"Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer","volume":"77","author":"Reimers","year":"2020","journal-title":"Eur. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"564.e1","DOI":"10.1016\/j.clgc.2021.07.012","article-title":"Analysis of the Prognostic Significance of Circulating Tumor DNA in Metastatic Castrate Resistant Prostate Cancer","volume":"19","author":"Shaya","year":"2021","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Garrido Castillo, L.N., Mejean, A., Vielh, P., Anract, J., Decina, A., Nalpas, B., Benali-Furet, N., Desitter, I., and Paterlini-Br\u00e9chot, P. (2022). Predictive Value of Circulating Tumor Cells Detected by ISET\u00ae in Patients with Non-Metastatic Prostate Cancer Undergoing Radical Prostatectomy. Life, 12.","DOI":"10.3390\/life12020165"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Labidi, S., Jiao, B., Tam, S., Fallah, P., Salehi, A., Rajan, R., Alameldin, M., Brimo, F., Foulkes, W.D., and Papadakis, A.I. (2025). Evaluating the Role of Liquid Biopsy to Detect Pathogenic Homologous Recombination Repair (HRR) Gene Alterations in Metastatic Prostate Cancer. Cancers, 17.","DOI":"10.1101\/2025.06.06.25328738"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2274123","DOI":"10.1080\/15384047.2023.2274123","article-title":"Clinical application of molecular residual disease detection by circulation tumor DNA in solid cancers and a comparison of technologies: Review article","volume":"24","author":"Dong","year":"2023","journal-title":"Cancer Biol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.cca.2021.05.033","article-title":"What do we need to obtain high quality circulating tumor DNA (ctDNA) for routine diagnostic test in oncology? Considerations on pre-analytical aspects by the IFCC workgroup cfDNA","volume":"520","author":"Danesi","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2500267","DOI":"10.1200\/PO-25-00267","article-title":"Generic protocols for analytical validation of tumor-informed circulating tumor DNA assays for molecular residual disease: The Blood Profiling Atlas in Cancer\u2019s Molecular Residual Disease Analytical Validation Working Group consensus recommendation","volume":"10","author":"Baden","year":"2026","journal-title":"JCO Precis. Oncol."},{"key":"#cr-split#-ref_31.1","unstructured":"European Parliament and Council of the European Union (2017). Regulation"},{"key":"#cr-split#-ref_31.2","unstructured":"(EU) 2017\/746 of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98\/79\/EC and Commission Decision 2010\/227\/EU. Off. J. Eur. Union, L117, 176-332."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1515\/cclm-2022-1252","article-title":"Clinical evidence requirements according to the IVDR 2017\/746: Practical tools and references for underpinning clinical evidence of IVD-MDs","volume":"61","author":"Pazart","year":"2023","journal-title":"Clin. Chem. Lab. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/5\/800\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T05:13:50Z","timestamp":1772687630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/5\/800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,28]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["cancers18050800"],"URL":"https:\/\/doi.org\/10.3390\/cancers18050800","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,28]]}}}