{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:43:00Z","timestamp":1771548180733,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Positron emission tomography (PET) and liquid biopsy have independently transformed prostate cancer management. This review explores the complementary roles of PET imaging and liquid biopsy in prostate cancer, focusing on their combined diagnostic, monitoring, and prognostic potential. A systematic search of PubMed, Scopus, and Cochrane Library databases was conducted to identify human studies published in English up to January 2025. Seventeen studies met the inclusion criteria and were analyzed according to PRISMA guidelines. Across the included studies, PET-derived imaging metrics, such as metabolic activity and radiotracer uptake, correlated consistently with liquid biopsy biomarkers, including circulating tumor cells and cell-free DNA. Their joint application demonstrated added value in early detection, treatment monitoring, and outcome prediction, particularly in castration-resistant prostate cancer. Independent and synergistic prognostic value was noted for both modalities, including survival outcomes such as overall survival and progression-free survival. Combining PET imaging and liquid biopsy emerges as a promising, non-invasive strategy for improving prostate cancer diagnosis, monitoring, and therapeutic stratification. While preliminary findings are encouraging, large-scale prospective studies are essential to validate their integrated clinical utility.<\/jats:p>","DOI":"10.3390\/biom15071041","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T10:10:38Z","timestamp":1752833438000},"page":"1041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synergizing Liquid Biopsy and Hybrid PET Imaging for Prognostic Assessment in Prostate Cancer: A Focus Review"],"prefix":"10.3390","volume":"15","author":[{"given":"Federica","family":"Stracuzzi","sequence":"first","affiliation":[{"name":"Nuclear Medicine Unit, Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi, 95124 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9504-7626","authenticated-orcid":false,"given":"Sara","family":"Dall\u2019 Armellina","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Unit, Service Area Department, Azienda Socio-Sanitaria Territoriale (ASST)-Rhodense P.O. Bollate, 994301 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5152-497X","authenticated-orcid":false,"given":"Gayane","family":"Aghakhanyan","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Unit, Department of Translational Research and of New Surgical and Medical Technology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4003-3320","authenticated-orcid":false,"given":"Salvatore C.","family":"Fanni","sequence":"additional","affiliation":[{"name":"Academic Radiology, Department of Translational Research and of New Surgical and Medical Technology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0842-5372","authenticated-orcid":false,"given":"Giacomo","family":"Aringhieri","sequence":"additional","affiliation":[{"name":"Academic Radiology, Department of Translational Research and of New Surgical and Medical Technology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5262-4489","authenticated-orcid":false,"given":"Lorenzo","family":"Faggioni","sequence":"additional","affiliation":[{"name":"Academic Radiology, Department of Translational Research and of New Surgical and Medical Technology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7950-4559","authenticated-orcid":false,"given":"Emanuele","family":"Neri","sequence":"additional","affiliation":[{"name":"Academic Radiology, Department of Translational Research and of New Surgical and Medical Technology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duccio","family":"Volterrani","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Unit, Department of Translational Research and of New Surgical and Medical Technology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5120-886X","authenticated-orcid":false,"given":"Dania","family":"Cioni","sequence":"additional","affiliation":[{"name":"Academic Radiology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"234","article-title":"Advances in molecular imaging and biomarkers for prostate cancer: A review","volume":"25","author":"Sekhoacha","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/S0140-6736(20)30314-7","article-title":"Prostate-specific membrane antigen PET-CT in patients with high-risk pros-tate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomized, multicenter study","volume":"395","author":"Hofman","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-018-0071-5","article-title":"Current and future perspectives of liquid biopsies in genomics-driven on-cology","volume":"20","author":"Heitzer","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1001\/jamaoncol.2016.0494","article-title":"Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer","volume":"2","author":"Wyatt","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1002\/cncr.30073","article-title":"Open\u2010label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors","volume":"122","author":"Graff","year":"2016","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sartor, O. (2023). Circulating Tumor DNA Biomarkers for Response Assessment in Prostate Cancer. Clin. Cancer Res., 2745\u20132747.","DOI":"10.1158\/1078-0432.CCR-23-1043"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fragkiadaki, V. (2024). Correlation of PSA blood levels with standard uptake value maximum (SUV max ) and total metabolic tumor volume (TMTV) in 18F-PSMA-1007 and 18F-choline PET\/CT in patients with biochemically recurrent prostate cancer. Nucl Med Commun., 924\u2013930.","DOI":"10.1097\/MNM.0000000000001881"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kluge, K., Einspieler, H., Haberl, D., Spielvogel, C., Stoiber, S., Vraka, C., Papp, L., Wunsch, S., Egger, G., and Kramer, G. Examining the relationship and prognostic significance of cell-free DNA levels and PSMA-positive tumor volume in men with prostate cancer: A retrospective-prospective [68Ga]Ga-PSMA-11 PET\/CT study. J. Nucl. Med., 2024. in press.","DOI":"10.2967\/jnumed.123.266158"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1007\/s00259-024-06698-7","article-title":"Comparison of discovery rates and prog-nostic 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_11","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1752-8062.2011.00375.x","article-title":"Measurement of circulating cell-free DNA in relation to 18F-fluorocholine PET\/CT imaging in chemotherapy-treated advanced prostate cancer","volume":"5","author":"Kwee","year":"2012","journal-title":"Clin. Transl. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1158\/1541-7786.MCR-17-0196","article-title":"Real-time transferrin-based PET detects MYC-positive prostate cancer","volume":"15","author":"Aggarwal","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1001\/jamaoncol.2020.0147","article-title":"A phase II randomized trial of observation versus stereotactic ablative radiation for oli-gometastatic prostate cancer (ORIOLE)","volume":"6","author":"Phillips","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_14","first-page":"2133","article-title":"Screening for circulating tumour cells allows early detection of cancer and monitoring of treatment effec-tiveness: An observational study","volume":"18","author":"Ried","year":"2017","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kyriakopoulos, C.E., Heath, E.I., Ferrari, A., Sperger, J.M., Singh, A., Perlman, S.B., Roth, A.R., Perk, T.G., Modelska, K., and Porcari, A. (2020). Exploring spatial-temporal changes in 18F-sodium fluoride PET\/CT and cir-culating tumor cells in metastatic castration-resistant prostate cancer treated with enzalutamide. J. Clin. Oncol., 38.","DOI":"10.1200\/JCO.20.00348"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ried, K., Tamanna, T., Matthews, S., Eng, P., and Sali, A. (2020). New screening test improves detection of prostate cancer using circulating tumor cells and prostate-specific markers. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00582"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"652","DOI":"10.7150\/thno.44556","article-title":"Molecular analysis of circulating tumor cells of metastatic castration-resistant prostate cancer patients receiving 177Lu-PSMA-617 radioligand therapy","volume":"10","author":"Kessel","year":"2020","journal-title":"Theranostics"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Emmett, L., Subramaniam, S., Joshua, A.M., Crumbaker, M., Martin, A., Zhang, A.Y., Rana, N., Langford, A., Mitchell, J., and Yip, S. (2021). ENZA-p trial protocol: A randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901). BJU Int., in press.","DOI":"10.1111\/bju.15491"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1002\/1878-0261.13120","article-title":"Combining liquid biopsy and functional imaging analysis in metastatic castra-tion-resistant prostate cancer helps predict treatment outcome","volume":"16","author":"Conteduca","year":"2022","journal-title":"Mol. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1002\/pros.24549","article-title":"PSMA-heterogeneity in metastatic castration-resistant prostate cancer: Circulat-ing tumor cells, metastatic tumor burden, and response to targeted radioligand therapy","volume":"83","author":"Derlin","year":"2023","journal-title":"Prostate"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101733","DOI":"10.1016\/j.nantod.2022.101733","article-title":"Prostate cancer extracellular vesicle digital scoring assay: A rapid noninvasive approach for quantification of disease-relevant mRNAs","volume":"48","author":"Wang","year":"2023","journal-title":"Nano Today"},{"key":"ref_22","first-page":"48","article-title":"Alternative and complementary therapies for early diagnosis of prostate cancer","volume":"34","author":"Ghous","year":"2023","journal-title":"Med. Forum"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1007\/s00262-023-03421-7","article-title":"A phase I prospective, non-randomized trial of autologous dendritic cell-based cryoimmunotherapy in patients with metastatic castration-resistant prostate cancer","volume":"72","author":"Thomsen","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Modlin, I.M., Kidd, M., Drozdov, I.A., Boegemann, M., Bodei, L., Kunikowska, J., Malczewska, A., Bernemann, C., Koduru, S.V., and Rahbar, K. (2024). Development of a multigenomic liquid biopsy (PROSTest) for prostate cancer in whole blood. Prostate, in press.","DOI":"10.1002\/pros.24704"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.33393\/jcb.2024.2636","article-title":"Detection of PSMA expression on circulating tumor cells by blood-based liquid biopsy in prostate cancer","volume":"13","author":"Gupta","year":"2024","journal-title":"J. Circ. Biomark."},{"key":"ref_26","first-page":"2382","article-title":"Liquid-biopsy glycan score biomarker accurately indicates and stratifies primary and metastatic prostate cancers","volume":"96","author":"Jochumsen","year":"2024","journal-title":"Anal. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1007\/s00259-025-07078-5","article-title":"Can PSMA PET Detect Intratumour Heterogeneity in His-tological PSMA Expression of Primary Prostate Cancer? Analysis of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007","volume":"52","author":"Waibel","year":"2025","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Alshamrani, A.F.A. (2024). Diagnostic Accuracy of Molecular Imaging Techniques for Detecting Prostate Cancer: A Systematic Review. Diagnostics, 14.","DOI":"10.3390\/diagnostics14131315"},{"key":"ref_29","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":"Athie","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_30","first-page":"259","article-title":"Genomic and phenotypic heterogeneity in prostate cancer","volume":"16","author":"Haffner","year":"2019","journal-title":"Nat. Rev. Urol."},{"key":"ref_31","first-page":"1","article-title":"Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer","volume":"4","author":"Armstrong","year":"2020","journal-title":"JCO Precis. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1158\/2159-8290.CD-17-0937","article-title":"Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer","volume":"8","author":"Annala","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_33","first-page":"80","article-title":"PSMA-targeted radionuclide therapy for metastatic castration-resistant prostate cancer: A review","volume":"8","author":"Tagawa","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.1200\/JCO.2023.41.16_suppl.5057","article-title":"Tumor Heterogeneity and Treatment Response Assessment Using Next Generation Imaging and Liquid Biopsy in Patients with Metastatic Castration Resistant Prostate Cancer Receiving Abiraterone (ANGELA): A Sin-gle-Center Prospective Observational Trial","volume":"41","author":"Wu","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_35","unstructured":"ENZA-p Study Investigators (2020). ENZA-p: Enzalutamide and [^177Lu]Lu-PSMA-617 Versus Enzalutamide Alone in Metastatic Cas-tration-Resistant Prostate Cancer (NCT04419402). ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT04419402."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1053\/j.semnuclmed.2023.07.005","article-title":"Standardized PSMA-PET Imaging of Advanced Prostate Cancer","volume":"Volume 54","author":"Seifert","year":"2024","journal-title":"Seminars in Nuclear Medicine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00259-017-3740-2","article-title":"EANM\/EARL Harmonization Strategies in PET Quantification: From Daily Practice to Multicentre Oncological Studies","volume":"44","author":"Aide","year":"2017","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40658-019-0257-8","article-title":"Quantitative Implications of the Updated EARL 2019 PET-CT Performance Standards","volume":"6","author":"Kaalep","year":"2019","journal-title":"EJNMMI Phys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jmoldx.2022.12.003","article-title":"Contrived Materials and a Data Set for the Evaluation of Liquid Biopsy Tests: A Blood Profiling Atlas in Cancer (BLOODPAC) Community Study","volume":"25","author":"Hernandez","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tapper, W., Carneiro, G., Mikropoulos, C., Thomas, S.A., Evans, P.M., and Boussios, S. (2024). The Application of Radiomics and AI to Molecular Imaging for Prostate Cancer. J. Pers. Med., 14.","DOI":"10.3390\/jpm14030287"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/7\/1041\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:11:46Z","timestamp":1760033506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/7\/1041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["biom15071041"],"URL":"https:\/\/doi.org\/10.3390\/biom15071041","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,18]]}}}