{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T14:14:56Z","timestamp":1776867296360,"version":"3.51.2"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"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: Metastatic prostate cancer (mPCA) poses challenges in treatment response assessment, particularly in cases where prostate-specific antigen (PSA) levels do not reliably indicate a response. Liquid biopsy, focusing on circulating cell-free DNA (ccfDNA) methylation analysis as a proxy for circulating tumor DNA, offers a non-invasive and cost-effective approach. This study explores the potential of two methylation markers, short stature homeobox 2 (SHOX2) and Septin 9 (SEPT9), as on-mPCA-treatment biomarkers. Methods: Plasma samples were collected from 11 mPCA patients undergoing various treatments. Quantitative assessment of hypermethylated SHOX2 (mSHOX2) and SEPT9 (mSEPT9) levels in ccfDNA was conducted through methylation-specific real-time PCR. Early and overall dynamics of PSA, mSHOX2, and mSEPT9 were analyzed. Statistical evaluation employed Wilcoxon tests. Results: mSHOX2 demonstrated a significant decline post-treatment in patients with a radiographic treatment response as well as in an early treatment setting. mSEPT9 and PSA exhibited non-significant declines. In individual cases, biomarker dynamics revealed unique patterns compared to PSA. Discussion: mSHOX2 and mSEPT9 exhibit dynamics on mPCA treatment. This proof-of-concept study lays the groundwork for further investigation into these markers as valuable additions to treatment response monitoring in mPCA. Further validation in larger cohorts is essential for establishing clinical utility.<\/jats:p>","DOI":"10.3390\/cancers16030482","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T07:22:32Z","timestamp":1705994552000},"page":"482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Feasibility of Monitoring Response to Metastatic Prostate Cancer Treatment with a Methylation-Based Circulating Tumor DNA Approach"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0316-9621","authenticated-orcid":false,"given":"Thomas","family":"B\u00fcttner","sequence":"first","affiliation":[{"name":"Department of Urology and Pediatric Urology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimo","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romina","family":"Zarbl","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3258-0586","authenticated-orcid":false,"given":"Niklas","family":"Kl\u00fcmper","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-0857","authenticated-orcid":false,"given":"J\u00f6rg","family":"Ellinger","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8213-9975","authenticated-orcid":false,"given":"Philipp","family":"Krausewitz","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,23]]},"reference":[{"key":"ref_1","unstructured":"Mottet, N., Cornford, P., van de Bergh, R.C.N., Briers, E., Eberli, E., De Meerleer, G., De Santis, M., Gillessen, S., Grummet, J., and Expert Patient Advocate (European Prostate Cancer Coalition\/Europa UOMO) (2023, November 24). EAU\u2013EANM\u2013ESTRO\u2013ESUR\u2013ISUP\u2013SIOG Guidelines on Prostate Cancer, 2023 Update. Available online: https:\/\/uroweb.org\/guidelines\/prostate-cancer."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sartor, A.O., la Foug\u00e8re, C., Essler, M., Ezziddin, S., Kramer, G., Elllinger, J., Nordquist, L., Sylvester, J., Paganelli, G., and Peer, A. (2021). Lutetium-177\u2013prostate-specific membrane antigen ligand following radium-223 treatment in men with bone-metastatic castration-resistant prostate cancer: Real-world clinical experience. J. Nucl. Med.","DOI":"10.2967\/jnumed.121.262240"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/bju.15542","article-title":"Safety and survival of docetaxel and cabazitaxel in metastatic castration-resistant prostate cancer","volume":"129","author":"Kreis","year":"2022","journal-title":"BJU Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10601","DOI":"10.1007\/s13277-014-2559-8","article-title":"PSA response rate as a surrogate marker for median overall survival in docetaxel-based first-line treatments for patients with metastatic castration-resistant prostate cancer: An analysis of 22 trials","volume":"35","author":"Francini","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s00345-017-2138-x","article-title":"PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: The non-interventional QoLiTime study","volume":"36","author":"Hammerer","year":"2018","journal-title":"World J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"282","DOI":"10.23736\/S1824-4785.19.03165-0","article-title":"Prognostic importance of prostatic specific antigen response in patients who received Lutetium-177 prostate-specific membrane antigen treatment for castration resistant prostate cancer","volume":"65","author":"Soydal","year":"2021","journal-title":"Q. J. Nucl. Med. Mol. Imaging"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1200\/JCO.2008.19.9810","article-title":"Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: Data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916","volume":"27","author":"Hussain","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12071","DOI":"10.1038\/s41598-019-48600-8","article-title":"Prognostic significance of early changes in serum biomarker levels in patients with newly diagnosed metastatic prostate cancer","volume":"9","author":"Narita","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.7150\/jca.7709","article-title":"Current approaches, challenges and future directions for monitoring treatment response in prostate cancer","volume":"5","author":"Wallace","year":"2014","journal-title":"J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4103\/1008-682X.179159","article-title":"Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: Implications for clinical practice","volume":"19","author":"Mizokami","year":"2017","journal-title":"Asian J. Androl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1002\/cncr.11821","article-title":"Clinical features of patients who present with metastatic prostate carcinoma and serum prostate-specific antigen (PSA) levels < 10 ng\/mL: The \u201cPSA negative\u201d patients","volume":"98","author":"Birtle","year":"2003","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.euo.2020.07.001","article-title":"Patterns of Cancer Progression of Metastatic Hormone-sensitive Prostate Cancer in the ECOG3805 CHAARTED Trial","volume":"3","author":"Bryce","year":"2020","journal-title":"Eur. Urol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5072","DOI":"10.1200\/JCO.2022.40.16_suppl.5072","article-title":"Radiographic progression in the absence of prostate-specific antigen (PSA) progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analysis of ARCHES","volume":"40","author":"Armstrong","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"863472","DOI":"10.3389\/fonc.2022.863472","article-title":"Liquid biopsy based circulating biomarkers in metastatic prostate cancer","volume":"12","author":"Dathathri","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.eururo.2016.05.023","article-title":"Decline in circulating tumor cell count and treatment outcome in advanced prostate cancer","volume":"70","author":"Lorente","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/annonc\/mdn544","article-title":"Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): A single-centre experience","volume":"20","author":"Olmos","year":"2009","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6302","DOI":"10.1158\/1078-0432.CCR-08-0872","article-title":"Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer","volume":"14","author":"Scher","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lozano, R., Lorente, D., Aragon, I.M., Romero-Laorden, N., Nombela, P., Mateo, J., Reid, A.H.M., Cend\u00f3n, Y., Bianchini, D., and Llacer, C. (2021). Value of Early Circulating Tumor Cells Dynamics to Estimate Docetaxel Benefit in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients. Cancers, 13.","DOI":"10.3390\/cancers13102334"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1200\/JCO.2017.75.2998","article-title":"Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison with Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials","volume":"36","author":"Heller","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103166","DOI":"10.1016\/j.critrevonc.2020.103166","article-title":"The main sources of circulating cell-free DNA: Apoptosis, necrosis and active secretion","volume":"157","author":"Hu","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.jmoldx.2020.04.205","article-title":"Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free SHOX2 and SEPT9 DNA Methylation in Blood: An Observational Prospective Study","volume":"22","author":"Jung","year":"2020","journal-title":"J. Mol. Diagn."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1111\/1759-7714.14206","article-title":"Diagnostic performance of SHOX2 promoter methylation as biomarker for lung cancer identification: A meta-analysis update","volume":"12","author":"Zhou","year":"2021","journal-title":"Thorac. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sun, J., Fei, F., Zhang, M., Li, Y., Zhang, X., Zhu, S., and Zhang, S. (2019). The role of mSEPT9 in screening, diagnosis, and recurrence monitoring of colorectal cancer. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5663-8"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Krausewitz, P., Kluemper, N., Richter, A.-P., B\u00fcttner, T., Kristiansen, G., Ritter, M., and Ellinger, J. (2022). Early Dynamics of Quantitative SEPT9 and SHOX2 Methylation in Circulating Cell-Free Plasma DNA during Prostate Biopsy for Prostate Cancer Diagnosis. Cancers, 14.","DOI":"10.3390\/cancers14184355"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.juro.2015.10.172","article-title":"Development of castration resistant prostate cancer can be predicted by a DNA hypermethylation profile","volume":"195","author":"Angulo","year":"2016","journal-title":"J. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1016\/S0140-6736(18)32486-3","article-title":"Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial","volume":"392","author":"Parker","year":"2018","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/978-1-4939-7481-8_32","article-title":"DNA methylation analysis of free-circulating DNA in body fluids","volume":"1708","author":"Jung","year":"2018","journal-title":"DNA Methylation Protoc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13148-017-0425-4","article-title":"Comparison of quantification algorithms for circulating cell-free DNA methylation biomarkers in blood plasma from cancer patients","volume":"9","author":"Gevensleben","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1007\/s00259-017-3895-x","article-title":"Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: A systematic review","volume":"45","author":"Roviello","year":"2018","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1056\/NEJMoa1911206","article-title":"Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer","volume":"381","author":"Sternberg","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1177\/1758834012449685","article-title":"Overcoming docetaxel resistance in prostate cancer: A perspective review","volume":"4","author":"Hwang","year":"2012","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.5489\/cuaj.1145","article-title":"A rapid PSA half-life following docetaxel chemotherapy is associated with improved survival in hormone refractory prostate cancer","volume":"3","author":"Hanninen","year":"2009","journal-title":"Can. Urol. Assoc. J."},{"key":"ref_33","first-page":"200","article-title":"Imaging and treatment recommendations in patients with castrate-resistant prostate cancer","volume":"19","author":"Albala","year":"2017","journal-title":"Rev. Urol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/3\/482\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:47:57Z","timestamp":1760104077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/3\/482"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,23]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["cancers16030482"],"URL":"https:\/\/doi.org\/10.3390\/cancers16030482","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,23]]}}}