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Recurrent tumors remain a major cause of HPV-OPC mortality, yet reliable biomarkers for post-treatment monitoring are lacking. This study evaluated HPV cell-free DNA (cfDNA) from blood plasma as a monitoring biomarker for the detection of HPV-OPC recurrence. Blood plasma from 59 OPC patients was collected at diagnosis and during follow-up. HPV cfDNA was quantified using a multiplex digital PCR assay targeting HPV16 and seven other high-risk types. Tumor HPV status was confirmed by p16\n                    <jats:sup>INK4A<\/jats:sup>\n                    immunohistochemistry, HPV DNA PCR, and E6 serology. At diagnosis, HPV cfDNA was detected with 95% sensitivity (36\/38; 95% CI 82\u201399%) and 95% specificity (19\/20; 95% CI 75\u2013100%). For 24 HPV-OPC patients, follow-up samples were available (median follow-up 1.5 years), with four patients experiencing recurrence or persistence of HPV-OPC. In two patients, HPV cfDNA detection after initial clearance preceded clinical recurrence by 3 and 8 months, respectively. The third patient experienced recurrence 7 months after collection of the last blood sample, which was HPV cfDNA-negative. The fourth patient had persistent disease without HPV cfDNA detection. HPV cfDNA positivity after therapy had a positive predictive value of 75% for HPV-OPC recurrence within one year on a per-test basis. HPV cfDNA has been shown to have great potential as a minimally invasive monitoring biomarker for HPV-OPC surveillance. Monitoring HPV cfDNA levels may identify patients at risk of recurrence early, thereby potentially facilitating timely intervention. Studies with more participants are needed to establish a solid evidence base for surveillance protocols that incorporate HPV cfDNA.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-56914-7","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T22:35:07Z","timestamp":1781303707000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Detection of recurrence of HPV-driven oropharyngeal cancer by HPV cell-free DNA"],"prefix":"10.1038","volume":"16","author":[{"given":"Noemi M.","family":"Fricke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Guarda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"H\u00f6fler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Waterboer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte S.","family":"Schouten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Ikenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Schroeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Rosing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina A.","family":"Broglie Daeppen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"issue":"5","key":"56914_CR1","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41571-022-00603-7","volume":"19","author":"M Lechner","year":"2022","unstructured":"Lechner, M., Liu, J., Masterson, L. & Fenton, T. 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