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Re\u2010irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re\u2010radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow\u2010up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV\u2010based ctDNA burden was detected in 8\/16 patients and 25\/94 plasma samples. Ten additional ctDNA\u2010positive samples were identified by tracking patient\u2010specific CNVs found in earlier sequential plasma samples. ctDNA\u2010positivity after 5 and 10 radiation fractions (both: log\u2010rank, <jats:italic>p<\/jats:italic>\u2009=\u2009.050) as well as at the end of irradiation correlated with short progression\u2010free survival (log\u2010rank, <jats:italic>p<\/jats:italic>\u2009=\u2009.006). Moreover, a pronounced decrease of ctDNA toward re\u2010radiotherapy termination was associated with worse treatment outcome (log\u2010rank, <jats:italic>p<\/jats:italic>\u2009=\u2009.005). Dynamic ctDNA tracking in serial plasma beyond re\u2010radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re\u2010radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow\u2010up intervals, and dose prescription.<\/jats:p>","DOI":"10.1002\/ijc.35152","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T12:30:20Z","timestamp":1725021020000},"page":"853-864","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Early circulating tumor <scp>DNA<\/scp> changes predict outcomes in head and neck cancer patients under re\u2010radiotherapy"],"prefix":"10.1002","volume":"156","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2406-7037","authenticated-orcid":false,"given":"Florian","family":"Janke","sequence":"first","affiliation":[{"name":"Division of Cancer Genome Research, German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"German Center for Lung Research (DZL), TLRC Heidelberg  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