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In recent years, new treatment approaches have led to higher rates of complete tumor eradication combined with organ\u2010preservation strategies. However, better tools are still needed to personalize therapy for the individual patient. In this prospective observational study, we analyzed colon\u2010derived cell\u2010free (cf)DNA (c\u2010cfDNA) using a tissue\u2010specific DNA methylation signature, and its association with therapy outcomes. Analyzing plasma samples (n\u00a0=\u00a0303) collected during nCRT from 37 patients with locally advanced rectal cancer (LARC), we identified colon\u2010specific methylation markers that discriminated healthy individuals from patients with untreated LARC (area under the curve, 0.81; 95% confidence interval, 0.70\u20100.92; <jats:italic>P<\/jats:italic>\u2009&lt;\u2009.0001). Baseline c\u2010cfDNA predicted tumor response, with increased levels linked to larger residual cancer. c\u2010cfDNA measured after the first week of therapy identified patients with maximal response and complete cancer eradication, who had significantly lower c\u2010cfDNA compared with those who had residual disease (8.6 vs 57.7 average copies\/ml, respectively; <jats:italic>P<\/jats:italic>\u00a0=\u00a0.013). Increased c\u2010cfDNA after 1 week of therapy was also associated with disease recurrence. Methylation\u2010based liquid biopsy can predict nCRT outcomes and facilitate patient selection for escalation and de\u2010escalation strategies.<\/jats:p>","DOI":"10.1002\/ijc.34392","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T08:39:25Z","timestamp":1670229565000},"page":"1444-1451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A universal cell\u2010free <scp>DNA<\/scp> approach for response prediction to preoperative chemoradiation in rectal cancer"],"prefix":"10.1002","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3351-5719","authenticated-orcid":false,"given":"Albert","family":"Grinshpun","sequence":"first","affiliation":[{"name":"Sharett Institute of Oncology Hadassah Medical Center  Jerusalem Israel"},{"name":"The Faculty of Medicine The Hebrew University  Jerusalem 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