{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T09:59:09Z","timestamp":1785578349403,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,29]]},"group-title":"Oncology","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01CA255442"],"award-info":[{"award-number":["R01CA255442"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P01CA210961"],"award-info":[{"award-number":["P01CA210961"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Circulating tumor DNA (ctDNA) is an emerging biomarker of treatment response and recurrence risk, while residual cancer burden (RCB) after neoadjuvant treatment (NAT) is a well-established risk factor for distant recurrence. Here, we examined the association between high ctDNA concentration at diagnosis and risk of distant recurrence after neoadjuvant treatment (NAT), in the context of RCB.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The study included 712 patients with high-risk breast cancer in the neoadjuvant I-SPY2 trial. Tumor- informed ctDNA test results at diagnosis were used to stratify patients into ctDNA-negative and ctDNA-positive groups. For this analysis, the ctDNA-positive group was divided into tertiles (low, intermediate, high) based on ctDNA concentration reported as mean tumor molecules per mL [MTM\/mL] of plasma. Correlations between MTM\/mL at diagnosis and ctDNA dynamics during NAT, residual cancer burden (RCB), and distant recurrence-free survival (DRFS) were examined across all subtypes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In all subtypes, high ctDNA concentration at diagnosis was associated with worse DRFS, whereas low ctDNA concentration or ctDNA-negative status was associated with improved DRFS, even with high tumor burden after NAT (RCB-II\/RCB-III). We also found that patients with high ctDNA concentration, regardless of subtype, were less likely to experience early ctDNA clearance; however, those who did had a significantly higher likelihood of achieving a favorable response (RCB-0\/RCB-I) than those with late or no ctDNA clearance. Furthermore, across all subtypes, patients with early ctDNA clearance, including those with substantial residual cancer (RCB-II\/RCB-III) after NAT, had improved DRFS, irrespective of the ctDNA concentration at diagnosis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Across all subtypes, pathologic response and ctDNA clearance reduce the risk of distant recurrence associated with high ctDNA concentration at diagnosis. ctDNA concentration at diagnosis and ctDNA clearance dynamics during NAT may facilitate the prediction of treatment response and further stratify the risk of metastatic recurrence in non-responders.<\/jats:p>\n                  <jats:p>\n                    Trial Registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01042379\">NCT01042379<\/jats:ext-link>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.28.26358343","type":"posted-content","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:40:20Z","timestamp":1785375620000},"source":"Crossref","is-referenced-by-count":0,"title":["Circulating tumor DNA concentration at diagnosis is a modifiable prognostic factor for distant metastatic recurrence in patients with high-risk breast cancer receiving neoadjuvant therapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2113-3593","authenticated-orcid":false,"given":"Mark Jesus M.","family":"Magbanua","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise M.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Yau","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayelis A.","family":"Manon","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalyn W.","family":"Sayaman","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamorna","family":"Brown Swigart","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian","family":"Hirst","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"Isaacs","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Shatsky","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy S.","family":"Clark","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Oregon Health and Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Mukhtar","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Delson","sequence":"additional","affiliation":[{"name":"Breast Science Advocacy Core, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Perlmutter","sequence":"additional","affiliation":[{"name":"I-SPY2 Advocacy Group, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula R.","family":"Pohlmann","sequence":"additional","affiliation":[{"name":"Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nola M.","family":"Hylton","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Nanda","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University of Chicago, Chicago, IL,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Yee","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Fraser","family":"Symmans","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Esserman","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hope S.","family":"Rugo","sequence":"additional","affiliation":[{"name":"Department of Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"DeMichele","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"van \u2019t Veer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080102150750000_2026.07.28.26358343v1.1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.65.2289"},{"key":"2026080102150750000_2026.07.28.26358343v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00589-1"},{"key":"2026080102150750000_2026.07.28.26358343v1.3","first-page":"457","article-title":"New and Important Changes in the TNM Staging System for Breast Cancer","volume":"38","year":"2018","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"2026080102150750000_2026.07.28.26358343v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.05.520"},{"issue":"3","key":"2026080102150750000_2026.07.28.26358343v1.5","doi-asserted-by":"crossref","first-page":"102390","DOI":"10.1016\/j.esmoop.2024.102390","article-title":"Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis","volume":"9","year":"2024","journal-title":"ESMO Open"},{"key":"2026080102150750000_2026.07.28.26358343v1.6","doi-asserted-by":"crossref","unstructured":"Papakonstantinou A , Gonzalez NS , Pimentel I et al. 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