{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:28:22Z","timestamp":1785421702688,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,13]]},"group-title":"Oncology","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012639","name":"METAvivor","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012639","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02nadbe75","id-type":"ROR","asserted-by":"publisher"}]},{"award":["7K08CA252639-06"],"award-info":[{"award-number":["7K08CA252639-06"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012292","name":"Gerstner Family Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012292","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fondazione Gianni Bonadonna"},{"name":"AIRC"},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Elaine and Eduardo Saverin Foundation"},{"name":"Goldfarb Family Fellowship"},{"DOI":"10.13039\/100001286","name":"Pan-Mass Challenge","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001286","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2R01CA221874-04"],"award-info":[{"award-number":["2R01CA221874-04"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NCI HCC SPORE in Breast Cancer","award":["P50 CA168504"],"award-info":[{"award-number":["P50 CA168504"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Exceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Patients and Methods<\/jats:title>\n                  <jats:p>We identified exceptional (real-world progression-free survival [rwPFS] \u22653 years) and conventional (rwPFS &lt;3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Of 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx &lt;100 ppm. MRD was associated with outcomes: 0\/27 [0%] exceptional versus 9\/12 [75%] conventional responders (p&lt;0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>MRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.09.26357137","type":"posted-content","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T20:45:18Z","timestamp":1783975518000},"source":"Crossref","is-referenced-by-count":0,"title":["Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5284-9944","authenticated-orcid":false,"given":"Stefania","family":"Morganti","sequence":"first","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Song","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningxuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Santos","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Jain","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurel","family":"Walsh","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Li","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Rhoades","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Gilligan","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Kirkner","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Stever","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashka","family":"Patel","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan","family":"Priedigkeit","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Mike","family":"Makrigiorgios","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E.","family":"Krop","sequence":"additional","affiliation":[{"name":"Yale Cancer Center, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Curigliano","sequence":"additional","affiliation":[{"name":"European Institute of Oncology, IRCCS, Milano, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric P.","family":"Winer","sequence":"additional","affiliation":[{"name":"Yale Cancer Center, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Tolaney","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabihah","family":"Tayob","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hillary","family":"Heiling","sequence":"additional","affiliation":[{"name":"Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy U.","family":"Lin","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor A.","family":"Adalsteinsson","sequence":"additional","affiliation":[{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"Parsons","sequence":"additional","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Gerstner Center for Cancer Diagnostics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071504000569000_2026.07.09.26357137v1.1","doi-asserted-by":"crossref","unstructured":"Giaquinto AN , Sung H , Newman LA , et al: Breast cancer statistics 2024 [Internet]. 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