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We tested if differential microRNA expression in primary tumors allows reliable identification of indolent LNN BC patients to provide an improved classification tool for overtreatment reduction in this patient group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We collected freshly frozen primary tumors of 80 LNN BC patients with recurrence and 80 recurrence\u2010free patients (mean follow\u2010up: 20.9\u2009years). The study comprises solely systemically untreated patients to exclude that administered treatments confound the metastasis status. Samples were pairwise matched for clinical\u2010pathological characteristics to minimize dependence of current markers. Patients were classified into risk\u2010subgroups according to the differential microRNA expression of their tumors via classification model building with cross\u2010validation using seven classification methods and a voting scheme. The methodology was validated using available data of two independent cohorts (<jats:italic>n<\/jats:italic>\u2009=\u2009123, <jats:italic>n<\/jats:italic>\u2009=\u2009339).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 80 indolent patients (who would all likely receive systemic treatments today) our ultralow\u2010risk classifier correctly identified 37 while keeping a sensitivity of 100% in the recurrence group. Multivariable logistic regression analysis confirmed independence of voting results from current clinical markers. Application of the method in two validation cohorts confirmed successful classification of ultralow\u2010risk BC patients with significantly prolonged recurrence\u2010free survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Profiles of differential microRNAs expression can identify LNN BC patients who could spare systemic treatments demanded by currently applied classifications. However, further validation studies are required for clinical implementation of the applied methodology.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.7089","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T07:48:15Z","timestamp":1714204095000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ensemble\u2010based classification using <scp>microRNA<\/scp> expression identifies a breast cancer patient subgroup with an ultralow long\u2010term risk of metastases"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-6031","authenticated-orcid":false,"given":"Ines","family":"Block","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Burton","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Human Genetics, Department of Clinical Research University of Southern Denmark  Odense Denmark"},{"name":"Clinical Genome Center University of Southern Denmark and Region of Southern Denmark  Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina P.","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Human Genetics, Department of Clinical Research University of Southern Denmark  Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thi T. 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