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We hypothesized that genetic and\/or phenotypic intra-tumor heterogeneity would predict clinical outcomes for DCIS since it serves as the substrate for natural selection among cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We profiled two samples from two geographically distinct foci from each DCIS in both cross-sectional (n\u2009=\u2009119) and longitudinal cohorts (n\u2009=\u2009224), with whole exome sequencing, low-pass whole genome sequencing, and a panel of immunohistochemical markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the longitudinal cohorts, the only statistically significant associations with time to non-invasive DCIS recurrence were the combination of treatment (lumpectomy only vs mastectomy or lumpectomy with radiation, HR 12.13,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003, Wald test with FDR correction), ER status (HR 0.16 for ER+\u2009compared to ER\u2212,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0045), and divergence in SNVs between the two samples (HR 1.33 per 10% divergence,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.018). SNV divergence also distinguished between pure DCIS and DCIS synchronous with invasive disease in the cross-sectional cohort. In contrast, the only statistically significant associations with time to progression to invasive disease were the combination of the width of the surgical margin (HR\u20090.67 per mm,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.043) and the number of mutations that were detectable at high allele frequencies (HR\u20091.30 per 10 SNVs,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.02). No predictors were significantly associated with both DCIS recurrence and progression to invasive disease, suggesting that the evolutionary scenarios that lead to these clinical outcomes are markedly different.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results imply that recurrence with DCIS is a clinical and biological process different from invasive progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13058-025-01966-2","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T15:20:22Z","timestamp":1742570422000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evolutionary measures show that recurrence of DCIS is distinct from progression to breast cancer"],"prefix":"10.1186","volume":"27","author":[{"given":"Angelo","family":"Fortunato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Mallo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Cisneros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine M.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aziz","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc D.","family":"Ryser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph Y.","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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