{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T04:31:26Z","timestamp":1783917086301,"version":"3.55.0"},"reference-count":73,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009465","name":"(Chilean Economic Development Agency)","doi-asserted-by":"publisher","award":["22CVID-206707"],"award-info":[{"award-number":["22CVID-206707"]}],"id":[{"id":"10.13039\/100009465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009465","name":"(Chilean Economic Development Agency)","doi-asserted-by":"publisher","award":["22CVC2-218129"],"award-info":[{"award-number":["22CVC2-218129"]}],"id":[{"id":"10.13039\/100009465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009465","name":"(Chilean Economic Development Agency)","doi-asserted-by":"publisher","award":["20IAT130292"],"award-info":[{"award-number":["20IAT130292"]}],"id":[{"id":"10.13039\/100009465","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Distant metastasis is the main cause of breast cancer (BC) mortality, yet current prognostic models remain largely tumor-centric and underutilize stromal biology. In this study, we quantified reactive stroma, a collagen-rich and fibrotic fraction of the stromal compartment, as a subtype-independent biomarker of metastatic risk. A retrospective cohort of 182 FFPE primary BC biopsies (2006\u20132020) was analyzed. Total stroma was quantified on H&amp;E-stained sections and reactive stroma on Masson\u2019s trichrome using QuPath with pathologist validation. Cutoffs were defined using maximally selected rank statistics, and overall survival (OS) and metastasis-free survival (MFS) were evaluated by Kaplan\u2013Meier analysis and multivariable Cox regression. RNA sequencing was performed in a subset of cases to characterize associated transcriptomic programs. While total stromal content showed univariate associations with OS and MFS, it was not independently prognostic after adjustment. In contrast, high reactive stroma (cutoff 53.2%) independently predicted shorter MFS (HR = 3.76; p &lt; 0.001), irrespective of molecular subtype and clinicopathological variables. Tumors with high reactive stroma exhibited upregulation of extracellular matrix and profibrotic genes (including FN1, OLR1, and EDN2), enrichment of collagen remodeling and TGF-\u03b2 signaling pathways, and reduced T-cell activation signatures. These findings demonstrate that quantitative assessment of reactive stroma from standard histological stains is a reproducible, subtype-independent biomarker of metastatic risk in BC and can be readily integrated into routine pathology workflows to improve risk stratification.<\/jats:p>","DOI":"10.3390\/ijms27052213","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:51:29Z","timestamp":1772117489000},"page":"2213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reactive Stroma as a Transversal Prognostic Biomarker for Metastasis in Breast Cancer: Integration of Digital Histopathology and Transcriptomic Profiling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8546-5941","authenticated-orcid":false,"given":"Daniela P.","family":"Barrera","sequence":"first","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"},{"name":"Facultad de Medicina y Ciencia, Universidad San Sebasti\u00e1n, Santiago 7510157, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel A.","family":"N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Cerda I.","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"},{"name":"Facultad de Medicina y Ciencia, Universidad San Sebasti\u00e1n, Santiago 7510157, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Sebasti\u00e1n","family":"Contreras-Riquelme","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Henr\u00edquez","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Pereira","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Toledo","sequence":"additional","affiliation":[{"name":"Unidad Cirug\u00eda Oncol\u00f3gica Mamaria, OECI Cancer Center, Fundaci\u00f3n Arturo L\u00f3pez P\u00e9rez, Santiago 7500921, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badir","family":"Chahuan","sequence":"additional","affiliation":[{"name":"Unidad Cirug\u00eda Oncol\u00f3gica Mamaria, OECI Cancer Center, Fundaci\u00f3n Arturo L\u00f3pez P\u00e9rez, Santiago 7500921, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Sapunar-Zenteno","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n e Innovaci\u00f3n en C\u00e1ncer, OECI Cancer Center, Fundaci\u00f3n Arturo L\u00f3pez P\u00e9rez, Santiago 7500921, Chile"},{"name":"Centro de Excelencia CIGES, Facultad de Medicina, Universidad de la Frontera, Temuco 4811230, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ximena","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Hospital San Jos\u00e9, Santiago 8380419, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Moreno","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"Red Salud UC-Christus, Santiago 8330024, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Tom\u00e1s","family":"Larach","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"Red Salud UC-Christus, Santiago 8330024, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjam\u00edn","family":"Prieto","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"},{"name":"Department of Pathology, School of Medicine, Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330077, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonor","family":"Moyano","sequence":"additional","affiliation":[{"name":"Instituto Nacional del C\u00e1ncer, Santiago 8380450, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"Red Salud UC-Christus, Santiago 8330024, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Cerda-Infante","sequence":"additional","affiliation":[{"name":"Environ, Startup and Spin-Off from Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7500571, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1038\/s41467-024-45307-x","article-title":"Causes of death among people living with metastatic cancer","volume":"15","author":"Mani","year":"2024","journal-title":"Nat. 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