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Among these high-risk subgroups, ERpHER2n Basal-like (ERpHER2n-Basal) breast cancer, as defined by PAM50 gene expression subtyping, remains poorly characterized due to limited available material. However, understanding the somatic molecular features driving treatment resistance and progression is critical for optimizing therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address these challenges, we comprehensively characterized the patient subgroup by comparing it to both ERpHER2n and triple-negative breast cancer (TNBC) patients. We investigated 4474 Swedish patients with primary ERpHER2n tumors (Basal-like\u2009=\u200976, Luminal A\u2009=\u20093049, Luminal B\u2009=\u20091349) with clinical and RNA-sequencing data available, including 16 Basal-like tumors with whole-genome sequencing and matched global DNA methylation data. For TNBC comparisons, we used an additional 228 cases with available WGS, RNA-sequencing, and DNA methylation data. ER-positivity was defined as\u2009\u2265\u200910% of tumor cells being IHC-stained according to Swedish national guidelines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinicopathological analyses highlighted ERpHER2n-Basal patients as a small subgroup comprising generally younger patients with high-grade and high-risk tumors. This patient group was associated with worse prognosis than Luminal A\/Luminal B subtypes, especially when treated only with endocrine therapy, independent of lymph node status, patient age, tumor size and grade. Molecularly, ERpHER2n-Basal tumors were distinguished by high proliferation and elevated immune response together with low\n                      <jats:italic>ESR1<\/jats:italic>\n                      mRNA expression and low activity of steroid-response pathways. High proportions of the mutational signatures associated with homologous recombination deficiency in ERpHER2n-Basal tumors suggest potential benefits from platinum or PARP inhibitor treatments. Additionally, their DNA methylation profile closely resembles that of Basal triple-negative breast cancer (TNBC), indicating shared epigenetic regulation despite differences in ER status. Further molecular similarities to TNBC such as high immune infiltration indicate immune checkpoint inhibitors as promising agents for improving patient care.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ERpHER2n-Basal breast cancer represents a clinically high-risk subgroup whose molecular resemblance to TNBC highlights potential therapeutic opportunities, particularly for immunotherapy and DNA repair\u2013targeting treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-025-01576-9","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T10:02:52Z","timestamp":1764583372000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular profiling of the Basal-like intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer"],"prefix":"10.1186","volume":"17","author":[{"given":"Lennart","family":"Hohmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah F.","family":"Nacer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias","family":"Aine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasin","family":"Memari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella","family":"Black","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramsay","family":"Bowden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen R.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5ke","family":"Borg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Vallon-Christersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Nik-Zainal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Staaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"issue":"1","key":"1576_CR1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13073-015-0131-9","volume":"7","author":"LH Saal","year":"2015","unstructured":"Saal LH, Vallon-Christersson J, H\u00e4kkinen J, Hegardt C, Grabau D, Winter C, et al. 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Available from: https:\/\/www.cancer.gov\/ccg\/research\/genome-sequencing\/tcga\/history\/ethics-policies."}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-025-01576-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-025-01576-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-025-01576-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T11:01:48Z","timestamp":1764586908000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomemedicine.biomedcentral.com\/articles\/10.1186\/s13073-025-01576-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1576"],"URL":"https:\/\/doi.org\/10.1186\/s13073-025-01576-9","relation":{},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"assertion":[{"value":"13 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The SCAN-B study (ClinicalTrials.gov ID NCT02306096) [\n                      \n                      ,\n                      \n                      ] is approved by the Regional Ethical Review Board in Lund, Sweden (registration numbers 2009\/658, 2010\/383, 2012\/58, 2013\/459, 2014\/521, 2015\/277, 2016\/541, 2016\/742, 2016\/944, 2018\/267) and the Swedish Ethical Review Authority (registration numbers 2019\u201301252, 2024\u201302040-02). All patients provided written informed consent prior to enrolment, and all analyses were performed in accordance with patient consent and ethical regulations and decisions. Ethical approvals and patient consent procedures for the METABRIC [\n                      \n                      ], BASIS [\n                      \n                      ], and TCGA [\n                      \n                      ] cohorts are reported in the respective original publications, and all analyses in the present study were conducted in accordance with these approvals and the associated ethical regulations. This study conformed to the principles of the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"S.N.-Z. and H.R.D. hold patents or have submitted applications on clinical algorithms of mutational signatures: HRDetect (PCT\/EP2017\/060294), clinical use of signatures (PCT\/EP2017\/060289) and clinical predictor (PCT\/EP2017\/060298. S.N.Z. also holds the following patents: MMRDetect (PCT\/EP2022\/057387), rearrangement signature methods (PCT\/EP2017\/060279) and hotspots for chromosomal rearrangements (PCT\/EP2017\/060298). Two further patent filings have been made recently (numbers are pending). All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"146"}}