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Despite their triple\u2010negative phenotype, breast MECs are generally considered low\u2010risk malignancies but their biology is largely unexplored; therefore, guidelines for clinical management are lacking. Here, we sought to characterize the molecular landscape of breast MECs. Thirteen cases were histologically reviewed, characterized for tumor\u2010infiltrating lymphocytes (TILs), and were subjected to immunohistochemistry for programmed death\u2010ligand 1 (PD\u2010L1, clone 22C3), EGFR, and amphiregulin (AREG). Rearrangements in <jats:italic>MAML2<\/jats:italic> and <jats:italic>EWSR1<\/jats:italic> were investigated by fluorescent in situ hybridization. Targeted next\u2010generation sequencing of 161 genes was performed on eight cases. Most MECs had low histological grade (<jats:italic>n<\/jats:italic>\u00a0=\u200910, 77%), with the presence of TILs (<jats:italic>n<\/jats:italic>\u00a0=\u20099\/12; 75%) and PD\u2010L1 combined positive score ranging from 10 to 20 (<jats:italic>n<\/jats:italic>\u00a0=\u20094\/6; 67%). All cases showed EGFR and AREG overexpression and were fusion negative. Enrichment of genetic alterations was observed in PI3K\/AKT\/mTOR and cell cycle regulation pathways, while only one case harbored <jats:italic>TP53<\/jats:italic> mutations. This is the first study providing extensive molecular data on breast MECs and the largest collection of cases available to date in the literature. Breast MECs lack <jats:italic>TP53<\/jats:italic> mutations found in high\u2010grade forms of triple\u2010negative breast cancers and <jats:italic>MAML2<\/jats:italic> or <jats:italic>EWSR1<\/jats:italic> rearrangements pathognomonic of salivary MECs. Triple\u2010negativity and PD\u2010L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR\/AREG axis activation, coupled with the mutational patterns in PI3K\/AKT\/mTOR and cell cycle pathways warrants caution in considering MECs as low\u2010risk neoplasms.<\/jats:p>","DOI":"10.1002\/cam4.5754","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T10:08:04Z","timestamp":1678788484000},"page":"10725-10737","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The molecular landscape of breast mucoepidermoid carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Konstantinos","family":"Venetis","sequence":"first","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"},{"name":"Department of Oncology and Hemato\u2010Oncology University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Sajjadi","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"},{"name":"Department of Oncology and Hemato\u2010Oncology University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariia","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Andaloro","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Pessina","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zanetti","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of 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Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umberto","family":"Malapelle","sequence":"additional","affiliation":[{"name":"Department of Public Health University Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Pagni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery Pathology, University Milan Bicocca  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Barberis","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Guerini\u2010Rocco","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"},{"name":"Department of Oncology and Hemato\u2010Oncology University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Viale","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"},{"name":"Department of Oncology and Hemato\u2010Oncology University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9101-9131","authenticated-orcid":false,"given":"Nicola","family":"Fusco","sequence":"additional","affiliation":[{"name":"Division of Pathology IEO, European Institute of Oncology IRCCS  Milan Italy"},{"name":"Department of Oncology and Hemato\u2010Oncology University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,14]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"WHO Classification of Tumours 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