{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T22:54:45Z","timestamp":1777676085871,"version":"3.51.4"},"reference-count":51,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005292","name":"Brigham and Women's Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005292","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Low\u2010grade serous carcinoma (LGSC) of the ovary presents unique therapeutic challenges due to its resistance to platinum\u2010based chemotherapies and a tendency to present at an advanced stage. Approximately 50% of LGSC possess activating mutations in <jats:italic>KRAS<\/jats:italic>, <jats:italic>NRAS,<\/jats:italic> and <jats:italic>BRAF<\/jats:italic>, a finding associated with better overall survival. However, many tumours lack obvious driver alterations against which to direct targeted treatment strategies, necessitating further investigation into molecular drivers of LGSC and their impact on clinical outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>We conducted a retrospective analysis of 84 LGSC patients who underwent tumour\u2010only targeted next\u2010generation sequencing at our institution. Molecular data were correlated with clinical outcomes, HER2 immunohistochemistry, and supplemented with additional tumour sequencing data from the AACR GENIE cohort v15.1 (<jats:italic>n<\/jats:italic>\u2009=\u2009295). Approximately 5% of LGSC cases across the combined cohort harboured activating alterations in <jats:italic>ERBB2<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u200917\/369), which encodes the HER2 receptor tyrosine kinase. These alterations were mutually exclusive of other MAP kinase pathway mutations and included exon 20 insertions (<jats:italic>n<\/jats:italic>\u2009=\u20096), extracellular domain\/transmembrane domain missense alterations (<jats:italic>n<\/jats:italic>\u2009=\u20094), and exon 16 skipping mutations (<jats:italic>n<\/jats:italic>\u2009=\u20097). <jats:italic>ERBB2<\/jats:italic> exon 16 emerged as a mutational hotspot in LGSC when compared to other tumour types. Immunohistochemistry revealed variable HER2 expression patterns that were independent of <jats:italic>ERBB2<\/jats:italic> mutational status. In our institutional cohort, patients with <jats:italic>RAS\/RAF<\/jats:italic> mutant tumours (<jats:italic>n<\/jats:italic>\u2009=\u200938) showed better overall survival compared to <jats:italic>RAS\/RAF<\/jats:italic> wildtype tumours (<jats:italic>n<\/jats:italic>\u2009=\u200935). No tumours in our internal cohort (<jats:italic>n<\/jats:italic>\u2009=\u200984) harboured <jats:italic>ERBB2<\/jats:italic> amplifications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>As the landscape of HER2\u2010directed therapies continues to evolve, these findings suggest that <jats:italic>ERBB2<\/jats:italic> alterations and HER2 expression may represent a potential therapeutic target in LGSC.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.15452","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T07:03:30Z","timestamp":1743491010000},"page":"310-320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular and immunohistochemical characterization of <i>ERBB2<\/i> activating mutations in low\u2010grade serous ovarian carcinoma"],"prefix":"10.1111","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3351-787X","authenticated-orcid":false,"given":"Alexander J","family":"Neil","sequence":"first","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3946-3016","authenticated-orcid":false,"given":"Dingani","family":"Nkosi","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital, Harvard Medical School  Boston MA USA"},{"name":"Department of Pathology University of Rochester Medical Center, University of Rochester School of Medicine  Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4632-0045","authenticated-orcid":false,"given":"Ju\u2010Yoon","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology St. Michael's Hospital, Unity Health Toronto, University of Toronto  Toronto ON Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7631-6525","authenticated-orcid":false,"given":"David L","family":"Kolin","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-9735","authenticated-orcid":false,"given":"Lynette M","family":"Sholl","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2275"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7219-7_1"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01392"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02005"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.09.010"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2022.1064598","article-title":"Investigation of the prevalence and clinical implications of ERBB2 exon 16 skipping mutations in Chinese pan\u2010cancer patients","volume":"12","author":"Shang Y","year":"2022","journal-title":"Front. Oncol."},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.11.2224"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/973584"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007474117"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2020-000985"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.01047"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2744(199810)23:2<62::AID-MC2>3.0.CO;2-O"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0295"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3186"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00558-1"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0007-9"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.129"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.05.023"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAP.0b013e3181b4fffa"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5438"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2021.11.019"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-022-01897-1"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-4183"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01164"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02175-9"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2023.12.004"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2021.03.019"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.0632"},{"key":"e_1_2_10_30_1","article-title":"Time for targeted treatment in low\u2010grade serous ovarian cancer?","author":"Matei Daniela","year":"2022","journal-title":"N. Engl. J. Med. J. Watch."},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atg.2015.08.005"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2016-0527-OA"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1200\/CCI.20.00108"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2019.12.005"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.87062"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2016.10.002"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3466"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0151"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2013.113"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2019.03.014"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2013.00086"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-00695-5"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25475"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100212"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2017.121"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2023-004610"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-08-0193"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2203690"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00575"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2112431"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2023.03.016"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.15452","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T13:03:48Z","timestamp":1752498228000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.15452"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1111\/his.15452"],"URL":"https:\/\/doi.org\/10.1111\/his.15452","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,31]]},"assertion":[{"value":"2025-01-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}