{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:29:59Z","timestamp":1787318999398,"version":"build-2736575974"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T00:00:00Z","timestamp":1705795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology CR"],"published-print":{"date-parts":[[2024,3]]},"abstract":"Abstract<\/jats:title>\n \n Most invasive lobular breast carcinomas (ILBCs) are luminal\u2010type carcinomas with an HER2\u2010negative phenotype (\n ERBB2 or HER2<\/jats:italic>\n un\u2010amplified) and\n CDH1<\/jats:italic>\n mutations. Rare variants include\n ERBB2<\/jats:italic>\n \u2010amplified subtypes associated with an unfavorable prognosis and less response to anti\u2010HER2 targeted therapies. We analyzed the clinicopathological and molecular features of\n ERBB2<\/jats:italic>\n \u2010amplified ILBC and compared these characteristics with\n ERBB2<\/jats:italic>\n \u2010unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin\u2010embedded formalin\u2010fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast\u2010specific markers was tested by immunohistochemistry (IHC). Hybrid capture\u2010based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent\n in situ<\/jats:italic>\n hybridization (FISH) or IHC positive for\n HER2<\/jats:italic>\n amplification\/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of\n ERBB2<\/jats:italic>\n amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were\n ERBB2<\/jats:italic>\n amplified.\n ERBB2<\/jats:italic>\n \u2010amplified ILBC had higher tumor stage (\n p<\/jats:italic>\n \u2009<\u20090.0001), more frequent positive nodal status (\n p<\/jats:italic>\n \u2009=\u20090.00022), more distant metastases (\n p<\/jats:italic>\n \u2009=\u20090.012), and higher histological grade (\n p<\/jats:italic>\n \u2009<\u20090.0001), and were more often hormone receptor negative (\n p<\/jats:italic>\n \u2009<\u20090.001) and more often SOX10 positive (\n p<\/jats:italic>\n \u2009=\u20090.005).\n ERBB2<\/jats:italic>\n short variant sequence mutations were more often detected in\n ERBB2<\/jats:italic>\n \u2010unamplified tumors (6\/10,\n p<\/jats:italic>\n \u2009=\u20090.027), whereas\n CDH1<\/jats:italic>\n mutations\/copy loss were frequently present in both subgroups (9\/10 and 7\/10, respectively). Amplification of pathogenic genes were more common in HER2\u2010positive ILBC (\n p<\/jats:italic>\n \u2009=\u20090.0009).\n CDK12<\/jats:italic>\n gene amplification (\u22656 copies) was detected in 7 of 10\n ERBB2<\/jats:italic>\n \u2010amplified ILBC (\n p<\/jats:italic>\n \u2009=\u20090.018). There were no\n CDK12<\/jats:italic>\n gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database.\n ERBB2<\/jats:italic>\n \u2010amplified ILBC is a distinct molecular subgroup with frequent coamplification of\n CDK12<\/jats:italic>\n , whereas\n ERBB2<\/jats:italic>\n sequence mutations occur only in\n ERBB2<\/jats:italic>\n \u2010unamplified ILBC.\n CDK12<\/jats:italic>\n \/\n ERBB2<\/jats:italic>\n co\u2010amplification may explain the poor prognosis and therapy resistance of\n ERBB2<\/jats:italic>\n \u2010amplified ILBC.\n <\/jats:p>","DOI":"10.1002\/2056-4538.12362","type":"journal-article","created":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T22:55:38Z","timestamp":1705877738000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["ERBB2<\/i>\n \u2010amplified lobular breast carcinoma exhibits concomitant\n CDK12<\/i>\n co\u2010amplification associated with poor prognostic features"],"prefix":"10.1002","volume":"10","author":[{"given":"Miriam","family":"Forster\u2010Sack","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Pathology University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Zoche","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Pestalozzi","sequence":"additional","affiliation":[{"name":"Department of Oncology University Hospital Zurich Z\u00fcrich Switzerland"},{"name":"Comprehensive Cancer Center, Breast Center University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabell","family":"Witzel","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, Breast Center University Hospital Zurich Z\u00fcrich Switzerland"},{"name":"Department of Gynecology University Hospital Zurich, University of Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther Irene","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Pulmonology University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel Julien","family":"Herzig","sequence":"additional","affiliation":[{"name":"Department of Pulmonology University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisham","family":"Fansa","sequence":"additional","affiliation":[{"name":"Breast Center Hospital Zollikerberg Zollikerberg Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Tausch","sequence":"additional","affiliation":[{"name":"Breast Center Seefeld Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Pathology, Urology and Medicine (Oncology) Upstate Medical University Syracuse NY USA"},{"name":"Foundation Medicine, Inc. Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-2839","authenticated-orcid":false,"given":"Holger","family":"Moch","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2855-983X","authenticated-orcid":false,"given":"Zsuzsanna","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology University Hospital Zurich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,21]]},"reference":[{"key":"e_1_2_7_2_1","volume-title":"WHO Classification of Tumours, Breast Tumours","author":"Editorial Board of the WHO Classification of Tumours","year":"2019"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3233\/BD-2009-0278"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12282-022-01432-3"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol28030150"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/aqz194"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-021-06432-z"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22716"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clbc.2018.04.006"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.50.9984"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.09.2775"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.77.8738"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140652"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-13-615"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105961"},{"key":"e_1_2_7_16_1","volume-title":"WHO Classification of Tumours of the Breast","author":"Lakhani SR","year":"2012"},{"key":"e_1_2_7_17_1","volume-title":"WHO Classification of Tumours: Pathology and Genetics of Tumours of the Breast and Female Genital Organs","author":"Tavassoli FA","year":"2003"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02309"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0424-2"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0386"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02767"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy263"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.778511"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0295"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-019-02163-2"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201948058"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-2827"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2020.11.045"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0760"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13734"}],"container-title":["The Journal of Pathology: Clinical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2056-4538.12362","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T21:40:47Z","timestamp":1760305247000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/2056-4538.12362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,21]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1002\/2056-4538.12362"],"URL":"https:\/\/doi.org\/10.1002\/2056-4538.12362","archive":["Portico"],"relation":{},"ISSN":["2056-4538","2056-4538"],"issn-type":[{"value":"2056-4538","type":"print"},{"value":"2056-4538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,21]]},"assertion":[{"value":"2023-09-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12362"}}