{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:49:41Z","timestamp":1791049781031,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers. Methods: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. Results: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p &lt; 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years). Conclusions: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.<\/jats:p>","DOI":"10.3390\/cancers16051062","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T11:26:59Z","timestamp":1709638019000},"page":"1062","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["High HER2 Intratumoral Heterogeneity Is a Predictive Factor for Poor Prognosis in Early-Stage and Locally Advanced HER2-Positive Breast Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Tomonori","family":"Tanei","sequence":"first","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3861-6444","authenticated-orcid":false,"given":"Shigeto","family":"Seno","sequence":"additional","affiliation":[{"name":"Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-652X","authenticated-orcid":false,"given":"Yoshiaki","family":"Sota","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Hatano","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Kitahara","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6164-5107","authenticated-orcid":false,"given":"Nanae","family":"Masunaga","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Tsukabe","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuhiro","family":"Yoshinami","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Miyake","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Shimoda","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4701-3779","authenticated-orcid":false,"given":"Hideo","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenzo","family":"Shimazu","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1080\/14737167.2018.1505505","article-title":"Health Economic Impact of Liquid Biopsies in Cancer Management","volume":"18","author":"IJzerman","year":"2018","journal-title":"Expert Rev. 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