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However, their predictive role in the neoadjuvant setting remains controversial. We retrospectively analyzed 59 patients with HER2-positive invasive breast carcinoma treated with neoadjuvant chemotherapy and anti-HER2 agents at the Agostino Gemelli University Hospital (2018\u20132020). HER2 ITH was assessed on pre-treatment biopsies and residual tumors (when applicable) by immunohistochemistry and SISH. HER3 expression was also evaluated using IHC and categorized as negative, low, or high. The association with pathological complete response (pCR) and event-free survival (EFS) was assessed. pCR was achieved in 49.2% of patients. HER2 ITH was present in 23.7% of biopsies and was significantly associated with a lower pCR rate (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.005). In multivariate analysis, HER2 ITH (OR 0.156,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.030), HER2 score (3\u2009+\u2009vs 2\u2009+\u2009, OR 9.63,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.044), and PgR negativity (OR 0.306,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.029) emerged as independent predictors of pCR. HER3 expression did not significantly correlate with pCR or EFS, although a non-significant trend toward reduced EFS was observed in HER3-high cases. HER2 ITH negatively impacts pathological response to neoadjuvant therapy in HER2-positive breast cancer and may serve as a potential predictive biomarker. HER3 expression, while not significantly associated with outcome in this cohort, warrants further investigation as a possible contributor to therapeutic resistance. Standardized assessment protocols for both markers could improve patient stratification, guide treatment intensification, and support the integration of novel targeted agents in HER2-positive breast cancer.\n                  <\/jats:p>","DOI":"10.1007\/s00428-025-04310-3","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T07:22:11Z","timestamp":1761808931000},"page":"1379-1391","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HER2 intratumoral heterogeneity predicts response to neoadjuvant therapy in HER2-positive breast cancer: impact and interplay with HER3 expression"],"prefix":"10.1007","volume":"488","author":[{"given":"Angela","family":"Santoro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Vegni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"d\u2019Amati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Addante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Angelico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Fabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther Diana","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Franco","family":"Zannoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Mule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"4310_CR1","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1016\/S0140-6736(20)32381-3","volume":"397","author":"S Loibl","year":"2021","unstructured":"Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G (2021) Breast cancer. 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The clinical information had been retrieved from the patient\u2019s medical records and pathology reports. Patients\u2019 initials or other personal identifiers did not appear in any image. Finally, all samples were anonymized before histology and immunohistochemistry. Due to the retrospective nature of the study, our institution did not deem the approval of an ethical committee as necessary because the analyzed data were collected as part of diagnosis, and patients were diagnosed and treated according to national\/international guidelines and agreements. Our analysis looked retrospectively at the treated patient outcomes. This was achieved internally as part of an audit\/evaluation to improve our quality of care.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no conflict of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}