{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T19:42:28Z","timestamp":1784662948197,"version":"3.55.0"},"reference-count":73,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HER2 testing represents a cornerstone of the treatment algorithm in advanced gastric and gastroesophageal junction adenocarcinoma (GC), yet its evaluation remains complex due to tumor heterogeneity and methodological variability. Unlike breast cancer, HER2 expression in GC is often incomplete and heterogeneous, resulting in discordant results between biopsies, resections, and metastatic sites. Both spatial and temporal HER2 heterogeneity are key determinants of testing reproducibility, diagnostic accuracy, and treatment selection and response in GC. Optimizing sampling through multiple, well-targeted biopsies, standardizing IHC\/ISH protocols, and reassessing HER2 status at progression may be crucial steps to ensure diagnostic accuracy. The recognition of HER2-low disease introduces a new pathological and clinical subgroup of GC with potential sensitivity to antibody\u2013drug conjugates, while emerging techniques such as circulating tumor DNA analysis are increasingly applied to detect HER2 amplification and co-existing genetic alterations. Integrating molecular tools and standardized reassessment strategies can enhance HER2 testing reliability and enable more precise treatment strategies, with the potential to minimize HER2 resistance mechanisms. This review provides a practice-oriented guide on the interpretation and optimization of HER2 testing in gastric cancer, while providing insight into the underlying molecular mechanisms driving heterogeneity and resistance.<\/jats:p>","DOI":"10.3390\/ijms27031542","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T14:55:11Z","timestamp":1770216911000},"page":"1542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Diagnostic and Therapeutic Challenges Related to HER2 Heterogeneity in Gastric Cancer: Bridging Molecular Pathology and Clinical Decision-Making"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8949-6286","authenticated-orcid":false,"given":"Nelia Marina","family":"Rosanu","sequence":"first","affiliation":[{"name":"European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy"},{"name":"Department of Oncology, Elias Emergency University Hospital, 011461 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-8527","authenticated-orcid":false,"given":"Lorenzo","family":"Gervaso","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Lobrano","sequence":"additional","affiliation":[{"name":"Division of Pathology, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2976-7032","authenticated-orcid":false,"given":"Alessandro","family":"Vanoli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"Unit of Anatomic Pathology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Alessandra","family":"Cella","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 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, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6869-0704","authenticated-orcid":false,"given":"Nicola","family":"Fazio","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/modpathol.2011.198","article-title":"HER2 testing in gastric cancer: A practical approach","volume":"25","author":"Hanna","year":"2012","journal-title":"Mod. 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