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This study evaluates an automated Ki67-area identification approach, combined with digital image analysis (DIA) for exact Ki67 quantification. A total of 61 tissue samples from breast cancer patients from two clinical trials (GeparSixto and GeparSepto) were analyzed. The supervised DIA workflow employed automated Ki67-stained tumor area identification, followed by automated Ki67 scoring and was quality-controlled by trained pathologists. Comparisons with manual assessments were conducted to evaluate concordance and scoring precision. The DIA approach identified 232 tumor areas across 61 whole slide images (WSIs). The supervised system demonstrated a high correlation with manual scores (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.78), and improved precision (standard deviation between evaluated tumor areas) was noted in therapy-na\u00efve samples (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). While manual assessments predominantly employed stepwise increments (5%), DIA provided finer, more continuous scoring, optimally reflecting the continuous nature of tumor proliferation. Overall, DIA scoring was more robust, with reduced inter-ROI variability and improved reproducibility compared with manual assessment. In conclusion, the study highlights the potential of supervised DIA to enhance Ki67 scoring accuracy and standardization. The methodology\u2019s effectiveness in addressing standardized Ki67 scoring suggests its utility in clinical diagnostic workflows. This approach contributes towards improved integration of computational pathology into routine practice for improved breast cancer management.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00428-026-04500-7","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T06:24:00Z","timestamp":1776925440000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of Ki67 digital image analysis in breast cancer by automated tumor area identification"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-0476","authenticated-orcid":false,"given":"Paul","family":"Jank","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian J.","family":"Kr\u00e4mer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Untch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattea","family":"Reinisch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"Link","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Grass","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens-Uwe","family":"Blohmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus","family":"Hanusch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Sophie","family":"Litmeyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Huober","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Gerber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Solbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vesna","family":"Bjelic-Radisic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Saeger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Schneeweiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerstin","family":"Rhiem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moritz","family":"Gleitsmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"von Gerlach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e4rbel","family":"Felder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moritz","family":"Jesinghaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carsten","family":"Denkert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sibylle","family":"Loibl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang D.","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"4500_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1111\/his.14355","volume":"79","author":"A Alataki","year":"2021","unstructured":"Alataki A, Zabaglo L, Tovey H, Dodson A, Dowsett M (2021) A simple digital image analysis system for automated Ki67 assessment in primary breast cancer. 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Jank reports grants and travel expenses from Gilead Sciences GmbH outside the submitted work. C. Denkert reports other support from MSD Oncology, personal fees from Daiichi Sankyo and AstraZeneca, and grants from Myriad Genetics and German Breast Group outside the submitted work. C. Denkert also reports a patent for VMscope digital pathology software with royalties paid, a patent for WO2020109570A1 issued, a patent for WO2015114146A1 issued, and a patent for WO2010076322A1 issued. W. D. Schmitt received speakers\u2019 honoraria from AstraZeneca, Bundesverband Deutscher Pathologen, Deutsche Akademie f\u00fcr Senologie, GlaxoSmithKline, NOGGO, and Roche outside of this study and adboard honoraria from AstraZeneca and Myriad outside of this study, and financial funding from Myriad outside of this study. K. Saeger is CEO of VMscope GmbH, which is the producer and distributor of the CMPS software and its modules \u201cKi67 Quantifier clinical\u201d and \u201cScan Connect.\u201d J. Huober received honoraria from Lilly, Novartis, Roche, Pfizer, AstraZeneca, Gilead, Daiichi, Stemline, MSD, and AbbVie and reports consulting or advisory relationships with Lilly, Novartis, Roche, Pfizer, AstraZeneca, Gilead, Daiichi, and AbbVie and received travel expenses from Roche, Daiichi, Gilead, and AstraZeneca. M. Reinisch reports honoraria and\/or consultancy fees from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, OnkowissenTV, Seagen, Streamed Up, and Somatex. M. Reinisch also reports travel support from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Novartis, Pfizer, and Roche.\u00a0T. Link reports\u00a0Honoraria for Lectures or presentations from\u00a0Amgen, Roche, MSD, Novartis, Pfizer, Lilly, GSK, Gilead, Astra Zeneca, Daiichi Sankyo, Stemline, Seagen; Advisory Board\/Advise from MSD, Roche, Pfizer, Lilly, Myriad, Esai, GSK, Gilead, Daiichi Sankyo, Roche, Astra Zeneca and support for attending meetings and\/or travel from\u00a0Pfizer, Astra Zeneca, Gilead, Daiichi Sankyo, Stemline, Seagen, MSD. C.\u00a0Hanusch reports\u00a0Speakers Bureau from\u00a0Astra Zeneca, Novartis, Roche.\u00a0S.\u00a0declares to be GBG Forschungs GmbH employee (CEO); The institution receives grants and\/or contracts from the following entities: AbbVie, AICME, AstraZeneca, Agendia, Amgen, Bayer, BeiGene, Bicycle, BioNTech, Celgene\/BMS, Cellcuity, Chugai Pharmaceuticals, Corcept Therapeutics, DSI, Exact Science, Gilead, GSK, Incyte, Lilly, Medscape, MICE ideas, Molecular Health, Jiangsu Hengrui, MSD, Novartis, Olema, Peerview, Pierre Fabre, Pfizer, Relay, Roche, Sanofi, Seagen, Stemline\/Menarini, JAZZ Pharmaceuticals; receives support for attending meetings and\/or travel from DSI, Gilead, Roche, Lilly, ESMO, SGBCC, ASCO, AGO Kommission Mamma; GBG Forschungs GmbH has following \/patents planned, issued or pending: EP14153692.0, EP21152186.9, EP18209672 and EP24210258 and receives licensing fees from VM Scope GmbH.\u00a0B.\u00a0Felder declares to be GBG Forschungs GmbH employee; The institution receives grants and\/or contracts from the following entities: AbbVie, AICME, AstraZeneca, Agendia, Amgen, Bayer, BeiGene, Bicycle, BioNTech, Celgene\/BMS, Cellcuity, Chugai Pharmaceuticals, Corcept Therapeutics, DSI, Exact Science, Gilead, GSK, Incyte, Lilly, Medscape, MICE ideas, Molecular Health, Jiangsu Hengrui, MSD, Novartis, Olema, Peerview, Pierre Fabre, Pfizer, Relay, Roche, Sanofi, Seagen, Stemline\/Menarini, JAZZ Pharmaceuticals; receives support for attending meetings and\/or travel from DSI, Gilead, Roche, Lilly, ESMO, SGBCC, ASCO, AGO Kommission Mamma; GBG Forschungs GmbH has following \/patents planned, issued or pending: EP14153692.0, EP21152186.9, EP18209672 and EP24210258 and receives licensing fees from VM Scope GmbH.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"During the preparation of this work, the authors used ChatGPT OpenAI (OpenAI Ireland Ltd., Dublin, Ireland) for spell and grammar checking. After using this tool\/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration of generative AI and AI-assisted technologies in the writing process"}}]}}