{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T11:12:19Z","timestamp":1762859539278,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001348","name":"Agency for Science, Technology and Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001348","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Precision Health Research Singapore Clinical Implementation Pilot"},{"DOI":"10.13039\/100008762","name":"Genome Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008762","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Genome Qu\u00e9bec","award":["PSR-SIIRI-701"],"award-info":[{"award-number":["PSR-SIIRI-701"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U19 CA148065","X01HG007492"],"award-info":[{"award-number":["U19 CA148065","X01HG007492"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C1287\/A10118","C1287\/A16563","C1287\/A10710"],"award-info":[{"award-number":["C1287\/A10118","C1287\/A16563","C1287\/A10710"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["HEALTH-F2-2009-223175","H2020 633784","634935"],"award-info":[{"award-number":["HEALTH-F2-2009-223175","H2020 633784","634935"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case\u2013control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (&lt;50 years) women (OR = 2.51, AUC = 0.622) than in women \u2265 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62\u20131.64, AUC = 0.551\u20130.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94\u20130.99, AUC = 0.523\u20130.533). Age interactions were observed for both PRS (p &lt; 0.001) and Gail (p &lt; 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p &lt; 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially \u226550 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p &lt; 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.<\/jats:p>","DOI":"10.3390\/cancers17213561","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:40:48Z","timestamp":1762180848000},"page":"3561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3017-4023","authenticated-orcid":false,"given":"Peh Joo","family":"Ho","sequence":"first","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore"},{"name":"Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3689-3970","authenticated-orcid":false,"given":"Christine Kim Yan","family":"Loo","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan Jak Yang","family":"Lim","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng Huang","family":"Goh","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3728-6535","authenticated-orcid":false,"given":"Mustapha","family":"Abubakar","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0771-7752","authenticated-orcid":false,"given":"Thomas U.","family":"Ahearn","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4226-6435","authenticated-orcid":false,"given":"Irene L.","family":"Andrulis","sequence":"additional","affiliation":[{"name":"Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada"},{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia N.","family":"Antonenkova","sequence":"additional","affiliation":[{"name":"N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040 Minsk, Belarus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristan J.","family":"Aronson","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Sinclair Cancer Research Institute, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3415-0536","authenticated-orcid":false,"given":"Annelie","family":"Augustinsson","sequence":"additional","affiliation":[{"name":"Oncology, Department of Clinical Sciences in Lund, Lund University, 221 85 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9714-104X","authenticated-orcid":false,"given":"Sabine","family":"Behrens","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6578-2678","authenticated-orcid":false,"given":"Clara","family":"Bodelon","sequence":"additional","affiliation":[{"name":"Department of Population Science, American Cancer Society, Atlanta, GA 30303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9736-4593","authenticated-orcid":false,"given":"Natalia V.","family":"Bogdanova","sequence":"additional","affiliation":[{"name":"N.N. 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R.","family":"Geurts-Giele","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gord","family":"Glendon","sequence":"additional","affiliation":[{"name":"Fred A. 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