{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T20:28:12Z","timestamp":1785875292324,"version":"3.56.0"},"reference-count":33,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"\n Importance<\/jats:title>\n Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 67\u202f692 women were studied, including 33\u202f841 who were diagnosed with breast cancer. PVs in\n ATM<\/jats:italic>\n ,\n BRCA1<\/jats:italic>\n ,\n BRCA2<\/jats:italic>\n ,\n CHEK2<\/jats:italic>\n , and\n PALB2<\/jats:italic>\n were strongly associated with breast cancer risk, with\n BRCA1<\/jats:italic>\n and\n PALB2<\/jats:italic>\n PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in\n PALB2<\/jats:italic>\n PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for\n PALB2<\/jats:italic>\n carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaoncol.2025.3875","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T15:00:31Z","timestamp":1760022031000},"page":"1458","source":"Crossref","is-referenced-by-count":9,"title":["Pathogenic Variants, Family History, and Cumulative Risk of Breast Cancer in US Women"],"prefix":"10.1001","volume":"11","author":[{"given":"Katie M.","family":"O\u2019Brien","sequence":"first","affiliation":[{"name":"Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander P.","family":"Keil","sequence":"additional","affiliation":[{"name":"Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarice R.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Polley","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, University of Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddhartha","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Boddicker","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunling","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine B.","family":"Ambrosone","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center, Buffalo, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda","family":"Anton-Culver","sequence":"additional","affiliation":[{"name":"University of California, Irvine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul L.","family":"Auer","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Data Science Institute, and Cancer Center, Medical College of Wisconsin, Milwaukee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Bodelon","sequence":"additional","affiliation":[{"name":"Department of Population Science, American Cancer Society, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Brantley","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth S.","family":"Burnside","sequence":"additional","affiliation":[{"name":"Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin\u2013Madison"},{"name":"Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin\u2013Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Chen","sequence":"additional","affiliation":[{"name":"Keck School of Medicine, University of Southern California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Domchek","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia"},{"name":"Basser Center for Breast Cancer, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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