Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

Ho, P. J.; Loo, C. K. Y.; Goh, M. H.; Abubakar, M.; Ahearn, T. U.; Andrulis, I. L.; Antonenkova, N. N.; Aronson, K. J.; Augustinsson, A.; Behrens, S.; Bodelon, C.; Bogdanova, N. V.; Bolla, M. K.; Brantley, K.; Brenner, H.; Byers, H.; Camp, N. J.; Castelao, J. E.; Cessna, M. H.; Chang-Claude, J.; Chanock, S. J.; Chenevix-Trench, G.; Choi, J. Y.; Colonna, S. V.; Czene, K.; Daly, M. B.; Derouane, F.; Dörk, T.; Eliassen, A. H.; Engel, C.; Eriksson, M.; Evans, D. G.; Fletcher, O.; Fritschi, L.; Gago-Dominguez, M.; Genkinger, J. M.; Geurts-Giele, W. R. R.; Glendon, G.; Hall, P.; Hamann, U.; Ho, C. Y. S.; Ho, W. K.; Hooning, M. J.; Hoppe, R.; Howell, A.; Humphreys, K.; Ito, H.; Iwasaki, M.; Jakubowska, A.; Jernström, H.; John, E. M.; Johnson, N.; Kang, D.; Kim, S. W.; Kitahara, C. M.; Ko, Y. D.; Kraft, P.; Kwong, A.; Lambrechts, D.; Larsson, S.; Li, S.; Lindblom, A.; Linet, M.; Lissowska, J.; Lophatananon, A.; MacInnis, R. J.; Mannermaa, A.; Manoukian, S.; Margolin, S.; Matsuo, K.; Michailidou, K.; Milne, R. L.; Taib, N. A. M.; Muir, K.; Murphy, R. A.; Newman, W. G.; O'Brien, K. M.; Obi, N.; Olopade, O. I.; Panayiotidis, M. I.; Park, S. K.; Park-Simon, T. W.; Patel, A. V.; Peterlongo, P.; Plaseska-Karanfilska, D.; Pylkäs, K.; Rashid, M. U.; Rennert, G.; Rodriguez, J.; Saloustros, E.; Sandler, D. P.; Sawyer, E. J.; Scott, C. G.; Shahi, S.; Shu, X. O.; Shulman, K.; Simard, J.; Southey, M. C.; Stone, J.; Taylor, J. A.; Teo, S. H.; Teras, L. R.; Terry, M. B.; Torres, D.; Vachon, C. M.; Van Houdt, M.; Verhoeven, J.; Weinberg, C. R.; Wolk, A.; Yamaji, T.; Yip, C. H.; Zheng, W.; Hartman, M.; Li, J.

Item

Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

Ho, P. J.
;
Loo, C. K. Y.
;
Goh, M. H.
;
Abubakar, M.
;
Ahearn, T. U.
;
Andrulis, I. L.
;
Antonenkova, N. N.
;
Aronson, K. J.
;
Augustinsson, A.
;
Behrens, S.
... show 10 more

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Abstract

BACKGROUND: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals. METHODS: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk ≥1·66% by the Gail model [GAIL(binary)]; first-degree family history of breast cancer [FH(binary)]; 5-year absolute risk ≥1·66% by a 313-variants polygenic risk score [PRS(binary)]; and carriers of pathogenic variants in breast cancer predisposition genes [PTV(binary)]. FINDINGS: The 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeans(vs controls): AUC(PRS)=0·635 [0·632-0·638] vs AUC(Gail)=0·492 [0·489-0·495]; Asians(vs controls): AUC(PRS)=0·564 [0·556-0·573] vs AUC(Gail)=0·506 [0·497-0·514]). PRS(binary) and GAIL(binary) identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRS(binary) and PTV(binary) was minimal (<0·65% Europeans, <0·15% Asians) compared to the proportion at high risk using PTV(binary) alone (Europeans: 4·6%, Asians: 4·4%) and PRS(binary) alone (Europeans: 13·9%, Asians: 8·5%). PRS(binary) and FH(binary) uniquely identified 5-6% and 9-11% of young BrCa, respectively. INTERPRETATION: The incomplete overlap between high-risk individuals identified by PRS(binary), GAIL(binary), FH(binary,) and PTV(binary) highlights the need for a comprehensive approach to breast cancer risk prediction.

Authors

Ho, P. J.
Loo, C. K. Y.
Goh, M. H.
Abubakar, M.
Ahearn, T. U.
Andrulis, I. L.
Antonenkova, N. N.
Aronson, K. J.
Augustinsson, A.
Behrens, S.
Bodelon, C.
Bogdanova, N. V.
Bolla, M. K.
Brantley, K.
Brenner, H.
Byers, H.
Camp, N. J.
Castelao, J. E.
Cessna, M. H.
Chang-Claude, J.
Chanock, S. J.
Chenevix-Trench, G.
Choi, J. Y.
Colonna, S. V.
Czene, K.
Daly, M. B.
Derouane, F.
Dörk, T.
Eliassen, A. H.
Engel, C.
Eriksson, M.
Evans, D. G.
Fletcher, O.
Fritschi, L.
Gago-Dominguez, M.
Genkinger, J. M.
Geurts-Giele, W. R. R.
Glendon, G.
Hall, P.
Hamann, U.
Ho, C. Y. S.
Ho, W. K.
Hooning, M. J.
Hoppe, R.
Howell, A.
Humphreys, K.
Ito, H.
Iwasaki, M.
Jakubowska, A.
Jernström, H.
John, E. M.
Johnson, N.
Kang, D.
Kim, S. W.
Kitahara, C. M.
Ko, Y. D.
Kraft, P.
Kwong, A.
Lambrechts, D.
Larsson, S.
Li, S.
Lindblom, A.
Linet, M.
Lissowska, J.
Lophatananon, A.
MacInnis, R. J.
Mannermaa, A.
Manoukian, S.
Margolin, S.
Matsuo, K.
Michailidou, K.
Milne, R. L.
Taib, N. A. M.
Muir, K.
Murphy, R. A.
Newman, W. G.
O'Brien, K. M.
Obi, N.
Olopade, O. I.
Panayiotidis, M. I.
Park, S. K.
Park-Simon, T. W.
Patel, A. V.
Peterlongo, P.
Plaseska-Karanfilska, D.
Pylkäs, K.
Rashid, M. U.
Rennert, G.
Rodriguez, J.
Saloustros, E.
Sandler, D. P.
Sawyer, E. J.
Scott, C. G.
Shahi, S.
Shu, X. O.
Shulman, K.
Simard, J.
Southey, M. C.
Stone, J.
Taylor, J. A.
Teo, S. H.
Teras, L. R.
Terry, M. B.
Torres, D.
Vachon, C. M.
Van Houdt, M.
Verhoeven, J.
Weinberg, C. R.
Wolk, A.
Yamaji, T.
Yip, C. H.
Zheng, W.
Hartman, M.
Li, J.

Affiliation

Human Genetics Division, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore City, 138672. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore City, 117549. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA, Bethesda, MD, 20850. Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Canada, Toronto, Ontario, M5G 1×5. Department of Molecular Genetics, University of Toronto, Canada, Toronto, Ontario, M5S 1A8. N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Belarus, Minsk, 223040. Department of Public Health Sciences, and Sinclair Cancer Research Institute, Queen's University, Canada, Kingston, ON, K7L 3N6. Oncology, Department of Clinical Sciences in Lund, Lund University, Sweden, Lund, 221 85. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120. Department of Population Science, American Cancer Society, USA, Atlanta, GA, 30303. Department of Radiation Oncology, Hannover Medical School, Germany, Hannover, 30625. Gynaecology Research Unit, Hannover Medical School, Germany, Hannover, 30625. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK, Cambridge, CB1 8RN. Department of Epidemiology, Harvard T.H. Chan School of Public Health, USA, Boston, MA, 02115. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, UK, Manchester, M13 9WL. Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, USA, Salt Lake City, UT, 84112. Oncology and Genetics Unit, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation, Complejo Hospitalario Universitario de Santiago, SERGAS, Spain, Vigo, 36312. Intermountain Healthcare, USA, Salt Lake City, UT, 84143. Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Germany, Hamburg, 20246. Cancer Research Program, QIMR Berghofer Medical Research Institute Vol. Locked Bag 2000, Herston, QLD 4029, Australia, Brisbane, Queensland, 4006. Department of Biomedical Sciences, Seoul National University Graduate School, Korea, Seoul, 03080. Cancer Research Institute, Seoul National University, Korea, Seoul, 03080. Institute of Health Policy and Management, Seoul National University Medical Research Center, Korea, Seoul, 03080. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden, Stockholm, 171 65. Department of Clinical Genetics, Fox Chase Cancer Center, USA, Philadelphia, PA, 19111. Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Belgium, Leuven, 3000. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, USA, Boston, MA, 02115. Department of Nutrition, Harvard T.H. Chan School of Public Health, USA, Boston, MA, 02115. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany, Leipzig, 04107. LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Germany, Leipzig, 04103. North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, UK, Manchester, M13 9WL. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, UK, London, SW7 3RP. School of Population Health, Curtin University, Australia, Perth, Western Australia, 6102. Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Spain, Santiago de Compostela, 15706. Department of Epidemiology, Mailman School of Public Health, Columbia University, USA, New York, NY, 10032. Herbert Irving Comprehensive Cancer Center, USA, New York, NY. Department of Clinical Genetics, Erasmus University Medical Center Vol. P.O. Box 2040, 3000 CA, the Netherlands, Rotterdam, 3015 CN. Department of Oncology, Södersjukhuset, Sweden, Stockholm, 118 83. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120. Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong. School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Malaysia, Semenyih, Selangor, 43500. Cancer Research Malaysia, Malaysia, Subang Jaya, Selangor, 47500. Department of Medical Oncology, Erasmus MC Cancer Institute Vol. P.O. Box 2040, 3000 CA, the Netherlands, Rotterdam, 3015 GD. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Germany, Stuttgart, 70376. University of Tübingen, Germany, Tübingen, 72074. Division of Cancer Sciences, University of Manchester, UK, Manchester, M13 9PL. Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Japan, Nagoya, 464-8681. Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Japan, Nagoya, 466-8550. Division of Epidemiology, National Cancer Center Institute for Cancer Control, Japan, Tokyo, 104-0045. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Poland, Szczecin, 171-252. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Poland, Szczecin, 70-115. Department of Epidemiology and Population Health, Stanford University School of Medicine, USA, Stanford, CA, 94305. Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, USA, Stanford, CA, 94304. Department of Preventive Medicine, Seoul National University College of Medicine, Korea, Seoul, 03080. Department of Surgery, Daerim Saint Mary's Hospital, Korea, Seoul, 07442. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA, Bethesda, MD, 20892. Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Germany, Bonn, 53177. Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong. Department of Surgery, The University of Hong Kong, Hong Kong. Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong. Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Belgium, Leuven, 3000. VIB Center for Cancer Biology, VIB, Belgium, Leuven, 3001. Institute of Environmental Medicine, Karolinska Institutet, Sweden, Stockholm, 171 77. Department of Surgical Sciences, Uppsala University, Sweden, Uppsala, 751 05. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Australia, Melbourne, Victoria, 3010. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Australia, Clayton, Victoria, 3168. Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden, Stockholm, 171 76. Department of Clinical Genetics and Genomics, Karolinska University Hospital, Sweden, Stockholm, 171 76. Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Oncology Institute, Poland, Warsaw, 02-034. Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK, Manchester, M13 9PL. Cancer Epidemiology Division, Cancer Council Victoria, Australia, Melbourne, Victoria, 3004. Translational Cancer Research Area, University of Eastern Finland, Finland, Kuopio, 70210. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Finland, Kuopio, 70210. Biobank of Eastern Finland, Kuopio University Hospital, Finland, Kuopio. Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy, Milan, 20133. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Sweden, Stockholm, 118 83. Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan, Nagoya, 464-8681. Biostatistics Unit, The Cyprus Institute of Neurology and Genetics Vol. P.O.Box 23462, 1683, Nicosia, Cyprus, Cyprus, Nicosia, 2371. Department of Surgery, Faculty of Medicine, University of Malaya, UM Cancer Research Institute, Malaysia, Kuala Lumpur, 50603. School of Population and Public Health, University of British Columbia, Canada, Vancouver, BC, V6T 1Z4. Cancer Control Research, BC Cancer Agency, Canada, Vancouver, BC, V5Z 1L3. Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, USA, Research Triangle Park, NC, 27709. Institute for Occupational and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany, Hamburg, 20246. Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Germany, Hamburg, 20246. Center for Clinical Cancer Genetics, The University of Chicago, USA, Chicago, IL, 60637. Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics Vol. P.O.Box 23462, 1683, Nicosia, Cyprus, Cyprus, Nicosia, 2371. Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Korea, Seoul, 03080. Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Italy, Milan, 20139. Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Republic of North Macedonia, Skopje, 1000. Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Finland, Oulu, 90220. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Finland, Oulu, 90220. Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Pakistan, Lahore, 54000. Faculty of Medicine, Technion - Israel Institute of Technology and Association for Promotion of Research in Precision Medicine, Israel, Haifa, 35254. Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Greece, Larissa, 411 10. School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, UK, London. Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, USA, Rochester, MN, 55905. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, USA, Nashville, TN, 37232. Clalit Regional Oncology Unit, Haifa and Western Galilee District, Israel, Haifa. Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Canada, Québec City, Québec, G1V 4G2. Department of Clinical Pathology, The University of Melbourne, Australia, Melbourne, Victoria, 3010. Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Australia, Perth, Western Australia, 6009. Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, USA, Research Triangle Park, NC, 27709. Institute of Human Genetics, Pontificia Universidad Javeriana, Colombia, Bogota, 110231. Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, USA, Rochester, MN, 55905. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, USA, Research Triangle Park, NC, 27709. Subang Jaya Medical Centre, Malaysia, Subang Jaya, Selangor, 47500. Department of Surgery, National University Health System, Singapore, Singapore City, 119228. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore City, 119077. National Cancer Centre, Singapore, Singapore City, 168583.

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2025

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Ho PJ, Loo CKY, Goh MH, Abubakar M, Ahearn TU, Andrulis IL, et al. Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries. medRxiv : the preprint server for health sciences. 2025 Mar 3. PubMed PMID: 40093266. Pubmed Central PMCID: PMC11908272. Epub 2025/03/17. eng.

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https://christie.openrepository.com/handle/10541/627954

Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

Ho, P. J.
;
Loo, C. K. Y.
;
Goh, M. H.
;
Abubakar, M.
;
Ahearn, T. U.
;
Andrulis, I. L.
;
Antonenkova, N. N.
;
Aronson, K. J.
;
Augustinsson, A.
;
Behrens, S.
... show 10 more

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Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

Ho, P. J. ; Loo, C. K. Y. ; Goh, M. H. ; Abubakar, M. ; Ahearn, T. U. ; Andrulis, I. L. ; Antonenkova, N. N. ; Aronson, K. J. ; Augustinsson, A. ; Behrens, S. ... show 10 more

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Ho, P. J.
;
Loo, C. K. Y.
;
Goh, M. H.
;
Abubakar, M.
;
Ahearn, T. U.
;
Andrulis, I. L.
;
Antonenkova, N. N.
;
Aronson, K. J.
;
Augustinsson, A.
;
Behrens, S.
... show 10 more