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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 PJ 1 , Loo CKY 1 , Goh MH 1 , Abubakar M 2 , Ahearn TU 2 , Andrulis IL 3 Show all authors , Antonenkova NN 4 , Aronson KJ 5 , Augustinsson A 6 , Behrens S 7 , Bodelon C 8 , Bogdanova NV 4 , Bolla MK 9 , Brantley K 10 , Brenner H 11 , Byers H 12 , Camp NJ 13 , Castelao JE 14 , Cessna MH 15 , Chang-Claude J 7 , Chanock SJ 2 , Chenevix-Trench G 16 , Choi JY 17 , Colonna SV 13 , Czene K 18 , Daly MB 19 , Derouane F 20 , Dörk T 21 , Eliassen AH 10 , Engel C 22 , Eriksson M 18 , Evans DG 12 , Fletcher O 23 , Fritschi L 24 , Gago-Dominguez M 25 , Genkinger JM 26 , Geurts-Giele WRR 27 , Glendon G 3 , Hall P 18 , Hamann U 28 , Ho CYS 29 , Ho WK 30 , Hooning MJ 27 , Hoppe R 31 , Howell A 32 , Humphreys K 18 , ABCTB Investigators , kConFab Investigators , SGBCC Investigators , MyBrCa Investigators , Ito H 33 , Iwasaki M 34 , Jakubowska A 35 , Jernström H 6 , John EM 36 , Johnson N 23 , Kang D 37 , Kim SW 38 , Kitahara CM 39 , Ko YD 40 , Kraft P 2 , Kwong A 41 , Lambrechts D 42 , Larsson S 43 , Li S 9 , Lindblom A 44 , Linet M 39 , Lissowska J 45 , Lophatananon A 46 , MacInnis RJ 47 , Mannermaa A 48 , Manoukian S 49 , Margolin S 50 , Matsuo K 51 , Michailidou K 9 , Milne RL 47 , Taib NAM 52 , Muir K 46 , Murphy RA 53 , Newman WG 12 , O'Brien KM 54 , Obi N 55 , Olopade OI 56 , Panayiotidis MI 57 , Park SK 37 , Park-Simon TW 21 , Patel AV 8 , Peterlongo P 58 , Plaseska-Karanfilska D 59 , Pylkäs K 60 , Rashid MU 28 , Rennert G 61 , Rodriguez J 18 , Saloustros E 62 , Sandler DP 54 , Sawyer EJ 63 , Scott CG 64 , Shahi S 53 , Shu XO 65 , Shulman K 66 , Simard J 67 , Southey MC 68 , Stone J 47 , Taylor JA 54 , Teo SH 69 , Teras LR 8 , Terry MB 26 , Torres D 28 , Vachon CM 70 , Van Houdt M 20 , Verhoeven J 20 , Weinberg CR 71 , Wolk A 43 , Yamaji T 34 , Yip CH 52 , Zheng W 65 , Hartman M 72 , Li J 1

Affiliations 

  • 1 Human Genetics Division, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore City, 138672
  • 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA, Bethesda, MD, 20850
  • 3 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Canada, Toronto, Ontario, M5G 1×5
  • 4 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Belarus, Minsk, 223040
  • 5 Department of Public Health Sciences, and Sinclair Cancer Research Institute, Queen's University, Canada, Kingston, ON, K7L 3N6
  • 6 Oncology, Department of Clinical Sciences in Lund, Lund University, Sweden, Lund, 221 85
  • 7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120
  • 8 Department of Population Science, American Cancer Society, USA, Atlanta, GA, 30303
  • 9 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK, Cambridge, CB1 8RN
  • 10 Department of Epidemiology, Harvard T.H. Chan School of Public Health, USA, Boston, MA, 02115
  • 11 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120
  • 12 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
  • 13 Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, USA, Salt Lake City, UT, 84112
  • 14 Oncology and Genetics Unit, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation, Complejo Hospitalario Universitario de Santiago, SERGAS, Spain, Vigo, 36312
  • 15 Intermountain Healthcare, USA, Salt Lake City, UT, 84143
  • 16 Cancer Research Program, QIMR Berghofer Medical Research Institute Vol. Locked Bag 2000, Herston, QLD 4029, Australia, Brisbane, Queensland, 4006
  • 17 Department of Biomedical Sciences, Seoul National University Graduate School, Korea, Seoul, 03080
  • 18 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden, Stockholm, 171 65
  • 19 Department of Clinical Genetics, Fox Chase Cancer Center, USA, Philadelphia, PA, 19111
  • 20 Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Belgium, Leuven, 3000
  • 21 Gynaecology Research Unit, Hannover Medical School, Germany, Hannover, 30625
  • 22 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany, Leipzig, 04107
  • 23 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, UK, London, SW7 3RP
  • 24 School of Population Health, Curtin University, Australia, Perth, Western Australia, 6102
  • 25 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
  • 26 Department of Epidemiology, Mailman School of Public Health, Columbia University, USA, New York, NY, 10032
  • 27 Department of Clinical Genetics, Erasmus University Medical Center Vol. P.O. Box 2040, 3000 CA, the Netherlands, Rotterdam, 3015 CN
  • 28 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Germany, Heidelberg, 69120
  • 29 Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong
  • 30 School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Malaysia, Semenyih, Selangor, 43500
  • 31 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Germany, Stuttgart, 70376
  • 32 Division of Cancer Sciences, University of Manchester, UK, Manchester, M13 9PL
  • 33 Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Japan, Nagoya, 464-8681
  • 34 Division of Epidemiology, National Cancer Center Institute for Cancer Control, Japan, Tokyo, 104-0045
  • 35 Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Poland, Szczecin, 171-252
  • 36 Department of Epidemiology and Population Health, Stanford University School of Medicine, USA, Stanford, CA, 94305
  • 37 Cancer Research Institute, Seoul National University, Korea, Seoul, 03080
  • 38 Department of Surgery, Daerim Saint Mary's Hospital, Korea, Seoul, 07442
  • 39 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA, Bethesda, MD, 20892
  • 40 Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Germany, Bonn, 53177
  • 41 Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong
  • 42 Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Belgium, Leuven, 3000
  • 43 Institute of Environmental Medicine, Karolinska Institutet, Sweden, Stockholm, 171 77
  • 44 Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden, Stockholm, 171 76
  • 45 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Oncology Institute, Poland, Warsaw, 02-034
  • 46 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
  • 47 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Australia, Melbourne, Victoria, 3010
  • 48 Translational Cancer Research Area, University of Eastern Finland, Finland, Kuopio, 70210
  • 49 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy, Milan, 20133
  • 50 Department of Oncology, Södersjukhuset, Sweden, Stockholm, 118 83
  • 51 Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Japan, Nagoya, 466-8550
  • 52 Department of Surgery, Faculty of Medicine, University of Malaya, UM Cancer Research Institute, Malaysia, Kuala Lumpur, 50603
  • 53 School of Population and Public Health, University of British Columbia, Canada, Vancouver, BC, V6T 1Z4
  • 54 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, USA, Research Triangle Park, NC, 27709
  • 55 Institute for Occupational and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany, Hamburg, 20246
  • 56 Center for Clinical Cancer Genetics, The University of Chicago, USA, Chicago, IL, 60637
  • 57 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
  • 58 Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Italy, Milan, 20139
  • 59 Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Republic of North Macedonia, Skopje, 1000
  • 60 Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Finland, Oulu, 90220
  • 61 Faculty of Medicine, Technion - Israel Institute of Technology and Association for Promotion of Research in Precision Medicine, Israel, Haifa, 35254
  • 62 Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Greece, Larissa, 411 10
  • 63 School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, UK, London
  • 64 Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, USA, Rochester, MN, 55905
  • 65 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, USA, Nashville, TN, 37232
  • 66 Clalit Regional Oncology Unit, Haifa and Western Galilee District, Israel, Haifa
  • 67 Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Canada, Québec City, Québec, G1V 4G2
  • 68 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Australia, Clayton, Victoria, 3168
  • 69 Cancer Research Malaysia, Malaysia, Subang Jaya, Selangor, 47500
  • 70 Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, USA, Rochester, MN, 55905
  • 71 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, USA, Research Triangle Park, NC, 27709
  • 72 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore City, 117549
medRxiv, 2025 Mar 03.
PMID: 40093266 DOI: 10.1101/2025.02.27.25323002

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 [GAILbinary]; first-degree family history of breast cancer [FHbinary]; 5-year absolute risk ≥1·66% by a 313-variants polygenic risk score [PRSbinary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTVbinary].

FINDINGS: The 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeansvs controls: AUCPRS=0·635 [0·632-0·638] vs AUCGail=0·492 [0·489-0·495]; Asiansvs controls: AUCPRS=0·564 [0·556-0·573] vs AUCGail=0·506 [0·497-0·514]). PRSbinary and GAILbinary 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 PRSbinary and PTVbinary was minimal (<0·65% Europeans, <0·15% Asians) compared to the proportion at high risk using PTVbinary alone (Europeans: 4·6%, Asians: 4·4%) and PRSbinary alone (Europeans: 13·9%, Asians: 8·5%). PRSbinary and FHbinary uniquely identified 5-6% and 9-11% of young BrCa, respectively.

INTERPRETATION: The incomplete overlap between high-risk individuals identified by PRSbinary, GAILbinary, FHbinary, and PTVbinary highlights the need for a comprehensive approach to breast cancer risk prediction.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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