PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

Basser Center for BRCA Abramson Cancer Center University of Pennsylvania Philadelphia PA USA

Biomedical Sciences Institute University of Porto Porto Portugal

BMC Faculty of Medicine University of Iceland Reykjavik Iceland

Breast Cancer Research Programme Cancer Research Malaysia Subang Jaya Selangor Malaysia

Cancer Genetics and Prevention Program University of California San Francisco San Francisco CA USA

Cancer Genetics Service National Cancer Centre Singapore Singapore

Cancer Research Institute Seoul National University Seoul Korea

Cancer Risk and Prevention Clinic Dana Farber Cancer Institute Boston MA USA

Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core Cedars Sinai Medical Center Los Angeles CA USA

Center for Clinical Cancer Genetics The University of Chicago Chicago IL USA

Center for Familial Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Center for Integrated Oncology Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Center for Medical Genetics NorthShore University HealthSystem Evanston IL USA

Center for Molecular Medicine Cologne Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne VIC Australia

Centre for Medical Genetics Ghent University Ghent Belgium

Centro de Investigación en Red de Enfermedades Raras Madrid Spain

Chronic Disease Epidemiology Yale School of Public Health New Haven CT USA

Clalit National Cancer Control Center Carmel Medical Center and Technion Faculty of Medicine Haifa Israel

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London UK

Clinical Genetics Karolinska Institutet Stockholm Sweden

Clinical Genetics Research Lab Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York NY USA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

David Geffen School of Medicine Department of Obstetrics and Gynecology University of California at Los Angeles Los Angeles CA USA

Département de Génétique CHU de Grenoble Grenoble France

Department of Biomedical Sciences Seoul National University Graduate School Seoul Korea

Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Cancer Biology and Genetics The Ohio State University Columbus OH USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark

Department of Clinical Genetics Erasmus University Medical Center CA Rotterdam The Netherlands

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia PA USA

Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

Department of Clinical Genetics Odense University Hospital Odence C Denmark

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Dermatology Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City UT USA

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA

Department of Epidemiology and Population Health Stanford University School of Medicine Stanford CA USA

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane QLD Australia

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics Portuguese Oncology Institute Porto Portugal

Department of Genetics University of Pretoria Arcadia South Africa

Department of Gynaecology and Obstetrics University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Kiel Germany

Department of Human Genetics Leiden University Medical Center Leiden The Netherlands

Department of Internal Medicine Division of Medical Oncology University of Kansas Medical Center Westwood KS USA

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Vol Box 134 Level 6 Addenbrooke's Treatment Centre Addenbrooke's Hosptital Cambridge UK

Department of Medical Oncology Beth Israel Deaconess Medical Center Boston MA USA

Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Medical Oncology Vall d'Hebron Barcelona Hospital Campus University Hospital of Vall d'Hebron Barcelona Spain

Department of Medicine Division of Oncology Stanford Cancer Institute Stanford University School of Medicine Stanford CA USA

Department of Medicine Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto ON Canada

Department of Obstetrics and Gynecology Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Oncology Lund University and Skåne University Hospital Lund Sweden

Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City KS USA

Department of Pathology Landspitali University Hospital Reykjavik Iceland

Department of Pathology Leiden University Medical Center Leiden The Netherlands

Department of Population Sciences Beckman Research Institute of City of Hope Duarte CA USA

Department of Preventive Medicine Seoul National University College of Medicine Seoul Korea

Department of Surgery Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Surgery Hong Kong Sanatorium and Hospital Happy Valley Hong Kong

Department of Surgery The University of Hong Kong Pok Fu Lam Hong Kong

Department of Tumour Biology INSERM U830 Paris France

Departments of Pediatrics and Medicine Columbia University New York NY USA

Dept of OB GYN and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Dept of OB GYN Medical University of Vienna Vienna Austria

Division of Evolution and Genomic Sciences School of Biological Sciences Faculty of Biology Medicine and Health University of Manchester Manchester Academic Health Science Centre Manchester UK

Division of Molecular Pathology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Division of Psychosocial Research and Epidemiology The Netherlands Cancer Institute Antoni van Leeuwenhoek hospital Amsterdam The Netherlands

Family Cancer Clinic The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Fred A Litwin Center for Cancer Genetics Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto ON Canada

Fundación Pública Galega de Medicina Xenómica Santiago de Compostela Spain

Genetic Epidemiology of Cancer team Paris France

Genome Diagnostics Program IFOM the FIRC Institute of Molecular Oncology Milan Italy

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center Québec City QC Canada

Hematology Oncology and Transfusion Medicine Center Department of Molecular and Regenerative Medicine Vilnius University Hospital Santariskiu Clinics Vilnius Lithuania

Hereditary cancer Genetics Group Vall d'Hebron Institute of Oncology Barcelona Spain

Hereditary Cancer Program ONCOBELL IDIBELL IGTP Catalan Institute of Oncology CIBERONC Barcelona Spain

Hong Kong Hereditary Breast Cancer Family Registry Cancer Genetics Centre Happy Valley Hong Kong

Human Cancer Genetics Programme Spanish National Cancer Research Centre Madrid Spain

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua Italy

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin Poland

Institut Curie Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute of Clinical Molecular Biology University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Kiel Germany

Institute of Human Genetics University Hospital Heidelberg Heidelberg Germany

Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain

Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore

Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Mines ParisTech Fontainebleau France

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research 'Demokritos' Athens Greece

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

Molecular Oncology Laboratory CIBERONC Hospital Clinico San Carlos IdISSC Madrid Spain

N N Petrov Institute of Oncology St Petersburg Russia

North West Genomics Laboratory Hub Manchester Centre for Genomic Medicine St Mary's Hospital Manchester University NHS Foundation Trust Manchester Academic Health Science Centre Manchester UK

NRG Oncology Statistics and Data Management Center Roswell Park Cancer Institute Buffalo NY USA

Oncogenetics Team The Institute of Cancer Research and Royal Marsden NHS Foundation Trust London UK

Parkville Familial Cancer Centre Peter MacCallum Cancer Center Melbourne VIC Australia

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal QC Canada

Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel

Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Centre UCLA Los Angeles CA USA

Service de Biologie de la reproduction Cytogénétique et Génétique Médicale CHI Poissy Saint Germain Poissy France

Service de Génétique Institut Curie Paris France

Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne VIC Australia

SOD Genetica Molecolare University Hospital Pisa Italy

State Research Institute Centre for Innovative Medicine Vilnius Lithuania

The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center Ramat Gan Israel

The University of Chicago Pritzker School of Medicine Chicago IL USA

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Université Paris Descartes Paris France

Waukesha Memorial Hospital Pro Health Care Waukesha WI USA

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds UK

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