Prospective Evaluation of a Breast Cancer Risk Model Integrating Classical Risk Factors and Polygenic Risk in 15 Cohorts from Six Countries
Prospective Evaluation of a Breast Cancer Risk Model Integrating Classical Risk Factors and Polygenic Risk in 15 Cohorts from Six Countries
ABSTRACT PURPOSERisk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk. METHODSFifteen prospective cohorts from six countries with 237,632 women (7,529 incident breast cancer patients) of European ancestry aged 19-75 years at baseline were included. Calibration of five-year risk was assessed by comparing predicted and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future breast cancer cases crossing clinically-relevant risk thresholds. RESULTSThe model integrating classical risk factors and PRS accurately predicted five-year risk. For women younger than 50 years, median (range) expected-to-observed ratio across the cohorts was 0.94 (0.72 to 1.01) overall and 0.9 (0.7 to 1.4) at the highest risk decile. For women 50 years or older, these ratios were 1.04 (0.73 to 1.31) and 1.2 (0.7 to 1.6), respectively. The proportion of women in the general population identified above the 3% five-year risk threshold (used for recommending risk-reducing medications in the US) ranged from 7.0% in Germany (～841,000 of 12 million) to 17.7% in the US (～5.3 of 30 million). At this threshold, 14.7% of US women were re-classified by the addition of PRS to classical risk factors, identifying 12.2% additional future breast cancer cases. CONCLUSIONEvaluation across multiple prospective cohorts demonstrates that integrating a 313-SNP PRS into a risk model substantially improves its ability to stratify women of European ancestry for applying current breast cancer prevention guidelines.
Sandler Dale P、Wilcox Amber N、Norman Aaron、Simard Jacques、Evans D. Gareth R、Winham Stacey J、Brandt Kathy、Vachon Celine M、Czene Kamila、Gabrielson Marike、Buring Julie E、Gao Chi、H¨1sing Anika、Eriksson Mikael、Shi Min、Carter Brian D、Harkness Elaine、Antoniou Antonis C、Swerdlow Anthony J、Sampson Sarah、Chasman Dan I、Kaaks Rudolf、Schmidt Marjanka K、Kraft Peter、Chatterjee Nilanjan、Mavaddat Nasim、Choudhury Parichoy Pal、van Veen Elke M、Khaw Kay-Tee、Gaudet Mia M、MacInnis Robert J、Ahearn Thomas U、Scott Christopher、Barrdahl Myrto、Chang-Claude Jenny、Milne Roger L、Newman William G、Martin Kara、Easton Douglas F、Southey Melissa、Hall Per、Schoemaker Minouk J、Weinberg Clarice R、Garcia-Closas Montserrat、van Gils Carla H、Jones Michael E、Giles Graham G、Gapstur Susan M、Ridker Paul M、Orr Nick、Brook Mark N
Epidemiology Branch, National Institute of Environmental Health SciencesDivision of Cancer Epidemiology and Genetics, National Cancer Institute||Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel HillDepartment of Health Sciences ResearchCentre Hospitalier Universitaire de Qu¨|bec¨CUniversit¨| Laval Research CenterDivision of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre||Manchester Centre for Genomic Medicine, St Mary?ˉs Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS, Foundation Trust, Manchester Academic Health Science CentreDepartment of Health Sciences Research, Division of Biomedical Statistics and InformaticsDepartment of RadiologyDepartment of Health Sciences Research, Division of EpidemiologyDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska Univ HospitalDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska Univ HospitalDivision of Preventive Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolProgram in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health||Department of Epidemiology, Harvard T.H. Chan School of Public HealthDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska Univ HospitalBiostatistics and Computational Biology Branch, National Institute of Environmental Health SciencesBehavioral and Epidemiology Research Group, American Cancer SocietyDivision of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre||Nightingale Breast Screening Centre, Wythenshawe Hospital, Manchester University NHS Foundation TrustCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of CambridgeDivision of Genetics and Epidemiology, The Institute of Cancer Research||Division of Breast Cancer Research, The Institute of Cancer ResearchPrevention Breast Cancer Unit and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust (South)Division of Preventive Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital||Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospitalProgram in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health||Department of Epidemiology, Harvard T.H. Chan School of Public HealthBloomberg School of Public Health, Johns Hopkins University||Department of Oncology, School of Medicine, Johns Hopkins UniversityCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of CambridgeDivision of Cancer Epidemiology and Genetics, National Cancer Institute||Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins UniversityDivision of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre||Manchester Centre for Genomic Medicine, St Mary?ˉs Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS, Foundation Trust, Manchester Academic Health Science CentreCancer Epidemiology Unit, University of CambridgeBehavioral and Epidemiology Research Group, American Cancer SocietyCancer Epidemiology Division, Cancer Council Victoria||Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of MelbourneDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDepartment of Health Sciences ResearchDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)||Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-EppendorfCancer Epidemiology Division, Cancer Council Victoria||Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne||Precision Medicine, School of Clinical Sciences at Monash Health, Monash UniversityDivision of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre||Manchester Centre for Genomic Medicine, St Mary?ˉs Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS, Foundation Trust, Manchester Academic Health Science CentreCancer Epidemiology Division, Cancer Council VictoriaCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge||Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of CambridgePrecision Medicine, School of Clinical Sciences at Monash Health, Monash University||Department of Clinical Pathology, The University of Melbourne||Cancer Epidemiology Division, Cancer Council VictoriaDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska Univ Hospital||Department of OncologyDivision of Genetics and Epidemiology, The Institute of Cancer ResearchBiostatistics and Computational Biology Branch, National Institute of Environmental Health SciencesDivision of Cancer Epidemiology and Genetics, National Cancer InstituteJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht UniversityDivision of Genetics and Epidemiology, The Institute of Cancer ResearchCancer Epidemiology Division, Cancer Council Victoria||Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne||Department of Epidemiology and Preventive Medicine, Monash UniversityBehavioral and Epidemiology Research Group, American Cancer SocietyDivision of Preventive Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolCentre for Cancer Research and Cell Biology, Queen?ˉs University Belfast, University RoadDivision of Genetics and Epidemiology, The Institute of Cancer Research
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Sandler Dale P,Wilcox Amber N,Norman Aaron,Simard Jacques,Evans D. Gareth R,Winham Stacey J,Brandt Kathy,Vachon Celine M,Czene Kamila,Gabrielson Marike,Buring Julie E,Gao Chi,H¨1sing Anika,Eriksson Mikael,Shi Min,Carter Brian D,Harkness Elaine,Antoniou Antonis C,Swerdlow Anthony J,Sampson Sarah,Chasman Dan I,Kaaks Rudolf,Schmidt Marjanka K,Kraft Peter,Chatterjee Nilanjan,Mavaddat Nasim,Choudhury Parichoy Pal,van Veen Elke M,Khaw Kay-Tee,Gaudet Mia M,MacInnis Robert J,Ahearn Thomas U,Scott Christopher,Barrdahl Myrto,Chang-Claude Jenny,Milne Roger L,Newman William G,Martin Kara,Easton Douglas F,Southey Melissa,Hall Per,Schoemaker Minouk J,Weinberg Clarice R,Garcia-Closas Montserrat,van Gils Carla H,Jones Michael E,Giles Graham G,Gapstur Susan M,Ridker Paul M,Orr Nick,Brook Mark N.Prospective Evaluation of a Breast Cancer Risk Model Integrating Classical Risk Factors and Polygenic Risk in 15 Cohorts from Six Countries[EB/OL].(2025-03-28)[2025-06-23].https://www.medrxiv.org/content/10.1101/19011171.点此复制
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