title: Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial.
abstract: Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Yiwey
authors.initials: Y
authors.lastname: Shieh
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Martin
authors.initials: M
authors.lastname: Eklund
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Lisa
authors.initials: L
authors.lastname: Madlensky
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Sawyer
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Carlie K
authors.initials: CK
authors.lastname: Thompson
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Allison
authors.initials: A
authors.lastname: Stover Fiscalini
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Elad
authors.initials: E
authors.lastname: Ziv
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Van't Veer
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
authors.affiliation: Affiliations of authors: Division of General Internal Medicine, Department of Medicine (YS, EZ, JAT), Department of Surgery (SDS, CKT, ASF, LJE), Department of Radiology (LJE), and Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center (LJvV), University of California, San Francisco, San Francisco, CA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (ME); Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA (LM).
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Tice
mesh_terms: D000367:Age Factors; D000071060:Breast Density; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics*; D055088:Early Detection of Cancer / Q000592:standards*; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008327:Mammography / Q000592:standards*; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D017410:Practice Guidelines as Topic; D064792:Pragmatic Clinical Trials as Topic; D057285:Precision Medicine; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D013997:Time Factors