Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial

• Published in: JNCI : Journal of the National Cancer Institute Vol. 109; no. 5; p. djw290
• Main Authors: Shieh, Yiwey, Eklund, Martin, Madlensky, Lisa, Sawyer, Sarah D, Thompson, Carlie K, Stover Fiscalini, Allison, Ziv, Elad, Van't Veer, Laura J, Esserman, Laura J, Tice, Jeffrey A
• Format: Journal Article
• Language: English
• Published: United States 2017
• Subjects: Age Factors; Breast Density; Breast Neoplasms - diagnostic imaging; Breast Neoplasms - genetics; Early Detection of Cancer - standards; Female; Genotype; Humans; Magnetic Resonance Imaging; Mammography - standards; Medicin och hälsovetenskap; Penetrance; Polymorphism, Single Nucleotide; Practice Guidelines as Topic; Pragmatic Clinical Trials as Topic; Precision Medicine; Risk Assessment - methods; Risk Factors; Time Factors
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djw290

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.