Journal Article

Integrating breast cancer polygenic risk scores at scale in the WISDOM Study: a national randomized personalized screening trial

Brain, Susie, Esserman, Laura J., Scheuner, Maren, Kaster, Andrea, Arasu, Vignesh A., Theiner, Sarah, Heise, Rachel S., Chapa, Lisa, Fiscalini, Allison, Ross, Katherine, Madlensky, Lisa, Tice, Jeffrey A., Goodman-Gruen, Deborah, Kapoor, Shreya, Soto, Irene A., Ziv, Elad, Sabacan, Leah, Olopade, Olufunmilayo I., Eklund, Martin, Shieh, Yiwey, Hu, Donglei, Heditsian, Diane, Fergus, Kirkpatrick B., Blanco, Amie, van ‘t Veer, Laura

2025

Overview

Background The Women Informed to Screen Depending On Measures of risk (WISDOM) Study is the first prospective, population-wide application of personalized breast cancer screening. We aim to demonstrate the feasibility of the study’s novel use of polygenic risk scores (PRSs) to tailor screening, evaluate our strategy for adapting PRSs to diverse populations, and quantify the impact of incorporating PRS on the study’s screening recommendations. Methods WISDOM is a randomized, preference-tolerant screening trial in the USA testing the safety and morbidity of risk-based versus annual screening in women aged 40–74 without a prior history of breast cancer. This early report includes participants in the risk-based arm only and compares screening recommendations generated by the Breast Cancer Surveillance Consortium (BCSC) clinical risk model alone versus the BCSC model modified by a PRS (BCSC-PRS). The main outcome of interest is the proportion of participants with a change in screening recommendation after integrating PRS for risk stratification. Results In the risk-based arm, 21,631 participants received a PRS. Small but statistically significant differences in the PRS were seen between major racial and ethnic groups ( p  < 0.001), and higher PRS was associated with greater extent of family history ( p  < 0.001) and denser breasts ( p  < 0.001). BCSC-PRS risk estimates changed the screening recommendations for 14% of women aged 40–49 compared to BCSC alone and for 10% of women aged 50–74. Projected net screening encounters at the population level were similar for both age groups. Conclusions In a first-in-kind application of PRS to inform breast cancer screening approaches, we demonstrate feasibility for scaled implementation, moderate changes to individual screening recommendations, and minimal projected downstream burden on the healthcare system. Trial registration Prospectively registered on ClinicalTrials.gov as NCT02620852 on 12/2/2015.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Age / Aged / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast neoplasms / Breast Neoplasms - diagnosis / Breast Neoplasms - epidemiology / Breast Neoplasms - genetics / Cancer / Cancer Research / Cancer screening / Early Detection of Cancer - methods / Ethnicity / Feasibility studies / Female / Genetic aspects / Genetic Predisposition to Disease / Genetic Risk Score / Genetic testing / Health aspects / Human Genetics / Humans / Mammography / Medical screening / Medicine/Public Health / Metabolomics / Middle Aged / Minority & ethnic groups / Morbidity / Multifactorial Inheritance / Oncology, Experimental / Polygenic risk scores / Population / Precision Medicine / Review boards / Risk Assessment / Risk Factors / Risk prediction / Statistical analysis / Systems Biology / Translational genetics / Womens health