Abstract GS3-07: Risk-based breast cancer screening is safe, preferred by women and identifies highest risk individuals: Results from WISDOM 1.0

Abstract Background: The goal of breast cancer (BC) screening is to reduce morbidity and mortality through the reduction of late-stage (Stage 2B or higher) cancers. Individual risk of BC varies substantially, and tailoring screening and prevention to individual risk could improve the focus on high risk women, reduce the burden of screening in low risk women and better allocate resources. Women Informed to Screen Depending On Measures of risk (WISDOM 1.0) Study was designed to test the non-inferiority of risk-based vs. annual screening for the primary outcome of Stage ≥2B BC, and to determine if risk-based screening is less morbid, preferred by women, and more conducive to prevention interventions. Methods: WISDOM 1.0, a randomized, preference sensitive pragmatic trial, compared the safety and morbidity of annual mammography versus risk-based screening, in which a woman’s BC risk is used to guide mammography initiation age, frequency, and the use of supplemental imaging and preventive interventions. Risk assessment included genetic testing (9 BC genes + polygenic risk scores (PRS)) and the Breast Cancer Surveillance Consortium (BCSC) v2 model, integrating breast density, to stratify women into four risk categories: highest (5-year risk >6%)/yearly mammography and MRI alternating every 6 months; elevated (top 2.5% of risk by age)/yearly mammography; average /biennial mammography; and lowest risk (no screening until 5-yr risk ≥1.3% or age 50). Risk-based participants had access to Breast Health Decisions, an educational tool to explain risk and options for risk reduction. Breast Health Specialists and genetic counselors provided consultations for women in the top 2.5% of risk by age or with pathogenic variants. Cancers, biopsies, chemoprevention, and imaging data were self-reported; 95% of all cancers were verified with medical records. Results: Over 7 years, 46,000 women enrolled, 61% chose to be randomized. Those who declined to randomize could elect to self-select their arm; 89% chose risk-based, regardless of age or geography. In the randomized cohort 77%, 6%, 4%, and 9% were White, African American, Asian, and Latina, respectively. There were 880 new BC diagnoses, of which 82 were Stage 2B or higher. Stage 2B cancer rate was non-inferior (p<0.001) and lower in the risk-based arm (42 vs. 28 stage ≥ IIB cancer per 100,000 person years in annual vs. risk-based, respectively, (p=0.15) for superiority). The proportion of participants in the randomized cohort assigned to the highest, elevated, average, and lowest risk was 2.1%, 8.0%, 63.2%, and 26.7%, respectively. Mammogram rates were lower in the risk-based arm (p<0.001). There was a trend towards more biopsies in the risk-based arm (p=0.08), driven by more biopsies in the highest two risk groups. The rates of invasive cancer, DCIS, mammograms, and biopsies varied by risk category, and were markedly higher in the high and elevated compared to average and lowest risk-based assignments (invasive cancer rates were 1279, 428, 233, and 169 per 100,000 women per year in the highest, elevated, average and lowest risk groups, respectively). Rates of chemoprevention increased among high risk groups in the risk-based arm from baseline to subsequent years (p<0.001). In women with pathogenic variants in BC susceptibility genes, 30% reported no family history of BC. Conclusions: A risk-based approach to BC screening and prevention is safe and acceptable to women and is an opportunity to improve breast cancer early detection and prevention by identifying the highest risk women who should be screened more frequently and offered risk reduction options while reducing screening burden for average risk women. WISDOM 2.0 is enrolling women 30-74 and is designed to identify younger women at high risk and improve prediction of fast and slow growing cancers using genetics and mammographic AI. Citation Format: L. J. Esserman, A. S. Fiscalini, A. Naeim, L. J. van 't Veer, A. Kaster, M. T. Scheuner, A. Z. LaCroix, A. D. Borowsky, H. Anton-Culver, O. I. Olopade, J. N. Esserman, R. Lancaster, Y. Shieh, E. Ziv, J. A. Tice, L. Madlensky, A. Blanco, K. S. Ross, D. L. Goodman, H. L. Park, R. A. Hiatt, N. Wenger, B. A. Parker, D. M. Heditsian, S. A. Brain, V. Lee, K. F. Rhoads, K. Fergus, K. Blum, L. P. Sabacan, M. Eklund. Risk-based breast cancer screening is safe, preferred by women and identifies highest risk individuals: Results from WISDOM 1.0 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS3-07.