Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Dec 12:e2524784.
doi: 10.1001/jama.2025.24784. Online ahead of print.

Risk-Based vs Annual Breast Cancer Screening: The WISDOM Randomized Clinical Trial

Laura J Esserman  1 , Allison S Fiscalini  1 , Arash Naeim  2 , Laura J Van't Veer  1 , Andrea Kaster  3 , Maren T Scheuner  1   4 , Andrea Z LaCroix  5 , Alexander D Borowsky  1 , Hoda Anton-Culver  6 , Olufunmilayo I Olopade  7 , James Esserman  8 , Rachael Lancaster  9 , Lisa Madlensky  5 , Amie M Blanco  1 , Katherine S Ross  1 , Deborah L Goodman  6 , Barry S Tong  1 , Michael Hogarth  5 , Diane Heditsian  1 , Susie Brain  1 , Vivian Lee  1 , Kelly Blum  1 , Mi-Ok Kim  1 , Leah P Sabacan  1 , Kirkpatrick B Fergus  1 , Christina Yau  1 , Hannah L Park  6 , Barbara A Parker  5 , Celia Kaplan  1 , Kim F Rhoads  10 , Suzanne Eder  1 , Kelly Adduci  1 , Jeffrey B Matthews  1 , Neil S Wenger  2 , Yiwey Shieh  11 , Robert A Hiatt  1 , Elad Ziv  1 , Jeffrey A Tice  1 , Martin Eklund  12
Affiliations

Risk-Based vs Annual Breast Cancer Screening: The WISDOM Randomized Clinical Trial

Laura J Esserman et al. JAMA. .

Abstract

Importance: Individual breast cancer risk can guide screening initiation, frequency, use of supplemental imaging, and preventive measures to improve breast cancer screening by shifting resources from low-risk women to high-risk women.

Objective: To determine whether risk-based breast cancer screening is a feasible alternative to annual mammography.

Design, setting, and participants: Parallel-group, pragmatic, multicenter randomized clinical trial comparing risk-based (n = 14 212) with annual (n = 14 160) breast cancer screening. Women aged 40 to 74 years without prior diagnoses of breast cancer or ductal carcinoma in situ, or prophylactic bilateral mastectomy, were recruited from all 50 US states from September 2016 to February 2023, with follow-up through September 5, 2025 (median follow-up, 5.1 years). Statistical analysis was conducted between July and November 2025. All study procedures were conducted via an online platform. Women who declined randomization were enrolled in an observational cohort.

Interventions: Risk assessment included sequencing of 9 susceptibility genes, polygenic risk score, and the Breast Cancer Surveillance Consortium version 2 model. The risk-based group received 1 of 4 recommendations: (1) highest risk (≥6% 5-year risk, high-penetrance pathogenic variant): alternating mammography and magnetic resonance imaging (MRI) every 6 months and counseling; (2) elevated risk (top 2.5 risk percentile by age): annual mammography and risk-reduction counseling; (3) average risk: biennial mammography; and (4) low risk (aged 40-49 years and <1.3% 5-year risk): no screening until risk is 1.3% or greater or age 50 years.

Main outcomes and measures: The coprimary outcomes included noninferiority for stage ≥IIB cancers and superiority in reducing biopsy rates. Secondary outcomes included identification of stage ≥IIA cancers, mammogram rates, uptake of prevention strategies in higher risk cohorts, preference for screening group in the observational cohort, ductal carcinoma in situ, MRI, and stage-specific cancer rates.

Results: A total of 28 372 women were randomized. The mean (SD) age was 54 (9.6) years and the majority were non-Hispanic White (77%). The rate of stage ≥IIB cancers was noninferior in the risk-based compared with the annual group (risk-based: 30.0 [95% CI, 16.3-43.8] vs annual: 48.0 [95% CI, 30.1-65.5] per 100 000 person-years; rate difference, -18.0 per 100 000 person-years [95% CI, -40.2 to 4.1]). The rate of breast biopsies was not lower in the risk-based group (rate difference, 98.7 per 100 000 person-years [95% CI, -17.9 to 215.3]) despite fewer mammograms (rate difference, -3835.9 [95% CI, -4516.8 to -3154.9]). The cumulative incidence of cancer, biopsy, mammogram, and MRI increased as risk category increased. In the observational cohort, 89% of participants (15 980/18 031) chose risk based.

Conclusions: Risk-based breast cancer screening that includes population-based genetic testing safely stratified risk and screening intensity, but did not reduce biopsy rates.

Trial registration: ClinicalTrials.gov Identifier: NCT02620852.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr L. Esserman reported receiving grants from National Cancer Institute (NCI), Patient-Centered Outcomes Research Institute (PCORI), Breast Cancer Research Foundation (BCRF), Safeway Foundation, Mount Zion Health Fund, Robert Wood Johnson Foundation (RWJF), and Bright Pink during the conduct of the study; grants from Quantum Leap Healthcare Collaborative to her institution outside the submitted work; being a member of the Blue Cross and Blue Shield Medical Advisory Panel; and serving as an investigator on a trial funded through her institution by Moderna (ended April 2025). Ms Stover Fiscalini reported receiving grants from NCI, PCORI, BCRF, Safeway Foundation, Mount Zion Health Fund, RWJF, and Bright Pink during the conduct of the study. Dr Naeim reported receiving grants from PCORI during the conduct of the study. Dr van’t Veer reported receiving personal fees from Agendia as a part-time employee and stockholder outside the submitted work. Dr Kaster reported receiving grants from Rising Tide during the conduct of the study. Dr Scheuner reported receiving grants from Veterans Affairs Health Services Research & Development Office; a donation from the Rubin family during the conduct of the study (Rubin Family Foundation at the University of California, San Francisco and the Northern California Institute for Research and Education); and having patents issued (US 7,951,078 B2; US 8,719,045). Dr LaCroix reported receiving grants to her institution from PCORI and BCRF during the conduct of the study. Dr Borowsky reported receiving grants from PCORI, NCI, BCRF, Safeway Foundation, Mount Zion Health Fund, and RWJF during the conduct of the study. Dr Olopade reported being a cofounder of CancerIQ; previously serving on the scientific advisory board of Tempus; and receiving research grant support from Color Foundation. Dr J. Esserman reported receiving grants from NCI during the conduct of the study. Dr Lancaster reported receiving grants from NCI during the conduct of the study. Dr Madlensky reported receiving grants from the National Institutes of Health (NIH) and PCORI during the conduct of the study. Ms Blanco reported receiving grants from PCORI during the conduct of the study. Ms Ross reported receiving grants from NIH/NCI, BCRF, Safeway Foundation, Mount Zion Health Fund, RWJF, and Bright Pink during the conduct of the study; being awarded grant funding by Mount Zion Health Fund outside the submitted work; and being a member of the National Society of Genetic Counselors Genetic Counseling Experience Initiative and a genetic counselor workplace representative for union UPTE-CWA 9119. Dr Goodman reported receiving grants from NCI, PCORI, and BCRF during the conduct of the study. Mr Tong reported receiving grants from PCORI during the conduct of the study. Dr Hogarth reported receiving personal fees from Medeloop and stock options from Virta Health and LifeLink outside the submitted work. Ms Heditsian reported receiving grants from PCORI, R01, and Bright Pink during the conduct of the study. Ms Brain reported receiving grants from PCORI, R01, and Bright Pink (144557A) during the conduct of the study. Ms Lee reported receiving grants from NCI, PCORI, BCRF, Safeway Foundation, Mount Zion Health Fund, RWJF, and Bright Pink during the conduct of the study. Ms Blum reported receiving grants from NCI R01, NCI P01, and US Department of Defense (DoD) during the conduct of the study. Ms Kim reported receiving grants from NCI during the conduct of the study. Ms Sabacan reported receiving grants from PCORI, NCI, DoD, and BCRF during the conduct of the study. Dr Fergus reported receiving an American Society of Clinical Oncology Young Investigator Award and T32 Institutional Training Research Grant in Surgical Oncology (awarded to Dr L. Esserman) during the conduct of the study. Dr Yau reported receiving grants from NCI, PCORI, BCRF, Mount Zion Health Fund, BWJF, and Bright Pink during the conduct of the study. Dr Park reported receiving grants from PCORI and BCRF during the conduct of the study. Dr Parker reported receiving grants from NCI, PCORI, BCRF, and Safeway Foundation; and funding from Breast Cancer Personalized Treatment Research Program Philanthropy Fund during the conduct of the study. Dr Kaplan reported receiving grants from NCI, PCORI, BCRF, Safeway Foundation, Mount Zion Health Fund, RWJF, and Bright Pink during the conduct of the study. Dr Rhoads reported receiving grants from NCI during the conduct of the study. Ms Eder reported receiving grants from NCI, PCORI, BCRF, Safeway Foundation, Mount Zion Health Fund, RWJF, and Bright Pink during the conduct of the study. Ms Adduci reported receiving grants from BCRF, PCORI, NCI, Safeway Foundation, Mount Zion Health Fund, RWJF, and Bright Pink during the conduct of the study. Dr Wenger reported receiving grants from PCORI to his institution during the conduct of the study. Dr Tice reported receiving grants from NCI and PCORI during the conduct of the study; and grants from NCI, Institute for Clinical and Economic Review, and DoD outside the submitted work. Dr Eklund reported receiving grants from PCORI and NCI during the conduct of the study; being a founding shareholder in A3P Biomedical and Clinsight; and receiving speaker honoraria from Johnson & Johnson and Ipsen outside the submitted work. No other disclosures were reported.

Comment in

References

    1. Hurson AN, Ahearn TU, Koka H, et al. Risk factors for breast cancer subtypes by race and ethnicity: a scoping review. J Natl Cancer Inst. 2024;116(12):1992-2002. doi: 10.1093/jnci/djae172 - DOI - PMC - PubMed
    1. Shieh Y, Hu D, Ma L, et al. Breast cancer risk prediction using a clinical risk model and polygenic risk score. Breast Cancer Res Treat. 2016;159(3):513-525. doi: 10.1007/s10549-016-3953-2 - DOI - PMC - PubMed
    1. Mavaddat N, Michailidou K, Dennis J, et al. ; ABCTB Investigators; kConFab/AOCS Investigators; NBCS Collaborators . Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. Am J Hum Genet. 2019;104(1):21-34. doi: 10.1016/j.ajhg.2018.11.002 - DOI - PMC - PubMed
    1. Guo F, Adekanmbi V, Hsu CD, Berenson AB, Kuo YF, Shih YT. Cost-effectiveness of population-based multigene testing for breast and ovarian cancer prevention. JAMA Netw Open. 2024;7(2):e2356078. doi: 10.1001/jamanetworkopen.2023.56078 - DOI - PMC - PubMed
    1. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA. 2009;302(15):1685-1692. doi: 10.1001/jama.2009.1498 - DOI - PubMed

Associated data