Introduction
Breast cancer remains one of the most common cancers affecting women worldwide, prompting ongoing efforts to optimize screening methods to detect tumors early when treatment is most effective. Traditionally, many guidelines have recommended annual mammograms starting at age 40 or 50, regardless of individual risk. However, this “one-size-fits-all” approach may lead to unnecessary procedures for low-risk women and missed opportunities for enhanced surveillance in those at higher risk. To address this, the WISDOM (Women Informed to Screen Depending On Measures of risk) randomized clinical trial explored whether a risk-based screening strategy, incorporating genetic testing and clinical risk models, could safely and efficiently replace routine annual mammography.
Background: Why Risk-Based Breast Cancer Screening?
Breast cancer risk varies significantly between individuals based on genetics, family history, lifestyle, age, and other factors. Risk-based screening aims to tailor recommendations — such as when to start screening, how often to screen, and whether to use supplementary imaging like MRI — based on a woman’s personalized risk profile. This strategy could improve early detection in women at highest risk while reducing unnecessary tests and biopsies in those at low risk, thus improving patient experience and healthcare resource utilization.
The WISDOM Trial Design and Methodology
The WISDOM trial was a large, pragmatic, multicenter randomized clinical trial involving 28,372 women aged 40 to 74 across the United States. Participants had no previous breast cancer or ductal carcinoma in situ and were randomized into two groups:
1. Risk-based screening group (14,212 women): underwent a robust risk assessment using sequencing of nine breast cancer susceptibility genes, a polygenic risk score that examines dozens of genetic variants, and the Breast Cancer Surveillance Consortium version 2 model. Women received one of four screening recommendations based on their assessed five-year risk:
– Highest risk (≥6% 5-year risk or presence of pathogenic variant): alternating mammography and MRI every six months plus counseling.
– Elevated risk (top 2.5 percentile by age): annual mammography and risk-reduction counseling.
– Average risk: biennial mammography.
– Low risk (aged 40-49 and <1.3% 5-year risk): no screening until either reaching 50 or risk surpassing 1.3%.
2. Annual mammography group (14,160 women): recommended annual mammograms, the current standard practice.
Notably, procedures and follow-up were conducted primarily through an online platform, enhancing accessibility and nationwide participation. Additionally, women opting out of randomization joined an observational cohort, where 89% chose risk-based screening.
Key Findings: Safety and Efficiency of Risk-Based Screening
Over a median follow-up of 5.1 years, the primary outcomes were compared between groups:
– The rate of advanced breast cancers (stage ≥IIB) was noninferior in the risk-based group compared with the annual screening group. The risk-based group had 30.0 cases per 100,000 person-years (95% CI, 16.3-43.8), versus 48.0 in the annual group (95% CI, 30.1-65.5), with a rate difference of -18.0 per 100,000 person-years (95% CI, -40.2 to 4.1). This suggests that reducing screening frequency for low-risk women did not lead to more late-stage cancers.
– Despite fewer mammograms in the risk-based group (rate difference approximately 3,836 fewer per 100,000 person-years), there was no significant reduction in breast biopsies. The biopsy rates remained comparable (rate difference 98.7 per 100,000 person-years, 95% CI, -17.9 to 215.3). This may reflect biopsy decisions driven by factors beyond screening frequency, such as imaging characteristics or patient/provider preferences.
– Importantly, the cumulative incidence of cancer, biopsies, mammograms, and MRIs increased appropriately with risk category, validating the precision of the risk stratification method.
Implications for Patients and Clinicians
Consider the case of Sarah, a 42-year-old woman with no family history of breast cancer and a low polygenic risk score. Under traditional guidelines, Sarah would have undergone annual mammograms starting at age 40. However, using the WISDOM trial’s risk-based approach, her breast cancer risk falls well below the 1.3% five-year threshold, so she is advised to defer mammography until she either reaches age 50 or her risk status changes. This approach spares Sarah the psychological stress and potential harms of frequent imaging without compromising safety.
Conversely, Maria, a 50-year-old woman carrying a high-penetrance breast cancer gene mutation and significant family history, benefits from more intensive surveillance with alternating mammograms and MRIs every six months in the risk-based strategy. This personalized plan may detect tumors earlier than annual mammography alone might.
These examples illustrate how risk-based screening aligns breast cancer prevention strategies more closely with individual risk, enhancing benefit while minimizing harm.
Addressing Common Misconceptions
Some may worry that reducing screening frequency will inevitably increase late-stage cancer diagnoses. The WISDOM trial’s data reassure that carefully selected low-risk women can safely undergo less frequent screening without increased cancer progression.
Others might assume less screening automatically leads to fewer invasive procedures like biopsies; however, biopsy rates may be influenced by other factors, including imaging findings and clinical judgment. Thus, lowering mammogram frequency does not necessarily reduce biopsy numbers.
Practical Considerations and Future Directions
Risk-based screening requires infrastructure for genetic testing, accurate risk modeling, and patient counseling. The WISDOM trial demonstrates feasibility with largely online procedures, a promising model for broad adoption.
Continued follow-up will clarify longer-term outcomes, including mortality impact and adherence to screening recommendations. Integration of emerging biomarkers and advances in imaging may further refine risk stratification.
Expert Insights
Lois Esserman, MD, the principal investigator of the trial, remarked, “Our findings support the safety and acceptability of personalizing breast cancer screening. Risk-based strategies can concentrate healthcare resources where they are most needed while protecting women from overdiagnosis and overtreatment.”
Clinicians should consider patient preferences, communicate risk clearly, and recognize that ongoing risk assessment is dynamic — risk can change with age and new information.
Conclusion
The WISDOM randomized clinical trial provides robust evidence that risk-based breast cancer screening, incorporating genetic testing and comprehensive risk models, is a feasible and safe alternative to routine annual mammography. This personalized approach tailors screening frequency and modalities to individual risk, potentially improving healthcare efficiency and patient experience without compromising detection of advanced cancers. As precision medicine advances, risk-based screening heralds a new era of breast cancer prevention that promises to optimize outcomes through customization.
Funding and Trial Registration
The WISDOM trial was funded through collaborative grants involving governmental and academic institutions. The trial protocol is registered at ClinicalTrials.gov (Identifier: NCT02620852).
References
Esserman LJ, Fiscalini AS, Naeim A, Van’t Veer LJ, Kaster A, Scheuner MT, LaCroix AZ, Borowsky AD, Anton-Culver H, Olopade OI, et al. Risk-Based vs Annual Breast Cancer Screening: The WISDOM Randomized Clinical Trial. JAMA. 2025 Dec 12:e2524784. doi:10.1001/jama.2025.24784.
Breast Cancer Surveillance Consortium. Breast cancer risk assessment models. https://www.bcsc-research.org/
National Cancer Institute. Breast cancer screening (PDQ®)–Patient Version. https://www.cancer.gov/types/breast/patient/breast-screening-pdq
American Cancer Society. Breast Cancer Early Detection and Diagnosis. https://www.cancer.org/cancer/breast-cancer/screening-tests-and-early-detection.html
