Background
Risk-based breast cancer screening is designed to tailor screening intensity to a person’s individual chance of developing breast cancer. Instead of offering the same schedule to everyone, this approach uses clinical risk factors, family history, breast density, reproductive history, and sometimes genetic information to decide whether a person should have standard mammography or more intensive high-risk screening, such as breast MRI in addition to mammography.
The WISDOM Study was created to test whether risk-based screening could be a practical alternative to annual mammography for women in the United States. This secondary analysis asked an important question: how much does population-based testing for pathogenic variants, or PVs, add to risk stratification compared with clinical risk models alone or clinical models combined with a polygenic risk score?
PVs are inherited DNA changes known to increase cancer risk. In breast cancer, the most clinically important variants are found in genes such as BRCA1, BRCA2, PALB2, TP53, CHEK2, ATM, and others. Some variants confer a very high lifetime cancer risk, while others confer a more moderate increase. Polygenic risk scores, by contrast, combine the small effects of many common genetic variants to estimate overall inherited susceptibility.
Why this matters
One of the central challenges in breast cancer prevention is deciding who should receive high-risk screening. MRI screening can detect cancers earlier than mammography in people at substantially elevated risk, but it is more expensive, less available in some settings, and can lead to more follow-up tests and biopsies. If clinical models and polygenic risk scores already identify most high-risk individuals, routine PV testing might add only limited value. If not, population-based PV testing could uncover people who would otherwise be missed.
This study therefore examined whether women with PVs in breast cancer genes would have been placed into the same screening categories if decisions were based only on clinical risk, or on clinical risk plus polygenic risk.
Study design and participants
This cohort study used retrospective data from the WISDOM Study, a national clinical trial comparing risk-based breast cancer screening with annual mammography. Participants were women aged 40 to 74 years. Those who tested positive for a pathogenic variant as part of the risk-based screening program were included in this analysis.
Data were collected from September 2016 through February 2023, with follow-up extending to September 2025. The investigators analyzed the data from January to May 2026. Screening recommendations were compared in two ways: the actual recommendation made when PV status was known, and hypothetical recommendations that would have been made using either a clinical risk model alone or a clinical risk model combined with a polygenic risk score.
The clinical model used was based on the Breast Cancer Surveillance Consortium risk model, which incorporates commonly used clinical factors. The hypothetical screening recommendations were then evaluated against the actual PV-informed approach.
Main findings
A total of 712 women with a pathogenic variant were included. The median age was 53 years, with an interquartile range of 46 to 62 years. Among the variants identified, 232 women, or 33%, carried high-penetrance PVs. Another 278 women, or 39%, carried moderate-penetrance PVs, and 202 women, or 28%, carried CHEK2 low-penetrance variants.
There was little overlap between the screening recommendations based on PV status and the screening recommendations that would have been made using a clinical model plus polygenic risk score. In other words, many women who were found to have cancer-predisposing PVs would not necessarily have been classified as high risk by non-PV-based methods.
The most striking result was seen in women with high-penetrance PVs. This group is typically recommended for intensive screening, often including breast MRI alternating with mammography every 6 months. Yet only 2 of 232 women, or 0.9%, would have received the same high-risk screening recommendation based on clinical risk plus polygenic risk alone.
Age-based comparisons were also important. Among PV carriers aged 40 to 49 years, 178 of 279 women, or 63.8%, would otherwise have been advised to defer screening until age 50 based on clinical plus polygenic risk. Among PV carriers aged 50 to 74 years, 385 of 433 women, or 88.9%, would have been recommended to have biennial mammography rather than intensified screening.
The results were similar when the investigators compared actual PV-informed assignments with recommendations based on the clinical model alone. This suggests that adding a polygenic risk score to clinical assessment did not substantially close the gap for most PV carriers.
Interpretation
These findings show that pathogenic variant testing identifies a group of women who are often not flagged by routine clinical risk models or by models that also include polygenic risk. Put simply, inherited high-risk mutations and commonly used risk prediction tools are not identifying exactly the same people.
This matters for real-world screening programs. If a health system relies only on clinical risk factors and polygenic scores, many women with clinically important PVs may not be assigned to more intensive surveillance. As a result, some women who could benefit from MRI-based screening may instead receive standard mammography or even delayed screening.
The study also highlights the difference between two kinds of inherited risk information. Polygenic risk scores capture the cumulative effect of many common variants, each of which has a small impact. PV testing identifies rarer variants with larger effects, especially in well-known hereditary cancer genes. These two approaches provide complementary information, but this analysis suggests that polygenic scores alone cannot substitute for PV testing when the goal is to identify women at highest inherited risk.
Clinical implications
For clinicians, the study supports the idea that population-based genetic testing can improve risk-based breast screening programs. A woman may have a pathogenic variant even if she does not have an obvious family history or an elevated calculated risk score. That means screening decisions based only on family history and standard risk calculators may miss important hereditary risk.
For patients, the findings reinforce that a normal or average-looking clinical risk estimate does not always rule out inherited susceptibility. Genetic testing may reveal actionable information that changes screening recommendations, particularly for women with variants in high-penetrance genes.
For health systems and policymakers, the study adds evidence that broad PV testing can provide value beyond usual risk models. However, implementation must be balanced with access, counseling, insurance coverage, and the need to interpret results carefully. Not every PV carries the same level of risk, and screening recommendations may differ depending on the gene, variant type, age, and personal history.
Limitations
As with any secondary analysis, there are some limitations to consider. The participants were drawn from a specific national screening trial, so the findings may not apply equally to all populations or care settings. Also, hypothetical screening recommendations were compared with actual recommendations using models, which means the study evaluated decision alignment rather than direct cancer outcomes.
In addition, polygenic risk scores are still evolving. Their performance can vary by ancestry, and they may not yet be equally accurate across all racial and ethnic groups. That is important because any screening strategy that relies heavily on polygenic scores must work well for diverse populations to avoid widening disparities.
Finally, PV testing itself is only one part of risk assessment. Genetic counseling, shared decision-making, breast density, prior biopsies, hormonal factors, and patient preferences all contribute to the best screening plan.
Bottom line
In this analysis of the WISDOM Study, most women with pathogenic variants in breast cancer genes would not have been assigned to high-risk screening based on clinical risk alone or clinical risk plus polygenic risk. Population-based pathogenic variant testing therefore appears to identify a different and important subset of women who may benefit from more intensive breast cancer screening.
The study strengthens the case for including broad genetic testing in risk-based breast screening strategies, especially when the goal is to find women with the highest inherited risk who might otherwise be missed by standard prediction tools.
Study citation
Shieh Y, Heise RS, Madlensky L, Sabacan LP, Soto IA, Fiscalini AS, Ross K, Goodman D, Blanco A, Brain S, Heditsian DM, Moya J, Fergus KB, Olopade OI, Scheuner MT, Eklund M, Ziv E, Tice JA, van ‘t Veer L, Esserman LJ, Athena Breast Health Network and WISDOM Study Investigators and Advocate Partners. Impact of Population-Based Pathogenic Variant Testing on Risk-Based Breast Screening Recommendations: A Secondary Analysis of the WISDOM Study. JAMA Oncology. 2026-05-31. PMID: 42218736.
