Genetic testing finds breast cancer risks that standard screening models miss

A WISDOM Study analysis shows that pathogenic variant testing can uncover high-risk women who may not qualify for earlier or more intensive breast screening under standard clinical and polygenic risk models alone.

Brief Report: Impact of Population-Based Pathogenic Variant Testing on Risk-Based Breast Screening Recommendations. Image Credit: Lightspring / Shutterstock

A recent report published in the journal JAMA Oncology suggests that women who carry pathogenic variants in breast cancer susceptibility genes may not be identified as high risk using clinical risk models, even when these are combined with polygenic risk scores.

Risk-based screening approaches may estimate breast cancer risk using a combination of medical and family history, breast density, lifestyle factors, and clinical characteristics, along with polygenic risk scores (PRS). In this analysis, these models would have missed most pathogenic variant carriers who were assigned more intensive screening based on genetic testing.

Genetic testing, therefore, may help identify women who, under current guideline-based approaches, may need closer monitoring and earlier screening for breast cancer. This suggests that genetic testing can reveal risks that traditional risk assessment methods may miss. The two approaches should therefore not be considered interchangeable.

Traditionally, breast cancer screening programs have relied heavily on mammography, with recommendations varying according to age and risk level. Women identified as high risk for breast cancer are often advised to undergo more intensive screening. This includes more frequent breast cancer checks, regular mammograms, and breast magnetic resonance imaging (MRI) scans.

In the United States (US), broad genetic testing is not recommended for everyone. Such tests are, instead, offered only to people who meet certain criteria, such as those with a family history of breast cancer. Medical experts are now exploring new risk-based approaches to tailor recommendations according to an individual’s risk of developing breast cancer. Such efforts support precision medicine and could help improve risk stratification and screening assignment by identifying women who may otherwise be missed.

WISDOM Secondary Analysis Design

In this secondary analysis, researchers evaluated the added value of genetic testing in identifying high-risk individuals based on pathogenic variants beyond conventional risk assessment models. To do so, they analyzed the Women Informed to Screen Depending on Measures of Risk (WISDOM) study data to identify participants carrying pathogenic variants (PVs) associated with breast cancer risk.

Among 712 women aged 40-74 years with PV, the team compared screening recommendations based on PV status with those generated by the Breast Cancer Surveillance Consortium (BCSC) clinical risk model, alone or combined with PRS. These models calculated five-year risk estimates using BCSC and PRS data.

The researchers grouped the inherited gene mutations or PVs based on how much they increase a woman’s risk of developing breast cancer. Mutations in genes such as BReast CAncer gene 1 (BRCA1), BRCA2, tumor protein 53 (TP53), partner and localizer of BRCA2 (PALB2), serine/threonine kinase 11 (STK11), and cadherin 1 (CDH1) greatly increased the risk. These women were recommended to undergo alternating MRI and mammogram scans every 6 months.

Among women carrying moderate-risk PVs in the checkpoint kinase 2 (CHEK2) and ataxia-telangiectasia mutated (ATM) genes, those with breast cancer among their close relatives were assigned a more intensive screening schedule.

Specific low-penetrance CHEK2 variants, I157T and S428T, were analyzed separately and generally assigned less intensive screening than high-penetrance variants. The researchers obtained data between September 2016 and February 2023, followed participants through September 2025, and analyzed data between January and May 2026.

Pathogenic Variants Missed By Models

Among women with pathogenic variants in breast cancer susceptibility genes and a median age of 53 years, about one-third of the study population had high-risk mutations. About four in ten women had moderate-risk mutations. The remaining women had CHEK2 low-penetrance variants. The two risk assessment methods, namely, genetic testing and clinical risk assessment-based models, identified different women as being high risk.

Women who were considered high risk because they carried a pathogenic variant were usually not identified as high risk using standard risk calculators. In fact, among women with high-risk PVs, less than one percent of them would have been included in the high-risk category using the hypothetical risk assessment models. In other words, almost all of these women would have been assigned a different risk screening strategy.

The findings were even more striking for younger women. Among women aged between 40 and 49 years who carried pathogenic variants in breast cancer susceptibility genes, nearly two-thirds (64%) would have been told to wait until the age of 50 years to begin screening if recommendations were based only on clinical and polygenic risk assessments.

The study also underscores why family-history-based testing criteria may miss some carriers. In the broader WISDOM analysis, unrestricted testing identified 714 PV carriers, 605 of whom were previously unaware of their PV status, while 30% did not report a family history of breast cancer.

Genetic Testing And Screening Implications

The findings demonstrate that clinical risk models, with or without PRS, would have missed many women carrying inherited breast cancer mutations. As a result, these women might not have received the earlier or more intensive screening that experts generally recommend for women at greater risk of breast cancer.

The findings suggest that genetic testing can identify high-risk individuals who may not be recognized by traditional risk assessment methods. However, the authors noted that the analysis did not directly assess cancer incidence, stage at diagnosis, or the overall benefit-harm balance of screening. 

Future studies are needed in larger and more diverse populations to confirm these findings. Researchers should also evaluate different healthcare settings, where access to genetic testing and breast cancer screening may vary. This will help determine whether high-risk women can actually receive and adhere to the recommended screening and follow-up care.

The authors also cautioned that most WISDOM participants self-reported as White and had high educational attainment, which may limit generalizability to more racially, ethnically, socioeconomically, or clinically diverse screening populations.

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