Broad Genetic Testing Reveals Hidden Breast Cancer Risk in Women Without Family History

Highlight

• Population-wide genetic testing identified pathogenic variants (PVs) in 3.1% of women without breast cancer.
• Nearly 30% of PV carriers had no family history or traditional risk factors for breast or ovarian cancer.
• CHEK2 and ATM mutations were more prevalent than BRCA1 or BRCA2 variants in this cohort.
• Findings suggest expanding genetic testing guidelines beyond current family-history-based criteria.

Background

Breast cancer remains a major public health concern and is the most commonly diagnosed malignancy among women globally. Pathogenic germline variants in susceptibility genes, such as BRCA1 and BRCA2, are well-established risk factors that dramatically increase lifetime risk. Current clinical guidelines predominantly recommend genetic testing for women with a strong family history of breast or ovarian cancer, or other high-risk features. However, this targeted testing approach may fail to identify individuals carrying actionable mutations without obvious family history.

The Women Informed to Screen Depending on Measures of Risk (WISDOM) trial introduces a personalized risk-based screening strategy. This secondary analysis explores how criteria-independent germline genetic testing can uncover previously unrecognized high-risk individuals.

Study Design

The WISDOM randomized clinical trial enrolled 40- to 74-year-old women without a diagnosis of breast cancer between August 2016 and February 2023. The pragmatic design compared annual screening mammography with personalized screening intervals guided by individual risk assessments.

In the personalized screening arm, participants were offered germline genetic testing for nine breast cancer susceptibility genes: BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, and TP53.

Main outcome measures included PV prevalence, demographic distribution, family history patterns, and self-reported ancestry data among PV carriers.

Key Findings

Among 23,098 women who underwent genetic testing (mean age 54.3 years), 714 (3.1%) carried a pathogenic or likely pathogenic variant. Excluding the 109 participants already aware of their mutation, the detection rate was 2.6%.

The gene distribution revealed:

• CHEK2: 337 cases (1.5%) — representing the most common PV detected
• ATM: 101 cases (0.4%)
• BRCA2: 82 cases (0.4%)
• PALB2: 44 cases (0.2%)
• BRCA1: 33 cases (0.1%)
• CDH1, PTEN, STK11, TP53: collectively less than 0.1%

Remarkably, 180 of 605 women (29.8%) who were newly identified as PV carriers lacked traditional referral factors — meaning they had no first-degree or second-degree relative with breast or ovarian cancer, no male relative with breast cancer, and no self-reported Jewish ancestry.

This finding underscores the limitations of guideline-based testing, as a sizable proportion of high-risk women would not have undergone testing under current protocols.

Expert Commentary

Genetic testing independent of family history criteria can improve early identification of individuals at risk for breast cancer. Given that nearly one-third of carriers in this study presented without conventional risk indicators, broader testing approaches could allow for earlier surveillance and risk-reducing interventions.

Public health implications are significant: shifting from selective to more inclusive germline testing could identify thousands more women at risk nationwide. However, widespread implementation requires careful consideration of cost-effectiveness, genetic counseling resources, psychosocial impacts, and healthcare system capacity.

Gene prevalence patterns in this study also highlight the importance of moderate-penetrance genes like CHEK2 and ATM, which are less frequently emphasized in counseling compared to BRCA1/2, yet still confer meaningful elevation in risk. Risk management strategies, including screening intervals and prophylactic considerations, must be tailored according to gene-specific penetrance and family histories.

Conclusion

This secondary analysis of the WISDOM trial demonstrates that criteria-independent genetic testing can uncover clinically actionable pathogenic variants in a significant number of women without breast cancer, many without significant family history. These results support broader access to genetic testing as part of personalized risk assessment for breast cancer and challenge the sufficiency of current guideline-based criteria.

Future research should address optimal implementation strategies, assess patient understanding and acceptability, and measure long-term outcomes, including cancer incidence reduction and cost-benefit ratios.

Funding and ClinicalTrials.gov

Trial registration: ClinicalTrials.gov Identifier: NCT02620852.

References

Fergus KB, Ross KS, Scheuner MT, Blanco AM, Tice JA, Ziv E, Shieh Y, van ‘t Veer L, Olopade OI, Goodman DL, Tong BS, Harvey H, DeRosa D, Risty L, Silver E, Kaster A, Fiscalini AS, Blum K, Heise R, Sabacan L, Heditsian D, Brain S, Petruse A, Eklund M, Hiatt RA, Borowsky AD, Naeim A, Park HL, LaCroix AZ, Parker BA, Lancaster R, Esserman J, Wenger N, Arasu V, Anton-Culver H, Esserman LJ, Madlensky L. Germline Pathogenic Variants Among Women Without a History of Breast Cancer: A Secondary Analysis of the WISDOM Randomized Clinical Trial. JAMA Intern Med. 2025 Dec 12:e257323. doi:10.1001/jamainternmed.2025.7323.