Unrestricted genetic testing in 23,098 women found 3.1% carried breast cancer pathogenic variants; 30% had no family history or Jewish ancestry, supporting broader testing.
Does unrestricted genetic testing identify pathogenic variants in women without breast cancer who would not qualify under standard guidelines?
Unrestricted genetic testing in women without breast cancer identifies a substantial number of pathogenic variants, including in 30% who lack traditional risk factors like family history.
Absolute Event Rate: 0% vs 0%
Abstract Background: The population prevalence of pathogenic variants (PVs) in breast cancer susceptibility genes (BCSG’s) remains largely unknown, in part due to restrictions in genetic testing guidelines. We report early BCSG prevalence estimates from the Women Informed to Screen Depending on Measures of Risk (WISDOM) Trial, where women in the personalized screening arm were offered unrestricted genetic testing, and evaluate the relationship of test positivity to family history and other patient characteristics. Methods: The WISDOM Trial enrolled women without breast cancer between 2016-2023 aged 40-74 in a pragmatic randomized screening trial comparing annual screening mammography to personalized risk-based screening. Participants in the personalized arm were offered germline testing for nine breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, TP53). We report the prevalence of PVs in the trial and the distribution of self-reported demographic and family history data in the sub-population with PVs. Results: Among 23,098 participants who enrolled in the trial and completed genetic testing, 714 (3.1%) carried a PV. After excluding those previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (1.47%) and less common in higher-penetrance BRCA1 (0.14%), BRCA2 (0.36%), and PALB2 (0.19%) variants. PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (0.1%). Notably, 30% of women with PVs did not report a first- or second-degree female relative with breast or ovarian cancer, a male relative with breast cancer, or Jewish ancestry. Conclusion and Relevance: Unrestricted access to genetic testing in a real-world setting identified a substantial number of women with clinically actionable results, many of whom would not have qualified for genetic testing under guideline-concordant criteria. These findings support expanding genetic testing to all women as part of personalized breast cancer risk assessment. Citation Format: K. B. Fergus, K. Ross, M. Scheuner, B. S. Tong, A. Blanco, A. Fiscalini, D. DeRosa, E. Silver, D. Goodman-Gruen, H. Anton-Culver, A. Borowsky, J. Esserman, A. Kaster, A. LaCroix, R. Lancaster, A. Naeim, H. Park, B. Parker, V. Arasu, N. Wenger, H. Harvey, D. Heditsian, S. Brain, V. Lee, D. Moorehead, A. Petruse, L. Sabacan, R. Hiatt, Y. Shieh, E. Ziv, O. I. Olopade, J. Tice, M. Eklund, L. Van 'T Veer, L. J. Esserman, L. Madlensky. Germline pathogenic variants in the personalized screening arm of the WISDOM Study: Findings from 23,098 women with no personal history of breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF5-04.
Fergus et al. (Tue,) reported a other. Unrestricted genetic testing in 23,098 women found 3.1% carried breast cancer pathogenic variants; 30% had no family history or Jewish ancestry, supporting broader testing.