Germline Pathogenic Variants Among Women Without a History of Breast Cancer: A Secondary Analysis of the WISDOM Randomized Clinical Trial.
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Fergus Kirkpatrick B, Ross Katherine S, Scheuner Maren T, Blanco Amie M, Tice Jeffrey A, Ziv Elad, Shieh Yiwey, van 't Veer Laura, Olopade Olufunmilayo I, Goodman Deborah L, Tong Barry S, Harvey Heather, DeRosa Diana, Risty Larissa, Silver Erica, Kaster Andrea, Fiscalini Allison Stover, Blum Kelly, Heise Rachel, Sabacan Leah, Heditsian Diane, Brain Susie, Petruse Antonia, Eklund Martin, Hiatt Robert A, Borowsky Alexander D, Naeim Arash, Park Hannah L, LaCroix Andrea Z, Parker Barbara A, Lancaster Rachael, Esserman James, Wenger Neil, Arasu Vignesh, Anton-Culver Hoda, Esserman Laura J, Madlensky Lisa
Аннотация
OBJECTIVE: To identify the prevalence of PVs in a large cohort of women offered criteria-independent genetic testing and to evaluate the relationship of test positivity to family history and other patient characteristics.
DESIGN, SETTING, AND PARTICIPANTS: The Women Informed to Screen Depending on Measures of Risk (WISDOM) randomized clinical trial enrolled women without breast cancer aged 40 to 74 years between August 2016 and February 2023 in a pragmatic randomized screening trial comparing annual screening mammography with personalized risk-based screening. Data were analyzed from August 2023 to November 2025.
EXPOSURES: All women in the personalized screening arm were offered germline testing for 9 breast cancer susceptibility genes: BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, and TP53.
MAIN OUTCOMES AND MEASURES: The prevalence of PVs in the trial and the distribution of self-reported demographic and family history data in this subpopulation of carriers.
RESULTS: Among 23 098 women who completed germline genetic testing (mean [SD] age, 54.3 [9.6] years), 714 (3.1%) carried a PV. Excluding 109 who were previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (337 [1.5%]) and ATM (101 [0.4%]) but less common in higher-penetrance genes (BRCA1, 33 [0.1%]; BRCA2, 82 [0.4%]; PALB2, 44 [0.2%]). PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (less than 0.1%). Notably, 180 of 605 women with PVs (29.8%) did not report a first-degree or second-degree female relative with breast or ovarian cancer, male relative with breast cancer, or Jewish ancestry.
CONCLUSIONS AND RELEVANCE: In this secondary analysis of the WISDOM trial, criteria-independent genetic testing in a pragmatic trial identified a substantial number of women with clinically actionable results, many of whom would not have qualified for genetic testing under current guidelines. These findings support broader access to genetic testing as part of personalized breast cancer risk assessment.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02620852.