Artigo

Germline Pathogenic Variants AmongWomenWithout a History of Breast Cancer A Secondary Analysis of the WISDOM Randomized Clinical Trial

Autor(es): Kirkpatrick B. Fergus, MD; Katherine S. Ross, MS; Maren T. Scheuner,MD, MPH; Amie M. Blanco, MS; Jeffrey A. Tice, MD; Elad Ziv, MD; Yiwey Shieh, MD; Laura van ‘t Veer, PhD; Olufunmilayo I. Olopade, MBBS; Deborah L. Goodman, MD, PhD; Barry S. Tong, MS; Heather Harvey, RN; Diana DeRosa, MS; Larissa Risty, MS; Erica Silver, MS; Andrea Kaster, MD; Allison Stover Fiscalini, MPH; Kelly Blum, MS; Rachel Heise, MS; Leah Sabacan, MBA; Diane Heditsian, BA; Susie Brain, BSc; Antonia Petruse, MBA; Martin Eklund, PhD; Robert A. Hiatt, MD; Alexander D. Borowsky, MD; Arash Naeim, MD; Hannah L. Park, PhD; Andrea Z. LaCroix, PhD; Barbara A. Parker, MD; Rachael Lancaster, MD; James Esserman, MD; NeilWenger, MD; Vignesh Arasu, MD, PhD; Hoda Anton-Culver, PhD; Laura J. Esserman, MD; Lisa Madlensky, PhD

ABSTRACT

IMPORTANCE The prevalence of pathogenic or likely pathogenic variants (PVs) in breast cancer susceptibility genes in the US population—regardless of family history risk factors—remains largely unknown because population-based genetic screening is not routinely performed.

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 TheWomen 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