Criteria-Independent Genetic Testing Enhances Breast Cancer Risk Identification: JAMA
Breast Cancer
Researchers have demonstrated in the WISDOM trial that integrating criteria-independent genetic testing into routine breast cancer risk assessment is both feasible and acceptable across diverse populations. The study identified pathogenic variants (PVs), including high-penetrance variants, in women who would not have qualified for traditional germline testing based on family history alone. The findings highlight the limitations of relying solely on family history and suggest that broader genetic testing could expand access to targeted cancer surveillance, prevention, and early detection strategies. The study was published in JAMA Internal Medicine by Kirkpatrick B. and colleagues.
The frequency of pathogenic or likely pathogenic variants (PVs) in breast cancer susceptibility genes in the general US population remains unclear because, historically, eligibility for genetic testing is based on family history criteria. Therefore, a substantial proportion of women with increased risk may not have undergone identification. The Women Informed to Screen Depending on Measures of Risk (WISDOM) trial presented a chance to examine in a large group of women, without pre-test risk strata criteria, the yield of genetic testing.
This secondary analysis occurred within a randomized controlled trial named WISDOM. The WISDOM trial recruited women aged 40 to 74 years without a prior diagnosis of breast cancer from August 2016 to February 2023. The WISDOM trial tested annual screening mammography against personalized risk screening. Analyses in this secondary analysis took place in the subset of women in the personalized screening group who underwent germline testing from August 2023 to November 2025.
Germline testing for 9 genes associated with breast cancer susceptibility was offered: BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, and TP53. The main study endpoints were the prevalence of pathogenic variants and their distribution according to demographic and family history factors among variant carriers.
Key Findings
Among 23,098 women participating in germline testing with a mean (SD) age of 54.3 (9.6) years, 714 women (3.1%) were found to have a pathogenic or likely pathogenic variant.
Excluding 109 women in whom the genetic status had previously been disclosed, the rate of new PV identification was 2.6%.
PVs were most commonly found in CHEK2 (337 women; 1.5%) and ATM (101 women; 0.4%) genes.
The higher-penetrance genes were less frequently mutated, including BRCA1 in 33 women (0.1%), BRCA2 in 82 women (0.4%), and PALB2 in 44 women (0.2%). The genes with mutations of CDH1, PTEN, STK11, and TP53 were all very uncommon.
Importantly, 180 of 605 women with PVs (29.8%) did not have a first- or second-degree female relative with breast or ovarian malignancies, a male relative with breast malignancies, and/or Jewish ancestry.
In this secondary analysis of a WISDOM trial, criteria-independent genetic testing found a relevant proportion of premenopausal women with pathogenic variants in breast cancer susceptibility genes, a relevant proportion of whom would not have fulfilled present testing criteria. Such findings can inform future guideline policies on population-screening strategies because these findings support a broader application of genetic testing in personalizing breast cancer risk assessment.
Reference:
Fergus KB, Ross KS, Scheuner MT, et al. Germline Pathogenic Variants Among Women Without a History of Breast Cancer: A Secondary Analysis of the WISDOM Randomized Clinical Trial. JAMA Intern Med. Published online December 12, 2025. doi:10.1001/jamainternmed.2025.7323
