Key takeaways:
- Criteria-independent genetic testing identified pathogenic breast cancer variants in women without personal or family cancer history.
- Overall pathogenic variant detection was 2.6% after excluding participants aware of prior results.
- Pathogenic variant rates were similar between self-selected and randomized participants.
- Younger age and European ancestry were associated with higher odds of pathogenic variants.
- Reliance on family history alone may miss women who could benefit from enhanced surveillance and risk reduction.
Women with high-penetrance and intermediate-penetrance breast cancer are more often identified through criteria-independent genetic testing, according to a recent study published in JAMA Network Open.1
Increased accessibility has been reported for genetic testing for breast cancer susceptibility genes (BCSGs), but current guidelines only recommend testing patients with Jewish ancestry or a personal or family history of cancer.2 Limited cancer history data and limited clinician training make it difficult to optimize BCSGs.1
“Health systems, clinicians, payors, patients, and other stakeholders have an interest in efficiently identifying patients with PVs to improve patient outcomes and reduce costs. However, this task is perceived to be onerous because it requires building infrastructure for population-based testing,” wrote investigators.
Genetic testing methods
The Women Informed to Screen Depending on Measures of Risk trial was conducted to evaluate the results of integrating germline BCSGs into breast cancer screening. Participants included women aged 40 to 75 years with no personal breast cancer history or prior bilateral mastectomy.
These patients were randomized to either a personalized or annual screening arm, with the former group offered a 9-gene panel for germline genetic testing. Saliva samples were obtained for DNA, with a NextSeq 500/550 kit (Illumina) used to perform sequencing.
American College of Medical Genetics and Genomics guidelines, alongside those from the Association for Molecular Pathology, were used to categorize variants, with only pathogenic variants (PVs) reported. CHEK2 low-penetrance (CHEK2LP) variants were reported separately.
Personalized screening and data collection
Personalized screening assignments were provided to patients with PVs, and those in the personalized arm also received genotyping for single-nucleotide variants. Previous germline genetic testing, alongside testing results, were reported by participants through a baseline questionnaire. Those with positive results were categorized as aware of prior germline PV and excluded.
Self-reported demographic information, health information, and family breast and ovarian cancer history were also obtained from baseline questionnaires. Patients with family cancer history also reported each family member’s status separately, including age of onset, sex, and lineage.
There were 30,192 women in the personalized screening arm, 47.1% of whom were randomized to this group and 52.9% of whom selected to be included. A mean age of 54.3 years was reported for patients who completed germline genetic testing, and 9.3% of participants identified as Hispanic, 0.3% as American Indian, 4.6% as Asian, 4.3% as Black, 77.3% as White, and 4% as multiracial or of another race.
Prevalence of pathogenic variants
Jewish ancestry was reported in 14.7% of patients, while a personal history of cancer besides breast cancer was reported in 13.5%. An overall PV detection of 2.6% was reported after exclusion of participants with awareness of prior PV. Being heterozygous for 2 different PVs was reported in 8 participants.
No personal cancer history was reported in the 5 women with TP53 PVs, with 4 not reporting any family history either. However, 1 reported a variety of cancers in multiple relatives. A personal history of gastric cancer was reported in 1 of 3 women with a CDH1 PV. There were no participants with a PTEN or STK11 PV reported.
PV rates did not significantly differ between self-selected vs randomized patients, with rates of 2.8% and 2.4%, respectively. Characteristics linked to increased PV odds included younger age and European ancestry.
Impact of family history
In women with no breast or ovarian cancer history, a PV rate of 2.3% was reported, vs 1.5% for high-penetrance and moderate-penetrance genes. These rates were increased in women with at least 2 relatives who had breast cancer, at 3.3% and 2.4%, respectively.
Of women receiving genetic testing, 14.7% had at least 1 grandparent with Jewish ancestry. When excluding those aware of their PV before joining the trial, this rate was 3.5%, with only 1.6% having PV in high-penetrance and moderate-penetrance genes. Overall, these results highlighted the efficacy of using genetic testing for breast cancer risk assessment.
“Our results demonstrate that relying on a reported family history of cancer has limitations in identifying women who carry a PV, and criteria-independent testing would broaden the group who could benefit from evidence-based cancer surveillance and risk-reduction interventions,” wrote investigators.
References
- 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. 2025. doi:10.1001/jamainternmed.2025.7323
- Owens DK, Davidson KW, Krist AH, et al; US Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement.JAMA. 2019;322(7):652-665. doi:10.1001/jama.2019.10987
