TOPLINE:

Among over 20,000 women without breast cancer who underwent genetic testing in a clinical trial, 714 (3.1%) carried pathogenic variants in breast cancer susceptibility genes. About 30% reported no family history of breast or ovarian cancer, making it unlikely they would have been offered genetic testing in routine practice.

METHODOLOGY:

• Genetic testing for breast cancer susceptibility genes is increasingly accessible, but under current guidelines it is generally only offered to women with a personal or family history of certain cancers or those of Jewish ancestry. Expanded testing eligibility might identify more women with potentially actionable pathogenic variants.
• Researchers conducted a secondary analysis of the WISDOM randomized clinical trial, which compared annual screening mammography with personalized risk-based screening among women aged 40-74 years with no history of breast cancer.
• Participants in the personalized screening group were offered germline testing for nine breast cancer susceptibility genes: BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, and TP53. The analysis included 23,098 women who completed testing, with a mean age of 54 years.

TAKEAWAY:

• Overall, 714 participants (3.1%) carried pathogenic variants, with 605 (2.6%) being previously unaware of their carrier status.
• Pathogenic variants were most frequent in CHEK2 (1.5%) and ATM (0.4%), which are moderate-penetrance genes, and were less common in the high-penetrance genes BRCA1 (0.1%), BRCA2 (0.4%), and PALB2 (0.2%).
• Notably, 29.8% of women with pathogenic variants did not report having first- or second-degree female relatives with breast or ovarian cancer, male relatives with breast cancer, or Jewish ancestry — making it unlikely they would have been offered genetic testing in clinical practice, the authors noted.
• High-penetrance variants were more common among younger women, at 0.8% among both women in their forties or fifties vs 0.1% of women aged 60-69 years (P = .02). PALB2 pathogenic variants were detected more often in non-Hispanic Black women compared with all other racial and ethnic groups (0.6% vs 0.2%; P = .01).

IN PRACTICE:

“These findings support broader access to genetic testing as part of personalized breast cancer risk assessment,” the authors wrote. “Our results demonstrate that relying on a reported family history of cancer has limitations in identifying women who carry a pathogenic variant, and criteria-independent testing would broaden the group who could benefit from evidence-based cancer surveillance and risk-reduction interventions.”

SOURCE:

This study was led by Lisa Madlensky, PhD, of Moores Cancer Center, University of California, San Diego. It was presented at San Antonio Breast Cancer Symposium (SABCS) 2025 and simultaneously published online on December 12 in JAMA Internal Medicine.

LIMITATIONS:

Variant classifications were determined at a single clinical laboratory, which might differ from other laboratories’ interpretations. Self-reported prior genetic testing results were not confirmed, and family history of cancer relied on self-report. Participants were not asked about family history of pancreatic, prostate, or other cancers that are incorporated into current testing criteria.

DISCLOSURES:

This study was supported by the National Cancer Institute, Patient-Centered Outcomes Research Institute, and Breast Cancer Research Foundation. The study authors reported numerous financial relationships; a full list of disclosures is available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.