Genetic testing reveals hidden breast cancer risk

Clinical Takeaway: Consider pathogenic variant testing as a key component of risk-based breast cancer screening strategies, as clinical risk models and polygenic risk scores alone may miss many women who warrant intensified surveillance.

As breast cancer screening shifts toward risk-based approaches, relying only on clinical risk factors and polygenic risk scores could leave many women with inherited cancer susceptibility genes unidentified and undertreated.

A secondary analysis of the WISDOM trial found strikingly little overlap between women identified as high risk through genetic testing and those identified through clinical risk assessment or polygenic risk scores. Among carriers of high-penetrance pathogenic variants (PVs)—who were recommended alternating breast MRI and mammography every 6 months—only 2 of 232 women (0.9%) would have received the same high-risk screening recommendation based on clinical and polygenic risk assessment alone.

The study also found that among PV carriers aged 40 to 49 years, 63.8% would have been advised to defer screening until age 50 based on clinical plus polygenic risk assessment. Among carriers aged 50 to 74 years, 88.9% would have been assigned only biennial mammography. Similar findings were observed when clinical risk models were used without polygenic risk scores.

Investigators analyzed data from 712 women aged 40 to 74 years enrolled in the WISDOM study who carried PVs in breast cancer susceptibility genes, including 232 high-penetrance variants, 278 moderate-penetrance variants, and 202 low-penetrance CHEK2 variants. The researchers compared screening recommendations based on genetic findings with recommendations that would have been generated using clinical risk factors alone or in combination with polygenic risk scores.

As the authors noted, “germline PV testing and risk models containing clinical risk factors and PRSs identify different subsets of high-risk women and are not interchangeable.” The findings support population-based PV testing as “a cornerstone of risk-based screening” and suggest that broader implementation of genetic testing could improve identification of women who may benefit from enhanced breast cancer surveillance.

Source: Shieh Y, et al; Athena Breast Health Network and WISDOM Study Investigators and Advocate Partners (2026, May 31). JAMA Oncol. Impact of Population-Based Pathogenic Variant Testing on Risk-Based Breast Screening Recommendations: A Secondary Analysis of the WISDOM Study