The Potential of Genetics in Identifying Women at Lower Risk of Breast Cancer

JAMA Oncol. 2024 Feb 1;10(2):236-239. doi: 10.1001/jamaoncol.2023.5468.


Importance: Genetic information is not being used to identify women at lower risk of breast cancer or other diseases in clinical practice. With the new US Preventive Services Task Force guidelines lowering the age for mammogram screening for all, there is a potential benefit in identifying women at lower risk of disease who may defer the start of mammographic screening. This genetic risk-based approach would help mitigate overscreening, associated costs, and anxiety.

Objective: To assess breast cancer incidence and age of onset among women at low genetic risk compared with women at average risk and evaluate the potential to delay mammography on the basis of genetic risk stratification.

Design, setting, and participants: This retrospective case-control study included 25 591 women from the Healthy Nevada Project sequenced by Helix between 2018 and 2022. Data extracted from electronic health records at the end of 2022 (mean length of electronic health record available was 12 years) were used for the analysis in 2023.

Main outcomes and measures: Breast cancer diagnosis was identified from electronic health records. Classification to the low-risk genetic group required (1) the absence of pathogenic variants or a variant of uncertain significance in BRCA1, BRCA2, PALB2, ATM, or CHEK2, and (2) a low polygenic risk score (bottom 10%) using a 313-single-nucleotide variant model.

Results: Of 25 591 women in the study (mean [SD] age was 53.8 [16.9] years), 2338 women (9.1%) were classified as having low risk for breast cancer; 410 women (1.6%) were classified as high risk; and 22 843 women (89.3%) as average risk. There was a significant reduction in breast cancer diagnosis among the low-risk group (hazard ratio, 0.39; 95% CI, 0.29-0.52; P < .001). By 45 years of age, 0.69% of women in the average-risk group were diagnosed with breast cancer, whereas women in the low-risk group reached this rate at 51 years. By 50 years of age, 1.41% of those in the average-risk group were diagnosed with breast cancer, whereas those in the low-risk group reached this rate at age 58 years. These findings suggest that deferring mammogram screening by 5 to 10 years for women at low risk of breast cancer aligns with new draft recommendations.

Conclusions and relevance: The findings of this retrospective case-control study underscore the value of genetics in individualizing the onset of breast cancer screening. Improving breast cancer risk stratification by implementing both high-risk and low-risk strategies in screening can refine preventive measures and optimize health care resource allocation.

MeSH terms

  • Adolescent
  • Breast Neoplasms* / diagnosis
  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / genetics
  • Case-Control Studies
  • Female
  • Humans
  • Infant
  • Mammography
  • Middle Aged
  • Retrospective Studies
  • Risk Factors