Pathogenic Variants, Family History, and Cumulative Risk of Breast Cancer in US Women

Area of Science:

• Oncology
• Genetics
• Epidemiology

Background:

• Inherited pathogenic variants (PVs) in predisposition genes elevate breast cancer risk.
• The combined impact of PV status, family history, and other factors on population-based breast cancer risk is not well understood.

Purpose of the Study:

• To evaluate population-based breast cancer risk estimates for individuals with established PVs.
• To stratify risk by first-degree family history of breast cancer and other relevant factors.

Main Methods:

• Pooled data from 13 US-based breast cancer case-control studies (CARRIERS consortium).
• Estimated breast cancer rate ratios for PVs in 7 genes.
• Utilized the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks, stratified by family history.

Main Results:

• PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2 were strongly associated with increased breast cancer risk.
• Cumulative breast cancer risk by age 50 ranged from 2.4% (no PVs, no family history) to 35.5% (PALB2 PV carriers with family history).
• Cumulative risk by age 80 ranged from 11.1% (noncarriers, no family history) to 70.5% (PALB2 carriers with family history).

Conclusions:

• Population-based breast cancer risk estimates for PV carriers vary significantly by family history and modifiable risk factors.
• These estimates are crucial for identifying individuals who would benefit most from enhanced screening and prevention strategies.