Genomic risk prediction for breast cancer in older women

Background: Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged less than 70 years. Prospective studies of women aged 70 years or older have been limited. Methods: We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6,339 women of European ancestry aged ≥70 years. We evaluated incident BC diagnoses over a median follow-up of 4.7 years. A multivariable Cox regression model including conventional risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) with BC in susceptibility genes (BRCA1/BRCA2/PALB2/CHEK2/ATM). Results: The PRS, as a continuous variable, was an independent predictor of incident BC (hazard ratio [HR] per standard deviation (SD)=1.4, 95% confidence interval [CI] 1.3-1.6, N=110 cases) and hormone receptor (ER/PR)-positive disease (HR=1.5 [CI 1.2-1.9], N=79 cases). Women in the top quintile of the PRS distribution had higher risk of BC than women in the lowest quintile (HR=2.2 [CI 1.2-3.9]). The concordance index of the model without the PRS was 0.62 (95% CI 0.56-0.68) which improved after addition of the PRS to 0.65 (95% CI 0.59-0.71). Among 41 (0.6%) carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Conclusion: The 313-variant PRS predicts BC risk in women aged 70 years and older.