Genomic Risk Prediction for Breast Cancer in Older Women

Abstract

Simple Summary We designed a study specifically to assess the performance of genomic risk prediction for breast cancer (BC) in older women aged ≥70 years. We assessed the effects of a polygenic risk score (PRS) for BC and rare pathogenic variants (PVs) in BC susceptibility genes, on incident BC risk in a prospective cohort of 6339 older women (mean age 75 years). During a median follow-up time of 4.7 years, the PRS was an independent predictor of incident BC risk, with women in the top quintile of the PRS distribution having over two-fold higher incident BC risk than women in the lowest quintile. Among 41 carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS still predicts incident BC risk in women aged 70 years and older, suggesting the potential clinical utility of the PRS extends to this older age group. Abstract Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40–69 years. Prospective studies of older women aged ≥70 years have been limited. We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) in BC susceptibility genes (BRCA1/BRCA2/PALB2/CHEK2/ATM). 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) and hormone receptor (ER/PR)-positive disease (HR = 1.5 (CI 1.2–1.9)). Women in the top quintile of the PRS distribution had over two-fold 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. Our study demonstrates that a PRS predicts incident BC risk in women aged 70 years and older, suggesting potential clinical utility extends to this older age group.