Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort.

Abstract

We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS₃₁₃) and other, nongenetic risk factors. Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS₃₁₃ was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS₃₁₃ and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS₃₁₃). C-statistics were used to evaluate discriminative ability. In total, 320 women developed BC. The PRS₃₁₃ was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS₃₁₃, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. The effect size of the PRS₃₁₃ is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.