Validation of the BOADICEA model in a prospective cohort of <i>BRCA1/2</i> pathogenic variant carriers.

Abstract

No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in <i>BRCA1/2</i> pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of <i>BRCA1/2</i> PV carriers ascertained through clinical genetic centres. We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 <i>BRCA1</i> and 1365 <i>BRCA2</i> PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information. The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in <i>BRCA1</i> or <i>BRCA2</i> PV carriers. The full model identified 5.8%, 12.9% and 24.0% of <i>BRCA1/2</i> PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options. BOADICEA may be used to aid personalised cancer risk management and decision-making for <i>BRCA1</i> and <i>BRCA2</i> PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).