Enhancing the BOADICEA cancer risk prediction model to incorporate new data on , , updates to tumour pathology and cancer incidence.

Background: BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) for breast cancer and the epithelial tubo-ovarian cancer (EOC) models included in the CanRisk tool (www.canrisk.org) provide future cancer risks based on pathogenic variants in cancer-susceptibility genes, polygenic risk scores, breast density, questionnaire-based risk factors and family history. Here, we extend the models to include the effects of pathogenic variants in recently established breast cancer and EOC susceptibility genes, up-to-date age-specific pathology distributions and continuous risk factors.

Methods: BOADICEA was extended to further incorporate the associations of pathogenic variants in , and with breast cancer risk. The EOC model was extended to include the association of pathogenic variants with EOC risk. Age-specific distributions of oestrogen-receptor-negative and triple-negative breast cancer status for pathogenic variant carriers in these genes and and were also incorporated. A novel method to include continuous risk factors was developed, exemplified by including adult height as continuous.

Results: , and explain 0.31% of the breast cancer polygenic variance. When incorporated into the multifactorial model, 34%-44% of these carriers would be reclassified to the near-population and 15%-22% to the high-risk categories based on the UK National Institute for Health and Care Excellence guidelines. Under the EOC multifactorial model, 62%, 35% and 3% of carriers have lifetime EOC risks of <5%, 5%-10% and >10%, respectively. Including height as continuous, increased the breast cancer relative risk variance from 0.002 to 0.010.

Conclusions: These extensions will allow for better personalised risks for , , and pathogenic variant carriers and more informed choices on screening, prevention, risk factor modification or other risk-reducing options.