Validation of the BOADICEA Model in a Prospective Cohort ofBRCA1/2Pathogenic Variant Carriers
Authors: Yang Xin , Mooij Thea M. , Leslie Goska , Ficorella Lorenzo , Andrieu Nadine , Kast Karin , Singer Christian F. , Jakubowska Anna , van Gils Carla H. , Tan Yen , Engel Christoph , Adank Muriel A. , van Asperen Christi J. , Ausems Margreet G.E.M. , Berthet Pascaline ,   EMBRACE collaborators, Collée J. Margriet , Cook Jackie , Eason Jacqueline , van Spaendonck-Zwarts K.Y. , Evans D Gareth , Gomez Garcia Encarna B. , Hanson Helen , Izatt Louise , Kemp Zoe , Lalloo Fiona , Lasset Christine , Lesueur Fabienne , Musgrave Hannah , Nambot Sophie , Noguès Catherine , Oosterwijk Jan C. , Stoppa-Lyonnet Dominique , Tischkowitz Marc , Tripathi Vishakha , Wevers Marijke R. , Zhao Emily , van Leeuwen Flora , Schmidt Marjanka K. , Easton Douglas F. , Rookus Matti A. , Antoniou Antonis C. 
Published: April 2024

Background

No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically inBRCA1/2pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting five-year breast cancer risks in a prospective cohort ofBRCA1/2PV carriers ascertained through clinical genetic centres.

Methods

We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1,614BRCA1and 1,365BRCA2PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 single nucleotide polymorphisms, and family history information.

Results

The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95%CI:0.92-1.24) and in quintiles of predicted risk. Discrimination was maximized when all risk factors were considered (Harrell’s C-index=0.70, 95%CI:0.67-0.74; AUC=0.79, 95%CI:0.76-0.82). The model performance was similar when evaluated separately inBRCA1orBRCA2PV carriers. The full model identified 5.8%, 12.9% and 24.0% ofBRCA1/2PV carriers with five-year breast cancer risks of <1.65%, <3% and <5% respectively, risk thresholds commonly used for different management and risk-reduction options.

Conclusion

BOADICEA may be used to aid personalised cancer risk management and decision making forBRCA1andBRCA2PV carriers. It is implemented in the free-access CanRisk tool (www.canrisk.org).

What is already known on this topic

No study has assessed the clinical validity of the multifactorial BOADICEA model for predicting future breast cancer risks specifically forBRCA1/2pathogenic variant (PV) carriers.

What this study adds

This is the first study to validate the BOADICEA model based on the joint effects of questionnaire-based risk factors (QRFs), a polygenic risk score (PRS) based on 313 single nucleotide polymorphisms, and cancer family history information inBRCA1/2PV carriers ascertained through clinical genetic centres. The model is well calibrated and discriminated well in bothBRCA1andBRCA2carriers. The inclusion of family history, alongside QRFs and the PRS, in predicting cancer risks for PV carriers in clinical genetics settings can improve the calibration within individual risk categories and can result in clinically meaningful levels of breast cancer risk stratification.

How this study might affect research, practice or policy

BOADICEA is freely available via the CanRisk tool (www.canrisk.org). Rather than relying solely on average published penetrance estimates commonly used in genetic clinics for counselling ofBRCA1/2PV carriers, BOADICEA offers more personalized BC risks. This can facilitate informed decision-making regarding the clinical management of BC risk, including considerations for surveillance and the timing of risk-reducing surgery.