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. 2024 Jul 19;61(8):803-809.
doi: 10.1136/jmg-2024-109943.

Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers

Xin Yang  1 , Thea M Mooij  2 , Goska Leslie  3 , Lorenzo Ficorella  3 , Nadine Andrieu  4   5   6   7 , Karin Kast  8 , Christian F Singer  9 , Anna Jakubowska  10   11 , Carla H van Gils  12 , Yen Y Tan  9 , Christoph Engel  13 , Muriel A Adank  14 , Christi J van Asperen  15 , Margreet G E M Ausems  16 , Pascaline Berthet  17 ; EMBRACE collaborators; Margriet J Collee  18 , Jackie A Cook  19 , Jacqueline Eason  20 , Karin Y van Spaendonck-Zwarts  21 , D Gareth Evans  22   23   24 , Encarna B Gómez García  25 , Helen Hanson  26 , Louise Izatt  27 , Zoe Kemp  28 , Fiona Lalloo  29 , Christine Lasset  30   31   32 , Fabienne Lesueur  4   5   6   7 , Hannah Musgrave  33 , Sophie Nambot  34   35 , Catherine Noguès  36   37 , Jan C Oosterwijk  38 , Dominique Stoppa-Lyonnet  39   40   41 , Marc Tischkowitz  42 , Vishakha Tripathi  43 , Marijke R Wevers  44 , Emily Zhao  3 , Flora E van Leeuwen  2 , Marjanka K Schmidt  15   45 , Douglas F Easton  3   46 , Matti A Rookus  2 , Antonis C Antoniou  3
Collaborators, Affiliations

Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers

Xin Yang et al. J Med Genet. .

Abstract

Background: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 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 BRCA1/2 PV carriers ascertained through clinical genetic centres.

Methods: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 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.

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 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 BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 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.

Conclusion: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).

Keywords: Early Diagnosis; Genetic Counseling; Public Health; Women's Health.

PubMed Disclaimer

Conflict of interest statement

Competing interests: ACA and DFE are named creators of the BOADICEA model which has been licensed by Cambridge Enterprise (University of Cambridge). All the other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Observed and expected (E/O) 5-year breast cancer risks in quintiles of predicted risks: (A) using the cohort-1 samples (N=2979) under the models considering null (age only), PV, PV+PRS, PV+QRFs and PV+QRFs+PRS; and (B) using the cohort-2 samples with FH information (N=1804) under the models considering PV+QRFs+PRS and FH+QRFs+PRS+PV. The dashed line is the diagonal line with slope equal to 1 (corresponding to E/O ratio of 1 for each quintile). FH, family history; PRS, polygenic risk score; PV, pathogenic variant status in BRCA1 and BRCA2; QRFs, questionnaire-based risk factors.
See this image and copyright information in PMC

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