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

• Published in: Journal of medical genetics Vol. 61; no. 8; pp. 803 - 809
• Main 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 Y, Engel, Christoph, Adank, Muriel A, van Asperen, Christi J, Ausems, Margreet G E M, Berthet, Pascaline, Collee, Margriet J, Cook, Jackie A, Eason, Jacqueline, Spaendonck-Zwarts, Karin Y van, Evans, D. Gareth, Gómez García, 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 E, Schmidt, Marjanka K, Easton, Douglas F, Rookus, Matti A, Antoniou, Antonis C, Kanani, Farah, Davidson, Rosemarie, Snape, Katie, Side, Lucy, Copeland, Harriet, Ahmed, Munaza, Brennan, Paul, Walker, Lisa, Murray, Jennie, Donaldson, Alan, Searle, Claire, Morrison, Patrick, Barwell, Julian, Rogers, Mark T, New, Rachel Hart, Brady, Angela, Gallagher, David, Miedzybrodzka, Zosia, Conti, Hector, Murray, Alex, Ong, Kai-Ren, Kennedy, John, Gregory, Helen
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.08.2024; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Adult; Age; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Calibration; Cancer Genetics; Decision making; Discrimination; Disease management; Early Diagnosis; Epidemiology; Family medical history; Female; Genetic Counseling; Genetic Predisposition to Disease; Heterozygote; Humans; Life Sciences; Mastectomy; Middle Aged; Performance evaluation; Polymorphism, Single Nucleotide - genetics; Prediction models; Prospective Studies; Public Health; Questionnaires; Regression analysis; Risk Assessment; Risk Factors; Single-nucleotide polymorphism; Surgery; Women's Health; Womens health; Poland; Netherlands; Austria; United Kingdom > UK; Germany; Public Health; Women's Health; Early Diagnosis; Genetic Counseling
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg-2024-109943

BackgroundNo 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.MethodsWe 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.ResultsThe 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.ConclusionBOADICEA 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/).