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

Xin Yang; Thea M. Mooij; Goska Leslie; Lorenzo Ficorella; Nadine Andrieu; Karin Kast; Christian F. Singer; Anna Jakubowska; Carla H. van Gils; Yen Y. Tan; Christoph Engel; Muriel A. Adank; Christi J. van Asperen; Margreet G. E. M. Ausems; Pascaline Berthet; Margriet J. Collee; Jackie A. Cook; Jacqueline Eason; Karin Y. van Spaendonck-Zwarts; D. Gareth Evans; Encarna B. Gómez-García; Helen Hanson; Louise Izatt; Zoe Kemp; Fiona Lalloo; Christine Lasset; Fabienne Lesueur; Hannah Musgrave; Sophie Nambot; Catherine Noguès; Jan C. Oosterwijk; Dominique Stoppa-Lyonnet; Marc Tischkowitz; Vishakha Tripathi; Marijke R. Wevers; Emily Zhao; Flora E. van Leeuwen; Marjanka K. Schmidt; Douglas F. Easton; Matti A. Rookus; Antonis C. Antoniou

doi:10.1136/jmg-2024-109943

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

Xin Yang, Thea M. Mooij, Goska Leslie, Lorenzo Ficorella, Nadine Andrieu, Karin Kast, Christian F. Singer, Anna Jakubowska, Carla H. van Gils, Yen Y. Tan, Christoph Engel, Muriel A. Adank, Christi J. van Asperen, Margreet G. E. M. Ausems, Pascaline Berthet, Margriet J. Collee, Jackie A. Cook, Jacqueline Eason, Karin Y. van Spaendonck-Zwarts, D. Gareth EvansEncarna B. Gómez-García, Helen Hanson, Louise Izatt, Zoe Kemp, Fiona Lalloo, Christine Lasset, Fabienne Lesueur, Hannah Musgrave, Sophie Nambot, Catherine Noguès, Jan C. Oosterwijk, Dominique Stoppa-Lyonnet, Marc Tischkowitz, Vishakha Tripathi, Marijke R. Wevers, Emily Zhao, Flora E. van Leeuwen, Marjanka K. Schmidt, Douglas F. Easton, Matti A. Rookus, Antonis C. Antoniou

Division of Evolution, Infection and Genomics

Research output: Contribution to journal › Article › peer-review

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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/).

Original language	English
Number of pages	7
Journal	Journal of Medical Genetics
Early online date	4 Jun 2024
DOIs	https://doi.org/10.1136/jmg-2024-109943
Publication status	E-pub ahead of print - 4 Jun 2024

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10.1136/jmg-2024-109943Licence: CC BY

jmg-2024-109943.fullFinal published version, 840 KBLicence: CC BY

Visiting Professorship for Prof. Peter Rutland
Tolz-Zilitinkevic, V. (PI)
1/01/16 → 31/10/16
Project: Research

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Yang, X., Mooij, T. M., Leslie, G., Ficorella, L., Andrieu, N., Kast, K., Singer, C. F., Jakubowska, A., van Gils, C. H., Tan, Y. Y., Engel, C., Adank, M. A., van Asperen, C. J., Ausems, M. G. E. M., Berthet, P., Collee, M. J., Cook, J. A., Eason, J., van Spaendonck-Zwarts, K. Y., ... Antoniou, A. C. (2024). Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers. Journal of Medical Genetics. Advance online publication. https://doi.org/10.1136/jmg-2024-109943

@article{9d54a0eb69fd4f1e95da6fd263c6be84,

title = "Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers",

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{\textquoteright}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/).",

author = "Xin Yang and Mooij, {Thea M.} and Goska Leslie and Lorenzo Ficorella and Nadine Andrieu and Karin Kast and Singer, {Christian F.} and Anna Jakubowska and {van Gils}, {Carla H.} and Tan, {Yen Y.} and Christoph Engel and Adank, {Muriel A.} and {van Asperen}, {Christi J.} and Ausems, {Margreet G. E. M.} and Pascaline Berthet and Collee, {Margriet J.} and Cook, {Jackie A.} and Jacqueline Eason and {van Spaendonck-Zwarts}, {Karin Y.} and Evans, {D. Gareth} and G{\'o}mez-Garc{\'i}a, {Encarna B.} and Helen Hanson and Louise Izatt and Zoe Kemp and Fiona Lalloo and Christine Lasset and Fabienne Lesueur and Hannah Musgrave and Sophie Nambot and Catherine Nogu{\`e}s and Oosterwijk, {Jan C.} and Dominique Stoppa-Lyonnet and Marc Tischkowitz and Vishakha Tripathi and Wevers, {Marijke R.} and Emily Zhao and {van Leeuwen}, {Flora E.} and Schmidt, {Marjanka K.} and Easton, {Douglas F.} and Rookus, {Matti A.} and Antoniou, {Antonis C.}",

year = "2024",

month = jun,

day = "4",

doi = "10.1136/jmg-2024-109943",

language = "English",

journal = "Journal of Medical Genetics",

issn = "1468-6244",

publisher = "BMJ ",

}

Yang, X, Mooij, TM, Leslie, G, Ficorella, L, Andrieu, N, Kast, K, Singer, CF, Jakubowska, A, van Gils, CH, Tan, YY, Engel, C, Adank, MA, van Asperen, CJ, Ausems, MGEM, Berthet, P, Collee, MJ, Cook, JA, Eason, J, van Spaendonck-Zwarts, KY, Evans, DG, Gómez-García, EB, Hanson, H, Izatt, L, Kemp, Z, Lalloo, F, Lasset, C, Lesueur, F, Musgrave, H, Nambot, S, Noguès, C, Oosterwijk, JC, Stoppa-Lyonnet, D, Tischkowitz, M, Tripathi, V, Wevers, MR, Zhao, E, van Leeuwen, FE, Schmidt, MK, Easton, DF, Rookus, MA & Antoniou, AC 2024, 'Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers', Journal of Medical Genetics. https://doi.org/10.1136/jmg-2024-109943

TY - JOUR

T1 - Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers

AU - Yang, Xin

AU - Mooij, Thea M.

AU - Leslie, Goska

AU - Ficorella, Lorenzo

AU - Andrieu, Nadine

AU - Kast, Karin

AU - Singer, Christian F.

AU - Jakubowska, Anna

AU - van Gils, Carla H.

AU - Tan, Yen Y.

AU - Engel, Christoph

AU - Adank, Muriel A.

AU - van Asperen, Christi J.

AU - Ausems, Margreet G. E. M.

AU - Berthet, Pascaline

AU - Collee, Margriet J.

AU - Cook, Jackie A.

AU - Eason, Jacqueline

AU - van Spaendonck-Zwarts, Karin Y.

AU - Evans, D. Gareth

AU - Gómez-García, Encarna B.

AU - Hanson, Helen

AU - Izatt, Louise

AU - Kemp, Zoe

AU - Lalloo, Fiona

AU - Lasset, Christine

AU - Lesueur, Fabienne

AU - Musgrave, Hannah

AU - Nambot, Sophie

AU - Noguès, Catherine

AU - Oosterwijk, Jan C.

AU - Stoppa-Lyonnet, Dominique

AU - Tischkowitz, Marc

AU - Tripathi, Vishakha

AU - Wevers, Marijke R.

AU - Zhao, Emily

AU - van Leeuwen, Flora E.

AU - Schmidt, Marjanka K.

AU - Easton, Douglas F.

AU - Rookus, Matti A.

AU - Antoniou, Antonis C.

PY - 2024/6/4

Y1 - 2024/6/4

N2 - 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/).

AB - 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/).

U2 - 10.1136/jmg-2024-109943

DO - 10.1136/jmg-2024-109943

M3 - Article

SN - 1468-6244

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

ER -

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

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