The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Inge M.M. Lakeman, Alexandra J. van den Broek, GEMO Study Collaborators, Epidemiological Study of Familial Breast Cancer (EMBRACE), OCGN Investigators, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), kConFab Investigators, Juliën A.M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A. CaligoWendy K. Chung, Kathleen B.M. Claes, Emmanuelle Barouk-Simonet, Muriel Belotti, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Brigitte Bressac-de Paillerets, Bruno Buecher, Sandrine Caputo, Olivier Caron, Laurent Castera, Virginie Caux-Moncoutier, Chrystelle Colas, Marie Agnès Collonge-Rame, Isabelle Coupier, Antoine de Pauw, Capucine Delnatte, Camille Elan, Laurence Faivre, Sandra Fert Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, J. Margriet Collée, Christoph Engel, Maartje J. Hooning, M Robson, Marjanka K Schmidt

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Abstract

Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

Original languageEnglish
Pages (from-to)1726-1737
Number of pages12
JournalGenetics in Medicine
Volume23
Issue number9
DOIs
Publication statusPublished - Sept 2021

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