<p>Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS<sub>313</sub>) 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 PRS<sub>313</sub> and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS<sub>313</sub> 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 PRS<sub>313</sub>, 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 &lt; age 40 years, the cumulative PRS<sub>313</sub> 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS<sub>313</sub> can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS<sub>313</sub> needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.</p>

doi.org/10.1038/s41436-021-01198-7, hdl.handle.net/1765/136769
Genetics in Medicine
Erasmus School of Law

GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, kConFab Investigators, IMM (Inge) Lakeman, … H.C. (Lena) van Doorn. (2021). 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. Genetics in Medicine, 23(9), 1726–1737. doi:10.1038/s41436-021-01198-7