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

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 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, HR per SD=1.12, 95%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.