Precision Breast Cancer Screening with a Polygenic Risk Score

Breast cancer (BC) is the leading cause of cancer deaths in women in the world. Genome-wide association studies have identified numerous genetic variants (SNPs) independently associated with BC. The effects of such SNPs can be combined into a single polygenic risk score (PRS). Stratification of women according to PRS could be introduced to primary and secondary prevention. Our aim was to revalidate a PRS model and to develop a pipeline for individualizing breast cancer screening. Previously published PRS models for predicting the risk of breast cancer were collected from the literature. Models were validated on the Estonian Biobank (EGC) dataset consisting of 32,548 quality-controlled genotypes with 315 prevalent and 365 incident BC cases and on 249,062 samples in the UK Biobank dataset consisting of 8637 prevalent and 6825 incident cases. The best performing model was selected based on the AUC in prevalent data and independently validated in both incident datasets. Using Estonian BC background information, we performed absolute risk simulations and developed individual risk-based recommendations for prevention. The best-performing PRS included 2803 SNPs. The C-index of the Cox regression model associating BC status with PRS was 0.656 (SE = 0.05) with a hazard ratio of 1.66 (95% confidence interval 1.5 - 1.84) on the incident EGC dataset. The PRS is able to stratify individuals with more than a 3-fold risk increase. The observed 10-year risks of individuals in the 99th percentile exceeded the 1st percentile more than 10-fold. PRS is a powerful predictor of breast cancer risk. Currently, PRS scores are not implemented in routine BC screening. We have developed PRS-based recommendations for personalized primary and secondary prevention and our approach is easily adaptable to other nationalities by using population-specific background data of other genetically similar populations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Antegenes has received a grant from the EIT Health The Digital Sandbox program and additional Innovation Voucher funding meant for business development of small and medium sized Estonian enterprises. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Estonian Genome Center: All human research was approved by the Research Ethics Committee of the University of Tartu, and conducted according to the Declaration of Helsinki and Human Research Act. All participants provided written informed consent to participate in the Estonian Biobank. UK Biobank: The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (UK Biobank reference: 16/NW/0274). All participants provided written informed consent to participate in the UK Biobank study. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual level genotype and phenotype data from Estonian Biobank or UK Biobank can not be explicitly shared. The UK Biobank Resource was used under Application Reference Number 53602. New users can request access to UK Biobank from http://www.ukbiobank.ac.uk/resources/. Similarly, Estonian Biobank data is available by request. Researchers interested in Estonian Biobank can request the access here: https://www.geenivaramu.ee/en/access-biobank