Implementing Integrated Genomic Risk Assessments for Breast Cancer: Lessons Learned from the eMERGE Study

Objective To develop and implement a pipeline for integrated breast cancer risk assessment using the BOADICEA model within the eMERGE study, incorporating polygenic risk scores (PRS), monogenic variants, family history, and clinical factors.

A pipeline was deployed across ten eMERGE clinical sites, integrating data from REDCap surveys, PRS reports, monogenic reports, and pedigrees via CanRisk Application Programming Interface (API). The process included design, customization, technical implementation, testing, and refinement.

The pipeline successfully generated integrated risk scores for >10,000 females. Of these, 3.6% were classified as high-risk (≥25% lifetime risk), and 0.9% harbored rare pathogenic variants in BRCA1, BRCA2, PALB2, or PTEN. High PRS only scores were identified in 5.6% of participants. Among those with high PRS, 34% also had high-risk based on integrated scores. API and User Interface (UI) results were highly concordant, with an average difference of 0.13%.

Key challenges included integrating diverse data sources, handling missing data, and standardizing pedigree formats. Risk classification discrepancies highlighted the need for refined communication strategies.

This study demonstrates the feasibility of PRS-integrated breast cancer risk assessment in clinical settings but underscores challenges in data integration and risk communication. Future work should enhance recalibration for diverse populations and streamline workflows for risk interpretation and update. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by National Institute of Health. 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: The central IRB at Vanderbilt University Medical Centre (IRB 211043) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available as supplementary materials.