Contribution of Risk Factors, Including Polygenic Score, to the Multifactorial Risk Assessment for the Implementation of Personalized Breast Cancer Screening: Insights from the PERSPECTIVE: Integration and Implementation Project

Risk-based breast cancer (BC) screening can provide tailored recommendations based on individual risk. We estimated 10-year BC risks in 3753 women aged 40-70 with no cancer history. The primary endpoint was risk reclassification, assessed as the proportion of women whose assigned 10-year risk category changed when using different risk factor combinations against a full multifactorial model including questionnaire-based risk factors (QRFs), polygenic score (PGS), mammographic density (MD), and pedigree-structured first- and second-degree family history (FH) of breast, ovarian, pancreatic and prostate cancer, including both affected and unaffected relatives. Excluding PGS from risk calculations led to the highest overall reclassification. Adding the PGS to risk factors already collected in provincial screening programs reduced reclassification from 23% to ~13%. PGS, MD, QRFs and FH of BC in affected and unaffected first- and second-degree relatives are key for refining risk stratification. These findings provide real-world evidence on how incorporating different sets of risk factors, both those routinely collected in screening programs and those requiring additional data collection, affect individual-level risk classification amongst a population-based cohort, and how the impacts differ across age groups.