Integrating Polygenic Risk Scores into Breast Cancer Risk Assessment: a Real-World Pilot Study

Polygenic Risk Scores (PRS) enhance breast cancer (BC) risk prediction when integrated into multifactorial models such as CanRisk. However, evidence on PRS integration into routine BC preventive pathways remains limited. This pilot study aims to evaluate the impact of incorporating PRS into BC risk assessment in a tertiary Italian hospital, within the national project Digital Lifelong Prevention (DARE). We enrolled women attending a Medical Genetics Clinic for BC risk assessment at Fondazione Policlinico Gemelli IRCCS since June 2025, including healthy women with BC familiarity or indication for high-penetrance genetic testing, and women with unilateral BC for contralateral risk assessment. All participants undergo CanRisk model assessment, calculated with and without PRS integration, and are classified into three categories: population, moderate, high risk. We measure PRS acceptance rate, lifetime BC risk distribution, and PRS-driven BC risk reclassification. Among eligible women, 168 (99%) agreed to participate and underwent PRS testing. Based on preliminary analyses conducted on the first 64 women (49 affected and 15 unaffected) who completed CanRisk assessment, the distribution across the population-, moderate-, and high-risk categories was 72%, 14%, and 14% among affected women and 66%, 7%, and 27% among unaffected women; with PRS integration, the corresponding proportions shifted to 64%, 18%, and 18% in affected and 60%, 0%, and 40% in unaffected women, with reclassification rates of 10% and 13% respectively, all toward higher risk categories. In conclusion, PRS adoption showed high uptake in a real-world clinical setting and resulted in non-negligible risk reclassification, supporting its potential role in personalized prevention. Ongoing analyses will assess feasibility, emotional impact of PRS communication, and through a multidisciplinary and patient-inclusive approach, how preventive pathways may be adapted for women whose risk classification changes.

Key messages

• Polygenic risk scores integration into CanRisk model for breast cancer showed high uptake and meaningful lifetime BC risk reclassification, supporting its use in preventive pathways.

• Polygenic risk scores increased risk estimates, especially in unaffected women, highlighting its potential to refine stratification and inform tailored prevention strategies in real-world settings.