Implementing polygenic risk scores for breast cancer prevention: protocol for a feasibility study in a real-world clinical setting

Introduction: Polygenic risk scores (PRSs) enhance breast cancer risk prediction when integrated into multifactorial models such as CanRisk. However, evidence on the real-world feasibility of incorporating PRS into routine hereditary breast cancer pathways remains limited, particularly within southern European healthcare systems. This study aims to evaluate the feasibility and acceptability of integrating PRS into clinical risk assessment in a real-world setting in Italy.

Methods and analysis: This is a single-arm feasibility implementation study to be conducted in a real-world clinical setting at a large university hospital in Rome, Italy. A minimum of 100 women attending a Medical Genetics Clinic for breast cancer risk assessment will be enrolled. Eligible participants include unaffected women with family history or increased baseline risk and women with unilateral breast cancer undergoing contralateral risk assessment. Participants will undergo CanRisk assessment to estimate lifetime breast cancer risk, calculated with and without PRS integration, and subsequently classified into three risk categories according to regional guidelines: general population risk, moderate risk and high risk. The primary outcome is feasibility of PRS integration into the clinical workflow, assessed using a validated questionnaire administered to participants and healthcare professionals. Secondary outcomes include PRS uptake, acceptability of receiving PRS-informed risk estimates, emotional response, risk reclassification rates and potential modifications to preventive recommendations. Quantitative analyses will include descriptive statistics, paired comparisons and multivariable regression models; qualitative perceptions will be explored through structured questionnaires.