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

Polygenic Risk Scores (PRS) represent a promising adjunct to established breast cancer risk prediction models, including the multifactorial CanRisk model. Despite growing evidence, data on the feasibility of integrating PRS into routine hereditary breast cancer assessment remain scarce, particularly within European clinical pathways. Systematic evaluation of operational requirements, patient and provider acceptability, and organizational impact is essential prior to any broader implementation. This single-arm feasibility study will be conducted at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome, Italy) and is expected to enrol approximately 700 women attending the Medical Genetics Clinic. Eligible participants comprise: unaffected women with a documented family history of breast cancer or known pathogenic variants associated with hereditary breast cancer predisposition; women with unilateral breast cancer undergoing oncogenetic counseling for contralateral risk assessment. All participants will be offered testing for pathogenic variants in breast cancer predisposition genes and PRS, and integrated risk estimates will be generated using the CanRisk model. The primary outcome is the feasibility of implementing PRS within the clinical workflow, assessed through a validated questionnaire administered to participants and healthcare professionals. Secondary outcomes include PRS uptake, perceptions of the integrated pathway, impact on risk category reclassification, and qualitative insights into risk communication processes. This study will generate empirical evidence on the operational, organizational, and perceptual considerations associated with incorporating PRS-enhanced risk assessment into hereditary breast cancer services in Italy. By characterizing feasibility and acceptability, the findings will support the refinement of clinical pathways and inform the sustainable integration of PRS into routine preventive care.