Clinical recommendations for polygenic risk score-enhanced breast cancer screening: Can.Heal project

Abstract Background The application of polygenic risk score (PRS) in breast cancer (BC) screening presents promising opportunities. Developing recommendations for future use and research on this topic is a key focus of the EU4Health project: Building the EU cancer and public health genomics platform (Can.Heal). We aim to provide these recommendations based on the analysis of available evidence through a transparent and rigorous development process. Methods The recommendations adopt the GRADE evidence to decision methodology, leveraging an evidence review team and a multidisciplinary panel of nine experts. A systematic review is being conducted to evaluate the evidence for PRS in BC screening, in the domains of benefits and harms, acceptability, feasibility, equity and cost-effectiveness. Results Regarding benefits and harms of adding PRS to BC standard screening, we identified 63 relevant articles. Forty-five (71%) discussed benefits, while 14 (22%) addressed harms. Forty-two (67%) were observational studies, 18 (28%) modeling studies and 1 non-randomised control trial (2%) that examined the diagnostic accuracy of PRS-enhanced screening for relative BC risk prediction using measures such as net reclassification index and area under the curve. Lastly, two modeling studies (3%) assessed the clinical utility of PRS-enhanced screening in terms of life years gained, BC deaths averted. The other domains are under examination. The panel convened to redefine the research question and outcomes of interest and will reconvene to assess the certainty of evidence collected, and subsequently to draft recommendations. Conclusions The integration of PRS into BC screening shows potential benefits in improving risk prediction. Ongoing trials, such as Wisdom and MyPEBS, are studying the clinical utility of integrating PRS in BC screening. The approach taken by the Can.Heal aims to ensure that the recommendations are based on a thorough and balanced evaluation of the available evidence. Key messages • The Can.Heal project aims to formulate policy and research recommendations for breast cancer screening using PRS through a thorough evidence review. • Upcoming PRS recommendations rely on expert opinion and modeling studies.