Polygenic risk scores in breast cancer screening: recommendations from the Can.Heal project

Abstract Background Polygenic risk scores (PRS) have the potential to personalize breast cancer screening by refining starting ages and intervals. Yet, evidence remains fragmented and largely based on modeling. The EU4Health Can.Heal project aimed to develop evidence-based recommendations to guide integration of PRS into screening programs across Europe. Methods Using the GRADE approach, we developed an Evidence to Decision (EtD) framework and systematically reviewed literature across relevant domains. In the absence of randomized controlled trials, the project synthesized four decision-analytic models to evaluate benefits & harms. Two systematic reviews informed analysis of feasibility, acceptability, equity and Cost-effectiveness. Evidence quality was appraised using ISPOR and GRADE standards. A multidisciplinary panel of nine experts-including clinicians, public health specialists and a patient representative-reviewed findings and formulated recommendations. Results All estimates came from modeling studies, with overall certainty rated as low to very low due to indirectness, imprecision, and variability. Models predicted modest reductions in breast cancer mortality and gains in quality-adjusted life years with PRS-enhanced screening, but also highlighted increased risk of overdiagnosis and false positives. Cost-effectiveness results varied widely and were sensitive to assumptions about PRS cost and protocol design. Key implementation challenges include limited preparedness, infrastructure gaps, and reduced predictive accuracy in non-European populations. Conclusions We conditionally recommend pilot and prospective implementation of PRS-enhanced screening in the EU, with real-time monitoring of outcomes, acceptability, and equity. Broader adoption should await stronger trial evidence (e.g., WISDOM, MyPeBS, BREATHE). National programs should prioritize local learning, risk communication, public engagement, and supportive infrastructures like genetic counseling and data protection. Key messages • Pilot PRS-based breast cancer screening via well-designed studies and phased programs, with real-time monitoring of benefits, harms, and costs due to low-certainty modeling evidence. • Uncertain, context-specific evidence on PRS screening calls for transparent, cautious stakeholder engagement, research investment, and strong support systems like counseling and data governance.