Projected clinical utility of polygenic risk score-stratified cancer screening: a systematic review

Background: Cancer screening programmes apply uniform criteria irrespective of inherited risk. Polygenic risk scores (PRSs) have been proposed as a promising tool to stratify individual cancer risk and tailor screening strategies. However, whether PRS-informed strategies improve health outcomes compared with current practices remains uncertain. We aimed to synthesise the available evidence on the projected clinical utility of PRS-stratified cancer screening across six malignancies. Methods: We searched PubMed, Scopus, and Web of Science from inception to March 15, 2026, for studies evaluating PRS-stratified screening for breast, colorectal, prostate, lung, gastric, or cervical cancer. Eligible outcomes included cancer-specific mortality, life-years gained (LYG), quality-adjusted life-years (QALYs), overdiagnosis, and false-positive rates. Risk of bias was assessed using the ISPOR-SMDM checklist for modelling studies and ROBINS-I for observational studies. Certainty of evidence was appraised using the GRADE framework. Findings: Of 8,454 records identified, 25 studies were included (22 decision-analytic modelling studies, 3 observational studies) covering five malignancies; no eligible studies were identified for cervical cancer. PRS-stratified strategies were associated with improvements in QALYs for breast, colorectal, gastric, and lung cancer, whereas results for prostate cancer were heterogeneous. Mortality reductions were observed for colorectal, gastric, and lung cancer, although evidence for the latter two rested on single studies. For breast cancer, mortality outcomes were inconsistent and dependent on comparator intensity. For prostate cancer, the principal benefit was a reduction in overdiagnosis rather than mortality improvement. Across all cancer sites, the absolute magnitude of incremental benefit over non-stratified screening was modest. Harms increased in high-risk groups receiving intensified surveillance. The certainty of evidence was rated very low for all outcomes across all cancer types, driven by serious risk of bias and very serious indirectness, reflecting limited transferability across populations and healthcare systems. Interpretation: PRS-stratified screening shows consistent but modest potential to improve the efficiency of cancer screening, particularly for breast, colorectal, and prostate cancer, although the certainty of evidence remains very low. PRS-stratified screening should remain investigational pending validation through prospective trials powered for clinical endpoints, conducted in ancestrally diverse populations, and incorporating equity-sensitive implementation frameworks.