Dynamic screening initiation using 16 plasma protein biomarkers with polygenic risk and PLCOm2012: a precision prevention framework for lung cancer

low-dose computed tomography (LDCT) screening strategies for lung cancer are primarily targeted at high-risk groups based on smoking history and age, leading to over-screening of low-risk individuals while delaying timely detection in high-risk groups. This study aimed to develop a precision screening framework integrating plasma proteomics, polygenic risk score (PRS), and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 model (PLCOm2012) to enable dynamic and optimized screening strategies. A multicenter, multimodal study was conducted across two prospective cohorts. Plasma protein profiling identified 16 biomarkers, which were combined with PRS and PLCOm2012 to develop a prediction model. Protein score, PRS, and PLCOm2012 score were used to develop a combined risk score (CRS). Risk advancement period (RAP) analysis quantified personalized screening initiation ages based on 10-year cumulative risk thresholds. The CRS demonstrated superior predictive accuracy, with 3-, 5-, and 10-year AUCs of 0.85 (95% CI: 0.80–0.93), 0.88 (95% CI: 0.83–0.92), and 0.85 (95% CI: 0.81–0.87), respectively. High-risk individuals yielded HR of 3.18 (95% CI: 2.34–4.31) with thresholds reached 11.71 (RAP: -11.71, 95% CI: –15.58 - −6.16) years earlier than those at medium-risk, while low-risk individuals could delay screening by 11.78 (RAP: 11.78, 95% CI: 6.95 - 15.08) years. Risk stratification revealed distinct differences in cumulative lung cancer incidence across groups. Personalized screening initiation ages suggested that high-risk individuals begin screening before age 40, while low-risk individuals could postpone screening until age 55 or later. This study developed a precision lung cancer screening framework by integrating plasma proteomics, genetic profiling, and clinical data. This approach enhanced early detection in high-risk individuals while safely delaying screening for low-risk groups. Clinical trial number: NCT06422637.