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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p> Trial registration <p>Clinical trial number: NCT06422637.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Runchen Wang,
  • Zhiming Ye,
  • Qixia Wang,
  • Rong Xu,
  • Yi Feng,
  • Na Zhao,
  • Yun Yan,
  • Yulin Zhao,
  • Xuanzhuang Lu,
  • Xiangyuan Zheng,
  • Jianqi Zheng,
  • Hongsheng Deng,
  • Ran Zhong,
  • Rui Gao,
  • Jie Li,
  • Wenhua Liang,
  • Jianxing He,
  • Hengrui Liang

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Trial registration

Clinical trial number: NCT06422637.