Equity Gaps in Pulmonary Nodule Risk Prediction for Never-Smokers: A Real-World Evidence-Informed Narrative Review and Policy Analysis

Background and Objective: Current lung cancer screening and pulmonary nodule management pathways were built largely around age, smoking exposure, and computed tomography (CT) morphology. These frameworks have reduced unnecessary invasive testing among many low-risk individuals, but they may under-recognize selected never-smoker subgroups because their risk scores often fall below conventional thresholds, especially East Asian women with molecularly enriched lung adenocarcinoma risk. This review evaluates whether real-world cohort evidence supports an equity concern in risk prediction and management for never-smokers with pulmonary nodules.

Methods: We conducted a targeted narrative evidence mapping of guideline documents, original prediction model studies, external validation studies, East Asian never-smoker screening cohorts, molecular epidemiology studies, and diagnostic-delay outcome studies. Priority was given to peer-reviewed primary studies, prospective cohorts, national or international guidelines, and official society statements. Commercial calculators, news reports, legal commentaries, and non-peer-reviewed secondary sources were excluded from core evidence synthesis.

Key Content and Findings: Smoking-centered screening eligibility remains the dominant entry point into low-dose computed tomography (LDCT) screening, while never-smokers are generally excluded from routine screening eligibility. Cancer Screening Program in Urban China (CanSPUC)-derived Chinese risk models demonstrate that non-smoking Chinese women and broader non-smoking Chinese populations have locally relevant predictors, including chronic respiratory disease, family history, menopause, education, tuberculosis history, and other non-tobacco factors. The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) prospective cohort showed clinically meaningful LDCT-detectable invasive lung cancer in selected never-smokers. Hospital-based persistent nodule cohorts suggest attenuation of screening-derived prediction models such as Brock when applied outside their original development setting. Model-based evidence from the National Lung Screening Trial (NLST) and International Association for the Study of Lung Cancer (IASLC) data indicates that diagnostic delays can materially reduce survival estimates for fast-growing early non-small cell lung cancer (NSCLC), and Veterans Health Administration (VHA) data show worse oncologic outcomes when surgery for clinical stage I NSCLC is delayed beyond 12 weeks. Molecular epidemiology further demonstrates that East Asian never-smoker lung adenocarcinoma is enriched for actionable drivers, particularly EGFR sensitizing mutations.

Conclusions: The available real-world evidence does not justify indiscriminate LDCT screening for all never-smokers. It does, however, support recalibrated, equity-aware risk pathways for selected never-smoker subgroups. Reforms should include subgroup calibration of nodule models, incorporation of non-tobacco and molecular risk proxies, closed-loop incidental nodule tracking, and shared decision-making that explicitly addresses false-negative consequences in populations outside the training distribution of traditional models.