Equity gaps in pulmonary nodule risk prediction for never-smokers: a real-world evidence-informed narrative review...

Current lung cancer screening and pulmonary nodule management pathways were built largely around age, smoking exposure, and computed tomography (CT) morphology. These frameworks 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.

We conducted targeted narrative evidence mapping of guideline documents, 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, guidelines, and official society statements. Commercial calculators, news reports, legal commentaries, and non-peer-reviewed secondary sources were excluded.

Smoking-centered screening eligibility remains the dominant entry point into low-dose computed tomography (LDCT) screening, while never-smokers are excluded. Cancer Screening Program in Urban China (CanSPUC)-derived Chinese risk models identified 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 reduce survival estimates for fast-growing early non-small cell lung cancer (NSCLC), and Veterans Health Administration (VHA) data show worse 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.

The available real-world evidence does not justify indiscriminate LDCT screening for all never-smokers. It supports 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 addresses false-negative consequences in populations outside the training distribution of traditional models.