Female-specific risk factors for lung cancer: insights from the All of Us Research Program

Lung cancer is the leading cause of cancer deaths in females, with slower declines in incidence compared to males. While smoking is the leading risk factor, it doesn’t fully explain the increasing lung cancer burden in females. Reproductive factors, metabolic disorders, family history, and their interactions may also influence risk; however, these remain poorly understood, particularly across diverse groups. To explore this, we conducted a case-control study using All of Us Research Program data to examine these factors and their association with lung cancer risk in adult females. Using de-identified data from the All of Us Research Program, we conducted an age-matched case-control study to investigate the relationship between sociodemographic factors, reproductive history, metabolic disorders, and family history and lung cancer risk in adult females. Cases and controls (n = 5,500) were identified using SNOMED-CT codes with 1:1 matching. We used descriptive statistics, as well as chi-square and t-tests for group comparisons, followed by multivariable logistic regression to adjust for confounders and estimate the odds of lung cancer. Lung cancer patients had a mean age of 67.9 years (SD ± 11.9) and BMI of 28.9 (SD ± 7.1). Most were non-Hispanic Whites (63.4%), followed by non-Hispanic Blacks (14.5%) and Hispanics (12.2%). Overweight females had lower odds (adjusted OR = 0.78, p = 0.0003), while smoking increased the risk (adjusted OR = 1.28, p = 0.0023). Postmenopausal bleeding (adjusted OR = 1.59, p < 0.001) and menopause (adjusted OR = 1.47, p < 0.001) increased the risk, especially in smokers (adjusted OR = 2.65, p < 0.001) and Asian menopausal females (adjusted OR = 2.67, p = 0.04). Hyperlipidemia (adjusted OR = 1.57, p < 0.001) and hypothyroidism (adjusted OR = 1.63, p < 0.001) were significant, with smoking amplifying hyperlipidemia risk (adjusted OR = 1.71, p < 0.001). Risk was also higher in smokers with lung cancer family history (adjusted OR = 1.94, p = 0.03), postmenopausal females with such a history (adjusted OR = 2.10, p = 0.03), and females with breast cancer family history combined with hypothyroidism (adjusted OR = 1.64, p = 0.0038) or postmenopausal bleeding (adjusted OR = 1.82, p = 0.017). Beyond smoking, sociodemographic, reproductive, metabolic, and family history factors, along with their interactions, also influence lung cancer risk in females. Identifying these can aid early detection and prevention.