Beyond tobacco: understanding the growing burden of lung adenocarcinoma in women

Primary lung adenocarcinoma is the most common histological subtype of lung cancer. It disproportionately affects female sex, especially never-smokers. The rising incidence among females without a smoking history suggests roles for hormonal, genetic, and environmental factors. We conducted a comprehensive literature review using several databases. We examined global epidemiology data, molecular mechanisms, hormone-related pathways, and new diagnostic and therapeutic approaches. The findings show that estrogen signaling, especially via estrogen receptor beta (ERβ), contributes to oncogenesis. The mechanism involves cross-talk with EGFR and downstream MAPK/PI3K pathways. EGFR mutations appear more frequently in females. The association between KRAS and other cell cycle drivers is mixed across studies. Non-tobacco exposures, including air pollution and secondhand smoke, further increase risk among females. Diagnostic disparities persist because current screening guidelines focus on smoking. This approach excludes many high-risk never-smoking females. This review aims to narrate and synthesize growing evidence highlighting how female sex is associated with a distinct epidemiological footprint, unique molecular and biological profiles, and tailored therapeutic strategies in lung adenocarcinoma, driven by mechanisms beyond traditional tobacco exposure. Incorporating sex-specific risk assessment, hormonal level modification, and targeted gene therapies into clinical practice may improve screening and outcomes for females with lung adenocarcinoma.