Clinical characteristics of lung cancer in never-smokers: a multicenter Saudi cohort

Lung cancer in never-smokers represents a distinct clinical and biologic entity. However, its epidemiologic characteristics remain incompletely described in the Middle East.

To characterize lung cancer in never-smokers and compare it with ever-smokers in a multicenter Saudi cohort.

Retrospective multicenter cohort study.

Three tertiary-care centers of King Faisal Specialist Hospital & Research Centre system in Saudi Arabia.

Adults with histologically confirmed primary lung cancer diagnosed between January 2020 and December 2024 were classified as never- or ever-smokers. Carcinoid tumors were excluded from the comparative analysis. Demographic, histologic, stage, and molecular characteristics were compared. Multivariable logistic regression identified factors independently associated with never-smoker status.

Clinical, histologic, stage, and molecular differences between never-smokers and ever-smokers expressed as crude and adjusted odds ratios (95% confidence interval).

301 patients reviewed; 253 in the primary analytic cohort (92 never-smokers, 161 ever-smokers).

Among 280 patients with available smoking history, 253 were included after excluding 27 carcinoid tumors (92 never-smokers [36%] and 161 ever-smokers [63.6%]). Never-smokers were mostly females (64/92 (70%) vs 12/161 (7.5%); P<.001) and younger than ever-smokers [mean age 59.2 (standard deviation 13.5) vs 62.3 (11.1) years; P=.065]. Adenocarcinoma predominated among never-smokers (81/92 (88%) vs 108/161 (67.1%); P<.001). Among patients tested, Epidermal growth factor receptor (EGFR) mutations(34/86 (39.5%) vs 12/128 (9.4%); P<.001) and Anaplastic lymphoma kinase (ALK) rearrangements [17/86 (20%) vs 9/128 (7.0%); P=.01] were significantly more frequent in never-smokers, whereas KRAS alterations were more common in ever-smokers [6/86 (7%) vs 21/128 (16.4%); P=.068]. Stage III-IV disease was common in both groups (70% vs 72%; P=.783). In multivariable analysis, female sex [adjusted odds ratio (OR) 31.9, 95% CI 14.2-71.6; P<.001] and adenocarcinoma histology (adjusted OR 5.3, 95% CI 2.0-14.2; P<.001) were independently associated with never-smoker status.

In this multi-center Saudi cohort, more than one-third of lung cancers occurred in never-smokers, characterized by female predominance, adenocarcinoma histology, and frequent EGFR and ALK alterations. These findings support comprehensive molecular testing regardless of smoking history and underscore the need for strategies to improve early recognition of lung cancer in never-smokers.

Retrospective design, incomplete molecular testing, tertiary-referral setting, and potential misclassification of smoking exposure, including unrecorded waterpipe and electronic-cigarette use.