Background: Pleural metastasis (PM), a driver of malignant pleural effusion (MPE) in lung cancer, remains an unmet clinical need due to the absence of PM/MPE-specific targeted therapies. Therefore, this study aims to explore the clinical and molecular characteristics associated with PM in advanced non-small cell lung cancer (NSCLC).

Methods: This retrospective study analyzed 195 advanced NSCLC patients. Study participants were classified into the PM and non-PM groups based on the occurrence of PM within three years of the initial diagnosis of advanced-stage disease. Clinical and baseline data, including age, gender, smoking history, tumor location, histological classification, tumor-node-metastasis staging (TNM) staging, metastasis profile, and lesion count, were obtained from the hospital's electronic medical records. Genomic DNA was extracted from tumor or liquid biopsy samples, and next-generation sequencing (NGS) was performed using a 139-gene lung cancer panel.

Results: The PM group tended to be older, smoked less, and presented with higher T stages, experiencing less bone metastasis (p < 0.05). Mutation frequencies of anaplastic lymphoma kinase (ALK), Erb-B2 receptor tyrosine kinase 4 (ERBB4), Kirsten rat sarcoma viral oncogene homolog (KRAS), and RB transcriptional corepressor 1 (RB1) were significantly lower in the PM group (p < 0.05) than those in the non-PM group. However, epidermal growth factor receptor (EGFR) driver mutations were significantly higher in the PM group than in the non-PM group (p < 0.05). The incidence of PM was highest (73.5%) in patients carrying only EGFR driver mutations, without ALK, ERBB4, KRAS, or RB1 mutations.

Conclusion: This study identified potential clinical and molecular factors involved in the development of PM in advanced NSCLC, providing valuable insights for future mechanistic research.