Pleural Fluid Outperforms Plasma for Detection of Clinically Relevant Mutations in Lung Cancer-Associated Malignant...

Malignant pleural effusion (MPE) is common in advanced lung cancer and often represents the only accessible source of tumor material. Beyond confirming malignancy, molecular characterization is increasingly important for guiding targeted therapies. The comparative performance of pleural fluid (PF) and plasma cell-free DNA (cfDNA) for detecting clinically relevant mutations remains uncertain.

We conducted a prospective study of 70 patients with non-small cell lung cancer (NSCLC) and pleural effusion who underwent diagnostic thoracentesis. Paired PF and plasma samples were analyzed using next-generation sequencing (NGS) panels targeting clinically relevant driver and resistance mutations. Mutation detection rates, variant allele frequencies (VAFs), and concordance between PF and plasma were assessed. Pleural effusions were classified as definite or probable malignant according to pathological or predefined clinical criteria.

Among patients with pathologically confirmed MPE (n=49), PF cfDNA detected clinically relevant mutations more frequently than plasma cfDNA (57% vs 41%), yielding a higher number of mutations (40 vs 27) and higher VAFs. Concordance between PF and plasma was low, with only 26% of mutations detected in both specimens. Among patients with probable MPE (n=21), clinically relevant mutations were identified in 11 cases (52%) when PF and plasma cfDNA were considered together. Despite frequent detection of actionable or resistance-associated mutations, only 16% of patients received targeted therapy.

Pleural fluid cfDNA analysis detects clinically relevant mutations more frequently than plasma and provides complementary molecular information in lung cancer-associated pleural effusions, including cases with negative cytology, potentially expanding access to targeted therapies.