Clinical utility of pleural effusion supernatant cell-free DNA genotyping in previously treated patients with advanced non-small-cell lung cancer and disease progression: a multicenter retrospective study.

BACKGROUND: Patients with lung cancer frequently develop pleural effusion as the disease progresses. This study evaluated the utility of cell-free DNA (cfDNA) from pleural effusion supernatant in identifying targetable mutations in non-small-cell lung cancer (NSCLC) patients who developed resistance to prior therapies. METHODS: We conducted a multicenter retrospective study involving 95 patients who experienced disease progression after at least one line of treatment and underwent pleural effusion cfDNA next-generation sequencing testing. RESULTS: Initial routine molecular testing detected various driver mutations in 70 (73.7%) patients, while 26.3% had no detectable driver mutations. Subsequent cfDNA next-generation sequencing identified additional genomic alterations during disease progression, increasing the detection rate for driver mutations from 73.7% to 85.3%. For patients whose disease progressed after treatment with first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, 40.7% developed an acquired EGFR T790M mutation, and showed clinical benefit with subsequent administration of osimertinib. Of the 29 patients who progressed following osimertinib treatment, 14 received osimertinib as a first-line therapy, and 15 received osimertinib as a second-line therapy. MET copy number gain (CNG) was identified in 28.6% of patients receiving first-line osimertinib and was associated with a significantly shorter progression-free survival (PFS) of 12.0 months versus 23.0 months for those without MET CNG [hazard ratio (HR) = 18.68, P = 0.00088]. CNG in MET and KRAS was linked to poorer overall survival. Among the patients for whom second-line osimertinib failed, five acquired the EGFR C797S mutation, and four exhibited MYC CNG. MYC CNG was associated with a median PFS of 8.5 months versus 25.0 months for those without MYC CNG (HR 8.4, P = 0.0046). CONCLUSION: CfDNA sampling from pleural effusion is a less invasive and more effective method for genomic profiling in NSCLC with disease progression, offering valuable insights to guide personalized treatment strategies.