Serial Functional and Genomic Analyses Illuminate Clonal Evolution in Metastatic NSCLC with 12-Year Survival

Background: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and a leading cause of cancer-related death. Despite therapeutic advances, long-term survival in stage IV disease is uncommon. Tumor analyses that combine genomic and functional platforms may provide the opportunity to monitor clonal dynamics and guide therapy selection. Case Presentation: We report a 67-year-old woman with metastatic poorly differentiated lung adenocarcinoma, who achieved four durable remissions and survived nearly 12 years. Serial studies using ex vivo analysis of programmed cell death (EVA/PCD) functional-profiling-guided therapeutic choices were correlated with next-generation sequencing (NGS). Molecular events included the emergence of a BRAF V600E mutation responsive to dabrafenib plus trametinib and the acquisition of an EGFR exon 19 deletion responsive to Osimertinib. EVA/PCD identified activity for targeted agents and revealed synergy for vinorelbine plus Osimertinib not predicted by genomic profiling, which provided additional response. Discussion: This case highlights clonal evolution in NSCLC and illustrates how serial tissue analyses correlating phenotypic and genomic events can offer therapeutic interventions to provide long-term survival. Conclusions: The integration of functional and genomic profiling may improve personalized treatment in NSCLC by interrogating tumor heterogeneity and clonal evolution to inform rational therapeutic selection.