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

## TL;DR

A woman with metastatic lung cancer survived 12 years through repeated genomic and functional testing to guide personalized treatments.

## Contribution

Demonstrates how serial functional and genomic analyses can track tumor evolution and inform therapy in long-term cancer survival.

## Key findings

- Serial analyses revealed distinct clonal expansions and mutations over time, such as BRAF V600E and EGFR del19.
- Functional profiling identified effective drug combinations not predicted by genomic data alone.
- The case achieved four durable remissions through adaptive therapy based on tumor heterogeneity.

## Abstract

The majority of non-small cell lung cancer patients present with advanced disease, whereby survival is less than 2 years. We report a woman with metastatic non-small cell lung cancer who survived 12 years, benefiting from serial tissue analyses that applied genomic and functional platforms to select therapies. Each recurrence manifested distinct biologic features that responded to drugs selected by genotypic and phenotypic analyses. Following laboratory-directed chemotherapy and subsequent immunotherapy, the patient was found positive for a BRAF V600E mutation and responded to Dabrafenib plus Trametinib. Subsequent progression revealed an EGFR del19 mutation, not present in initial genomic analysis, as the previously identified BRAF mutation disappeared. Serial interrogations identified clonal expansions with distinct phenotypes. Each intervention selected highly adapted resistant subpopulations that revealed new therapeutic vulnerabilities. The case represents the application of serial tissue analyses to identify therapies, offering hope for more effective personalized cancer strategies in the future.

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.