Background NSCLC tumors in younger patients may be enriched for targetable genomic alterations, yet these patients have lower rates of insurance coverage for tissue-based genomic profiling compared to older patients who are Medicare-eligible in the United States. Various age cutoffs have been used to compare genomic alterations in younger versus older NSCLC patients, making inter-study comparisons difficult. Additionally, age-related differences in the tumor immune microenvironment that may affect therapeutic strategy are not well-described. This study sought to describe the genomic and tumor immune landscape of NSCLC patients using comprehensive, real-world testing across various age thresholds, including younger (pre-Medicare) and older (Medicare-eligible) patient groups.

Methods A retrospective analysis of 5,091 patients with NSCLC tested by CGIP during standard care was performed to compare the biomarker landscape of pre-Medicare aged (<65y, N=1,367, mean age=58±6.3) versus Medicare age-qualified (≥65y, N=3,724, mean age=75±6.4) patients. DNA-seq of 523 genes analyzed mutations, copy number alterations (gain/loss) and tumor mutational burden (TMB). RNA-seq analyzed fusions/splice variants for 57 genes and gene expression of 395 immune genes. A 5-year sliding threshold from <45y to <65y was used to define younger patients within the pre-Medicare group. Differences between younger and older patients were tested using regression adjusted for tumor stage. Multiple testing corrected p-values <0.25 were considered significantly different.

Results Younger patient tumors were enriched for EGFR, RAD51B, SMARCB1, and IDH2 single nucleotide variants, MET amplifications, and ALK and ROS1 fusions. They were significantly enriched for known targetable alterations (p=1E-3), yet total number of detected pathogenic alterations were similar (mean detected=3.2±2.1 at lowest vs 3.7±2.4, p=0.1). Of the genes tested, 50% (196/395) had significantly lower expression in younger versus older patient tumors, while only 4% (16/395) had significantly higher expression. Younger patient tumors had significantly lower TMB (mean=6.8±7.1 at lowest vs 11±10.8, p=8E-4) and gene expression signature scores for both tumor immunogenic signature (TIGS) and cancer testis antigen burden (CTAB) (p≤0.02).

Conclusions CGIP revealed a distinct genomic and immune gene expression profile for younger patients compared to older patients. Younger patient tumors had less mutational burden overall, higher prevalence of targetable genomic alterations, and were significantly less immunogenic than older patients, suggesting younger patients may benefit less from immunotherapy and more from matched targeted therapy. This study highlights the importance of increasing non-Medicare insurance coverage for younger patients with NSCLC to support greater access to genomic profiling, increasing the potential for matching to a targeted therapy and/or clinical trial.

Ethics Approval Ethics approval for this study was obtained from WCG IRB (Study #1340120), an independent institutional review board, including waiver of informed consent.