Background: Approximately 30% of patients (pts) with non-small cell lung cancer (NSCLC) have alterations(alt) in KRAS. How co-alt such as STK11 affect the tumor microenvironment and survival requires further characterization. Recently, our group found that lower expression of lipid metabolic genes in KRAS G12C co-alt tumors was associated with worse overall survival (OS).Here, we seek to confirm these findings utilizing a large real-world (rw) patient de-identified database.

Methods: Approximately 2,187 pts (61%, stage IV) with KRAS G12C alt NSCLC who underwent sequencing via the Tempus xT/xR assay with co-alt in TP53 (44%), STK11 (17%), or LRP1B(4%) were selected. The groups are mutually exclusive. Single-sample GSEA (ssGSEA) based on 775 lipid metabolic genes (LMG) was used to calculate enrichment scores (LMG ES) foreach pt. Pts were dichotomized into low vs. high groups based on their median LMG ES.Immune cell infiltration predicted from gene expression patterns, TMB, and PD-L1 from IHC was evaluated. Risk-set adjusted rwOS was calculated from sample collection date to death from any cause. Hazard ratios (HR) were calculated using Cox proportional hazards model, and p-values were calculated using the Wald test.

Results: Among pts with KRAS G12C alt, the median age was 68, 58% were female, and 84% wereWhite. Pts with KRAS G12C/STK11 alt had the lowest TMB, neoantigen burden, and PDL-1positivity compared to other cohorts (p < 0.001 for all). Importantly, the proportion of total immune cells, M1, M2, NK cells, CD8 T cells and regulatory T cells was lowest in tumors withKRAS G12C/STK11 alt (p < 0.001 for all). To determine if lipid genes were associated with immunogenic changes, LMG ES was compared to immune infiltration. The ES was associated with immune cell infiltration percentages for M1 macrophages (OR 1.11 (1.03-1.21) p = 0.012),M2 macrophages (OR 1.27 (1.15-1.40) p < 0.001) and neutrophils (OR 1.12 (1.04-1.22)p = 0.005), with a trend towards significant association with CD4 T cells (OR 1.08 (1.00-1.17)p = 0.062). Pts with KRAS G12C/STK11 alt and low LMG ES had decreased median rwOS (5.4vs 18.2 months, p = 0.0002) compared to pts with a high ES. Multivariate analysis demonstrated that lower LMG ES correlated with reduced rwOS (HR = 1.75 (1.22-2.51, p =0.002) compared to pts with high ES. Individual gene analysis showed that low LPL (HR = 1.85(1.147-2.97) p = 0.012), LDLRAD4 (HR = 1.72 (1.082-2.72) p = 0.022) and LDLR (HR = 1.58(1.009-2.46) p = 0.045) expression was associated with poorer rwOS.

Conclusions:Low lipid gene expression in KRAS–STK11 NSCLC was associated with decreased OS. Lipid gene expression and tumor immune cell infiltration were associated, suggesting that lipid metabolism may regulate tumor immunogenicity. These data suggest that lipid metabolic genes should be further explored as potential therapeutic targets for pts with NSCLC and KRAS–STK11 alt.

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