Genomic characteristics of tumour necrosis in lung squamous cell carcinoma.

e20030 Background: Tumor necrosis and cavity on enhanced chest CT are common hallmarks of lung squamous cell carcinoma (LUSC). However, the genetic characteristics of necrosis on CT scan remain unclear. This study aims to elucidate the genetic landscape of LUSC with tumor necrosis. Methods: We implemented transcriptome and whole-exome sequencing to analyze early postoperative LUSC specimens. They were classified into necrosis and non-necrosis group based on preoperative enhanced chest CT. Subsequently, the genomic landscape between the two groups were compared. To substantiate our findings, we further employed immunohistochemistry and analysis of a clinical cohort as comprehensive methods of validation. Results: In study cohort (65 samples), the necrosis group (n = 37) showed a higher number and length of copy number variations (CNVs) and elevated Genomic Instability Index (GII) compared to the non-necrosis group (n = 28). Transcriptome sequencing revealed increased hypoxic hallmarks and activation of 11 fundamental metabolic pathways in the necrosis group. Endothelial cells were observably fewer, but matrix remodeling score was higher in the necrosis group. Here, the decreased activity of several immune-related pathways, such as antigen processing and presentation, natural killer cell-mediated cytotoxicity, etc, were notably suppressed in the necrosis group. Immunohistochemistry indicated that the expressions of hypoxy-related genes (HIF-1, NDRG1), proliferation-related genes (ki-67) and angiogenesis related genes (CD31) in necrosis group were significantly higher than those in non-necrosis group. In the clinical validation cohort, we enrolled 538 advanced LUSC patients from 25 medical centers receiving systemic treatment, categorized into chemotherapy (n = 270) and ICIs (n = 268) groups. A notable difference in progression-free survival (PFS) was observed in the ICIs group, with patients without tumor necrosis or cavity exhibiting significantly longer PFS (8.7 vs. 6.5 months; HR 0.67; 95% CI 0.42–0.63; p < 0.001). Multivariate Cox analysis identified necrosis or cavity as an independent predictor of reduced PFS (HR 0.68; 95% CI, 0.51-0.9; p = 0.007). Conclusions: LUSC with necrosis is distinguished by increased genomic instability, hypoxia, enhanced tumor proliferation, matrix remodeling, and an immunosuppressive tumor microenvironment. Baseline chest CT findings of tumor necrosis or cavities may serve as negative predictors for the efficacy of ICIs treatment in LUSC.