Improvement of prognosis among patients with lung adenocarcinoma through precision therapy: analysis based on The...

Lung adenocarcinoma (LUAD) is a malignancy with a high global incidence and cancer-related mortality rate. Over decades of development, the treatment of lung cancer has evolved from empirical approaches such as traditional chemotherapy and radiotherapy to a precision model that integrates targeted therapy, immunotherapy, and combination treatments. Through "molecular profiling and individualized treatment planning", targeted therapies focusing on biomarkers like EGFR and ALK, along with immunotherapy using programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, have become landmark achievements in precision medicine for lung cancer. Although various clinical trials have improved the prognosis of LUAD patients, their 5-year survival rate remains low, and precision therapy for lung cancer still faces multiple challenges. This study aims to improve the prognosis of LUAD patients through molecular subtype-based precision treatment.

LUAD RNA-sequencing data sourced from an online database were used to screen for differentially expressed genes (DEGs). Weighted gene coexpression network analysis combined with univariate and multifactorial Cox analysis was used to identify hub prognostic genes. Based on these genes, partitioning around medoids clustering was applied to classify LUAD into two subtypes. The estimation of stromal and immune cells in malignant tumor via using expression data, immunophenoscore, and microenvironment cell populations counter algorithm was used to determine the microenvironmental purity and immune response of the two subtypes. Gene set enrichment analysis was performed to analyze the biological function. The correlation between hub gene and EGFR mutations was detected in clinical samples via immunohistochemical (IHC) staining.

This study delineated two distinct subtypes of LUAD, and the survival rate for patients in cluster 2 was found to be significantly superior to that of cluster 1. Additionally, patients in cluster 2 had greater immune cell infiltration, a greater microenvironmental component, and a higher rate of EGFR mutation. In contrast, patients in cluster 1 exhibited a higher degree of fibroblast infiltration and a notable prevalence of NTRK3 mutations, as observed in the study of the tumor microenvironment. In addition, functional analysis suggested cluster 1 was associated with nucleotide sequence repair, while cluster 2 was mainly related to lipid metabolism and angiogenic pathways. IHC staining revealed that the expression level of BIRC5 was notably downregulated in early-stage patients with EGFR-mutant LUAD. Furthermore, in the advanced stage, the expression level of BIRC5 in the tissues of these patients was significantly higher compared to those in patients with the EGFR wild type.

Patients in cluster 1 may benefit from anti-nucleotide repair therapies such as platinum therapy, radiotherapy, targeting of fibroblasts, and targeting of NTRK3, while patients in cluster 2 may benefit from immunotherapy, antiangiogenic therapy, targeting of lipid metabolism, and targeting of EGFR. This study may offer novel insights into improving the overall prognosis of patients with LUAD by leveraging molecular subtype-based precision therapy, as demonstrated by recent advancements in the identification of prognostic biomarkers and therapeutic targets.