Introduction: IMA constitutes a rare subset of lung adenocarcinomas. Due to its low incidence, the IMA’s biology and prognosis remain poorly understood. In this study, we analyzed the tumor microenvironment, gene expression, and clinical outcomes of IMA patients.

Methods: A retrospective cohort of de-identified records of patients with primary lung cancer were identified in the Tempus database and stratified into IMA or non-IMA. Clinical, biopsy, and molecular characteristics were assessed. Normalized RNA-seq data were used to test for differential gene expression (DGE). Real-world overall survival (OS) was compared by histological subgroup using Kaplan-Meier curves and Cox proportional hazards models using a prospective-like approach. Immune cell infiltration measures were estimated using the quanTIseq algorithm.

Results: The overall cohort consisted of 20,071 patients, with 699(3.5%) in IMA and 19,372(96.5%) in non-IMA. IMA demonstrated significantly lower tumor mutational and neoantigen burdens(3.1 vs. 4.2 mutations/Mb and 7 vs. 9 neoantigens/Mb; p<0.001) with fewer positive PD-L1 status(28% vs. 59%; p<0.001). The tumor microenvironment in IMA patients had higher infiltration of M2 macrophages, regulatory T cells, and NK cells(Table 1). DGE analysis highlighted significant upregulation in genes such as ERVW-1, REG4, TFF2, and TM4SF4 and significant downregulation in IL36RN, NAT8L, and LIN28B in IMA compared to non-IMA. Additionally, hundreds of additional genes were differentially expressed in IMA vs. non-IMA. OS for IMA patients was significantly worse compared to that of non-IMA(Fig 1, HR 1.46, [95% CI 1.07-2.01], p=0.018).

Conclusions: Our study demonstrates the unique pathological and molecular characteristics of IMA vs. non-IMA. IMA showed significantly worse overall survival compared to non-IMA. Our findings warrant further prospective investigation.

VIEW THE PUBLICATION (EP.03G.02)

VIEW THE POSTER