An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non–small-cell lung cancer

Abstract

Background: Dissemination of nonesmall-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts. Methods: We identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter â PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software.

Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a ‘Real-Life’ Setting

“…In our cohort, the discordance rate in patients with active BMs was 24%, which was closer to the rates reported in the two above-mentioned trials. Comparative gene expression and tissue analyses of matched extracranial and BM samples of the same patients have demonstrated that the TME in BM is characterized by increased expression of molecular markers attributed to a high density of M2 macrophages, reduced CD8+ T cell infiltration [20] and downregulation of gene expression of CCL19 and CCL21, which are responsible for T cell chemotaxis [21]. These significant differences in the TME context between the CNS and the extracranial tissues justify our findings, but further research at a clinical and molecular level is required.…”

“…High PD-L1 expression of ≥50% in extracranial biopsy samples was not associated with increased IC ORR. Despite being the only approved biomarker for clinical decision making, PD-L1 status may not sufficiently reflect the immune status of the CNS metastases due to the inherent differences in brain and extracranial tissue [20,21]. Therefore, in a patient with high PD-L1 expression levels on a biopsy sample from an extracranial tissue, we should not solely rely on ICIs as a single agent for the patient's treatment plan; physicians should exploit other treatment options with either systemic (combining chemotherapy-immunotherapy) or local treatment modalities (surgery, SRS).…”

“…Several recent first-line studies with ICIs alone or in combination with chemotherapy represent the new standard-of-care [15][16][17][18][19]. However, the use of ICIs in NSCLC patients with BM is a matter of ongoing debate due to the scarcity of available data and the concerns about immunotherapy efficacy in the context of the divergent tumor microenviroment (TME) in the CNS [20,21].…”

An immune-related gene expression signature predicts brain metastasis in lung adenocarcinoma patients after surgery: gene expression profile and immunohistochemical analyses

“…Previous studies have shown that the expression or mutation of some specific genes promotes BM in lung cancer (9)(10)(11). In a recent study by Tsakonas et al, a 12gene immune signature was significantly downregulated in BM compared to matching primary tumors (12). Several previous studies, including Tsakonas et al, compared BM samples to matched primary lung tumor samples (12,13).…”

“…In a recent study by Tsakonas et al, a 12gene immune signature was significantly downregulated in BM compared to matching primary tumors (12). Several previous studies, including Tsakonas et al, compared BM samples to matched primary lung tumor samples (12,13). When BM occurs, the prognosis is very poor; therefore, the most important goal of predicting BM is to do so before BM occurs.…”