Georgios Tsakonas1, Rolf Lewensohn1, Johan Botling2, Cristian Ortiz-Villalon3, Patrick Micke2, Signe Friesland1, Helena Nord4, Magnus Lindskog5, Martin Sandelin6, Per Hydbring3, Simon Ekman7. 1. Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology and Pathology, Karolinska Institutet, Visionsgatan 4, 17164 Stockholm, Sweden. 2. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala Sweden. 3. Department of Oncology and Pathology, Karolinska Institutet, Visionsgatan 4, 17164 Stockholm, Sweden. 4. Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 5. Department of Immunology, Genetics and Pathology, Uppsala University/Department of Oncology, Uppsala University Hospital, Sweden. 6. Department of Medical Sciences, Uppsala University/ Department of Oncology, Uppsala University Hospital, Sweden. 7. Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology and Pathology, Karolinska Institutet, Visionsgatan 4, 17164 Stockholm, Sweden. Electronic address: simon.ekman@ki.se.
Abstract
BACKGROUND: Dissemination of non-small-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® 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. RESULTS: We compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours. CONCLUSIONS: We identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.
BACKGROUND: Dissemination of non-small-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® 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. RESULTS: We compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours. CONCLUSIONS: We identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.