Genomic and Immune Landscape of Non–Small Cell Lung Cancer Brain Metastases

PURPOSE Metastatic spread of non–small cell lung cancer (NSCLC) to the brain is a commonly occurring and challenging clinical problem, often resulting in patient mortality. Systemic therapies including immunotherapy have modest efficacy in treating brain metastases. Moreover, the local immune environment of brain metastases remains poorly described. This study aims to understand the genomic and immune landscape of NSCLC brain metastases. METHODS A total of 3,060 patients with NSCLC sequenced with the Strata Select assay on the Strata Oncology Platform were analyzed. Genomic alterations, tumor mutation burden (TMB), PD-L1 expression, and immune gene expression were compared across different tissue sites and histologies and within brain metastases. RESULTS A significant increase in TMB was observed in the brain metastasis samples compared with nonbrain metastasis samples. Mutations in TP53 , KRAS , and CDKNA2A were more prevalent within the brain metastasis cohort compared with other tissue locations. In addition, PD-L1 expression was significantly decreased within brain metastasis samples compared with other sites. The overall immune landscape within the brain metastasis samples was largely reduced compared with primary lung samples. However, an immune-enriched brain metastasis cohort was identified with higher expressions of PD-L1 and other immune-related genes. CONCLUSION The overall TMB is increased within brain metastases compared with primary lung and other metastasis sites and is associated with a markedly diminished overall immune landscape. The identification of an immune-enriched brain metastasis subgroup suggests potential heterogeneity within the brain metastasis patient cohort, which might have implications for the development of targeted therapies.