Heterogenous Profiles Between Matched Primary Tumors and Brain Metastases Reveal Tumor Evolution

Abstract Background: Brain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary tumors and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary tumors and BMs, and the evolutionary process remains little known. Methods: To deeply insight the extent of inter-tumor heterogeneity at single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 11 patients with matched primary tumors and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary tumors and BMs was evaluated by utilizing the whole-exome sequencing (WESeq) and immunohistochemical analysis.Results: In addition to inheriting genomic phenotype and molecular phenotype from the primary tumors, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at single-patient level. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0013) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary tumors. Additionally, tumor microvascular density (MVD) and tumor invasiveness were also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.Conclusion: We verified the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary tumors and BMs, which also provided novel insight for formulating individualized treatment strategies of BMs.