Mutational and inflammatory microenvironment characteristics in primary and matched local recurrent non-small cell lung cancer brain metastases

Abstract

Background: Tumor heterogeneity inmutational as well as inflammatory characteristics is a proposedmajor driver of treatment resistance and tumor progression.Given that the majority of patients with brainmetastases (BM) develop brain relapse during their clinical course, we aimed to investigate the mutational and immunological heterogeneity in BM. Methods: Patients treated with neurosurgical resection of a newly diagnosed BM from non-small cell lung cancer and subsequent neurosurgical resection of the local BM recurrence were identified from the Vienna Brain Metastasis Registry. Whole exome sequencing and analysis of tumor infiltrating lymphocytes (TILs) using immunohistochemistry was performed. Results: 24 matched BMspecimens from 12 patients (9/12 (75%) male; median age 60 years) were available for analysis. A high concordance in CD3+ TIL (p=0.004) and CD8+ TIL (p=0.004) density as well as in the tumor mutational burden (TMB; p<0.001) was evident between the two specimens of the same patient. A single case (1/12 (8.3%)) changed from low CD3+ and CD8+ TIL density to high density although no radiotherapy or immunotherapy was applied in-between. TMB in the first resection specimen (median 39.2 mutations / Mb) correlated with TMB in the second resection specimen (39.3 mutations / Mb; p<0.001). A single case (1/12 (8.3%)) presented with marked TMB increase (154 mutation/Mb to 217 mutation/Mb) after application of stereotactic radiotherapy to the resection cavity. No correlation of TIL density and TMB was evident in the investigated specimens (p>0.05). Overall the mutational characteristics were stable between the two specimens at the same location but at different time points of the same patients as 88% (range 80%-93%) of mutations were shared by both samples. Conclusions: High concordance in mutational and immunological characteristics was observed in this homogenous cohort of local non-small cell lung cancer BM recurrences. TIL density as well as TMB were consistent between BM and the matching local recurrence, although radiotherapy might impact the mutational characteristics. Further analysis of the mutational differences might reveal new therapeutic approaches for secondary BM prevention.