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Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p< 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p< 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.

INTRODUCTION Predictors of postoperative leptomeningeal disease (LMD) after resection of brain metastases (BMs) are not well defined. OBJECTIVE This study examined rates and predictors of LMD, including subtypes, in patients who underwent resection of a BM followed by postoperative radiation.Method: A retrospective, single-center study was conducted examining overall LMD, classical LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression and a Cox proportional hazards analyses were performed to identify risk factors associated with LMD. Random forest models were constructed to predict LMD and differentiate cLMD versus nLMD. Accuracy and the area under the receiver operating characteristic curve (AUROC) were calculated to evaluate the models.Result: Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD with 19(8.8%) cLMD cases and 28(12.9%) nLMD cases . Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from LMD diagnosis compared to nLMD (2.4 vs 6.9 mo, Log-rank p=0.02), and treatment of LMD was associated with improved survival for both cLMD and nLMD subtypes. Multivariate Cox hazard analysis identified cerebellar/insular/occipital location (HR 3.25, 95% CI 1.73-6.11, p=0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p=0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p=0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an AUROC of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Both regression analysis and random forest analysis identified postoperative systemic therapy exposure as the main factor differentiating cLMD from nLMD development. CONCLUSION Tumor location, absence of extracranial disease at the time of surgery, contact with a ventricle, and increased tumor volume are associated with LMD. Classical LMD is associated with worse prognosis compared to nLMD.

BACKGROUND While resection of brain metastases (BMs) offers favorable local disease control, factors and genetic alterations associated with local recurrence are not well defined. This study examined patient, tumor, treatment, and genetic factors associated with local recurrence. METHODS A retrospective, single-center study was conducted with patients who underwent resection of a BM with available clinical outcome and genetic data available. Local recurrence was the primary outcome of the study. Next-generation sequencing of coding regions in over 500 cancer genes was performed to detect mutations. Cox proportional hazards analysis was performed to identify patient, tumor, treatment, and genetic factors associated with local recurrence. RESULTS We identified 91 patients who underwent surgical resection of a BM with available data, of which 80 (87.1%) underwent preoperative radiotherapy or received some form of adjuvant radiation to the resection cavity. Primary pathologies in the cohort included non-small cell lung cancer (24.2%), melanoma (24.2%), breast cancer (16.5%), gastrointestinal cancers (13.2%), gynecologic cancers (4.4%), renal cell carcinoma (4.4%), and other cancers (13.2%). Eleven patients (12.1%) developed postoperative recurrence at the surgical site with 6- and 12-month PFS of 91.2% and 84.2%. Multivariate Cox proportional hazard analysis identified cancer type (Gyn and RCC vs Others: OR 39.4, p=0.002), CDK2NA/B co-deletion (OR 37.52, p=0.0009), PIK3R1 mutation (OR 56.88, p=0.003), and SMAD4 mutation (OR 134.8, p=0.0007) to be associated with time to local recurrence. Overall survival and length of follow-up were not different based on mutational status of these genes, demonstrating that results were not due to survival bias. CONCLUSIONS Genetic alterations within BMs impact clinical outcomes after surgical resection. Further work is needed to determine if targeted therapies for BMs with these alterations can decrease rates of local recurrence.