Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.

Objective: Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients.Study Design: Retrospective study. Setting: Tertiary referral centerPatients: 31 consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas.Main Outcome Measure: Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a ≥20% decrease in tumor volume compared with baseline. Results:The median age was 26 years (range, 12-73). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6-41) with a total of 45 patient-years of follow up. A hearing response occurred in 13/23 (57%) evaluable patients, and a radiographic response in 17/31 (55%) of target vestibular schwannomas. The median time to response was 3 months for both endpoints. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient (ADC) value, a radiologic marker of edema (p=0.036). 90% of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years. 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated.Conclusion: Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in over 50% of progressive vestibular schwannomas in NF2 patients. Stable or 2 improved hearing was retained in the majority of patients.3

We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.