Molecular and translational advances in meningiomas.

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas

Imaging and diagnostic advances for intracranial meningiomas

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-Invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine

Advances in multidisciplinary therapy for meningiomas

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-Institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas

Systemic therapy following craniotomy in patients with a solitary breast cancer brain metastasis

Purpose To describe practice patterns and patient outcomes with respect to the use of postoperative systemic therapy (ST) after resection of a solitary breast cancer brain metastasis (BCBM). Methods A multi-institutional retrospective review of consecutive patients undergoing resection of a single BCBM without extracranial metastases was performed to describe subtype-specific postoperative outcomes and assess the impact of types of ST on site of recurrence, progression-free survival (PFS), and overall survival (OS). Results Forty-four patients were identified. Stratified estimated survival was 15, 24, and 23 months for patients with triple negative, estrogen receptor positive (ER+), and HER2+ BCBMs, respectively. Patients receiving postoperative ST had a longer median PFS (8 versus 4 months, adjusted p-value 0.01) and OS (32 versus 15 months, adjusted p-value 0.21). Nine patients (20%) had extracranial progression, 23 (52%) had intracranial progression, three (8%) had both, and nine (20%) did not experience progression at last follow-up. Multivariate analysis showed that postoperative hormonal therapy was associated with longer OS (HR 0.26; 95% CI 0.08-0.89; p = 0.03) but not PFS (HR 0.35, 95% CI 0.08-1.47, p = 0.15) in ER+ patients. Postoperative HER2-targeted therapy was not associated with longer OS or PFS in HER2+ patients. Conclusions Disease progression occurred intracranially more often than extracranially following resection of a solitary BCBM. In ER+ patients, postoperative hormonal therapy was associated with longer OS. Postoperative HER2-targeted therapy did not show survival benefit in HER2+ patients. These results should be validated in larger cohorts.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Subtype switching in breast cancer brain metastases: a multicenter analysis

Background. Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM.Methods. BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed.Results. In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio = 1.80, P= 0.03). Patients gaining HER2 status (n =8) showed a nonsignificant tendency toward improved survival (hazard ratio = 0.64, P= 0.17).Conclusions. In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas

Background. Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making. Methods. To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas. Results. The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. Conclusion. 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

The impact of histopathology and NAB2\u2013STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20\u201387)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2\u2013STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2\u2013STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme

Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq.

Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses