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Purpose To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature. Results Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. Recommendations Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non–small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy. Additional information is available at www.asco.org/neurooncology-guidelines.

Background Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management. Methods We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms. Results We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score. Conclusion We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

Background Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy. Methods Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO. Conclusion Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.

The clinical behavior of meningiomas often belies their histopathologic grade. Increasing data suggest that molecular features augment classic World Health Organization (WHO) classification in predicting recurrent risk. We investigated the influence of histopathology, chromosome copy number, and treatment on meningioma outcome to construct a simple, scalable, molecularly integrated classifier. METHODS: We analyzed 684 meningiomas with genome-wide chromosomal copy-number profiling for clinical features, pre-/post-operative tumor volume, histopathology, and recurrence. We devised a point-based molecularly-integrated classification system (IC 1-3), incorporating mitotic count and nine common molecular alterations consistently associated with risk of recurrence across four independent statistical tests. We used brier curves, time-dependent area-under-the-curve, and average precision to assess model performance. We added treatment variables, including primary or recurrent status, tumor size, and extent of resection, to the Integrated class to formulate a nomogram of recurrence risk at 5 years. RESULTS: The Integrated Class significantly associated with recurrence in a multivariate model (IC Class 2 vs 1: HR 3.60, 95% CI 2.19-5.91; Class 3 vs 1: HR 5.15, 95% CI 3.28-8.09) and outperformed WHO grade in predicting recurrence (by integrated brier score, 0.093 vs 0.178, internally and independently validated). WHO Grade I and IC-1 exhibited 86% concordance, 31.5% between Grade II and IC-2, and 64% between Grade III and IC-3. WHO grade I meningiomas with IC 2-3 fared significantly worse than WHO grade II-III meningiomas with IC-1 designation. Each additional molecular feature incrementally strengthens the classifier, allowing for application of single-arm FISH or combinatorial genome-wide signatures based on available resources. Intriguingly, receipt of adjuvant radiation in newly diagnosed WHO Grade II-III or IC 2-3 meningiomas was associated with greater propensity for recurrence, after controlling for extent of resection. CONCLUSION: We present a scalable, molecularly-integrated classification for meningioma that better predicts recurrence compared to classic histopathologic grades to aid in clinical management.

Background Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. Methods We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. Results OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Conclusions Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.

Background Brain metastases are associated with significant morbidity and mortality. Population-level data describing the incidence and prognosis of patients with brain metastases are lacking. The aim of this study was to characterize the incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy using recently released data from the Surveillance, Epidemiology, and End Results (SEER) program. Methods We identified 1302166 patients with diagnoses of nonhematologic malignancies originating outside of the CNS between 2010 and 2013 and described the incidence proportion and survival of patients with brain metastases. Results We identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%), lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. Patients with brain metastases secondary to prostate cancer, bronchioloalveolar carcinoma, and breast cancer displayed the longest median survival (12.0, 10.0, and 10.0 months, respectively). Conclusions In this study we provide generalizable estimates of the incidence and prognosis for patients with brain metastases at diagnosis of a systemic malignancy. These data may allow for appropriate utilization of brain-directed imaging as screening for subpopulations with cancer and have implications for clinical trial design and counseling of patients regarding prognosis.

BACKGROUND: Tumors involving the central nervous system (CNS) include over 200 primary and metastatic subtypes with major clinical impact. Research on CNS neoplasms has been hampered by the lack of appropriate models for many subtypes. We established a robust workflow and systematic culturing approach to create cancer cell line models from all adult and pediatric CNS cancer patients and here report the results of these ongoing efforts. METHODS: Tumor samples from consented patients with CNS cancers were systematically collected from 2008–18. Tumors were grown in different media and substrates and growth verified by >5 passages. Genomic verification was performed using NGS analysis (focused SNV and CNA) and expression profiling assays. RESULTS: We attempted to generate cell line models from >1500 consented brain tumor patients at the Brigham and Women’s and Boston Children’s Hospital (IRB-10–417) under the DFCI Living Tissue Bank Program as well as within the Broad Institute Cancer Cell Line Factory (CCLF) Project and the Leuven Living Tissue Bank (IRB-S59804, Belgium). 120 different tumor types, including high and low-grade brain tumors of both adult and pediatric origin, were evaluated for in vitro growth in >2000 culturing attempts. The success rate of growing high-grade tumors (i.e. glioma and of other origin) was robustly high (~50%), while the growth verification rate for low-grade tumors remained low (150 novel model systems covering >20 primary and metastatic diagnoses. CONCLUSION: Patient-derived cell lines may be created at scale from primary and metastatic CNS tumors to support pre-clinical cancer research but technological improvements will be required to culture even more tumor types.

INTRODUCTION: Brain metastases are the most common type of brain tumor, though determining candidates for resection may be challenging. Patients’ unfavorable prognoses make pre-operative risk stratification critical in the selection of patients that are likely to benefit from resection. METHODS: Multivariable logistic regression was applied to 3,532 cases of secondary neoplasms of the brain in the American College of Surgeons National Surgical Quality Improvement Program database. The validated 5-criteria modified frailty index (mFI-5) score was utilized to quantify frailty, characterized as an mFI-5 score of 2 or higher. RESULTS: The median age in the cohort was 61 years, and the majority of patients were female (55%). Frailty was present in 17% of patients. The most frequent 30-day post-operative medical complications were venous thromboembolism (3.1%), pneumonia (2.7%), and urinary tract infections (2.2%). Unplanned readmissions and reoperations occurred in 12.2% of patients and 4.9% of patients, respectively. The incidence of death was 4.2% across the cohort, including 1.2% during index hospitalization. Frailty was associated with pneumonia (OR 2.7, p DISCUSSION: Frailty was associated with post-operative medical complications and death, in particular during the post-discharge phase. Frailty should be used in risk-stratifying patients.

Background Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. Methods We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. Results Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base. Conclusion This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

Meningiomas are the most common primary brain tumor. The majority are benign, low-grade lesions which can be effectively managed with surgery. However, around 15% are high-grade tumors, which have a nearly 100% recurrence rate, and demonstrate an aggressive clinical course despite administration of high-dose adjuvant radiation. While much is known about the genetic events which constitute low-grade meningiomas, relatively little is known about the genomic drivers of high-grade tumors. We analyzed the genomes of 274 high-grade meningiomas and compared this information with data from 456 low-grade meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from NF2, which is the most frequently altered gene in low-grade tumors. High-grade meningiomas possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas, correlated with subsequent progression to a higher grade. We observed a striking degree of mutational heterogeneity across tumor recurrences, which was likely due to extensive geographic heterogeneity in the primary tumor. Although we observed significantly fewer mutations amenable to targeted inhibition among high-grade meningiomas, we found that they contained numerous mutations predicted to be neoantigens, suggesting that efforts to harness the power of the immune system may be beneficial.

The impact of adjuvant radiation in patients with atypical meningioma remains poorly defined. We sought to determine the impact of adjuvant radiation therapy in this population.We identified 91 patients with World Health Organization grade II (atypical) meningioma managed at Dana-Farber/Brigham and Women's Cancer Center between 1997 and 2011. A propensity score model incorporating age at diagnosis, gender, Karnofsky performance status, tumor location, tumor size, reason for diagnosis, and era of treatment was constructed using logistic regression for the outcome of receipt versus nonreceipt of radiation therapy. Propensity scores were then used as continuous covariates in a Cox proportional hazards model to determine the adjusted impact of adjuvant radiation therapy on both local recurrence and the combined endpoint of use of salvage therapy and death due to progressive meningioma.The median follow-up in patients without recurrent disease was 4.9 years. After adjustment for pertinent confounding variables, radiation therapy was associated with decreased local recurrence in those undergoing gross total resection (hazard ratio, 0.25; 95% CI, 0.07-0.96; P = .04). No differences in overall survival were seen in patients who did and did not receive radiation therapy.Patients who have had a gross total resection of an atypical meningioma should be considered for adjuvant radiation therapy given the improvement in local control. Multicenter, prospective trials are required to definitively evaluate the potential impact of radiation therapy on survival in patients with atypical meningioma.

BACKGROUND: The genetic underpinnings of sporadic pituitary adenomas remain incompletely understood, despite their prevalence in adults. We describe a comprehensive genetic characterization of the largest mixed cohort of pituitary macroadenomas, including hormonally active and atypical adenomas. METHODS: 42 pituitary adenomas were selected to represent a spectrum of histopathologic subtypes, de novo and recurrent tumors, and MIB-1 proliferative indices to interrogate the heterogeneity intrinsic to pituitary tumors. Whole-exome sequencing was performed on tumor and paired blood to identify somatic copy-number alterations, mutations, insertions and deletions. RESULTS: We appreciated two classes of pituitary tumors based upon the fraction of the genome disrupted. The first class (71% of tumors) had somatic copy-number alterations involving less than 6% of the genome; the other class (29%) had significantly greater levels of genomic disruption, up to 99% of the genome involved. The widespread genomic disruption observed in the second class was largely accounted for by arm-level events, with minimal involvement of focal events, which is rare among tumor types. Levels of genomic disruption were associated with phenotype. Among the less disrupted group, 87% (26/30) were clinically non-functional adenomas, whereas the majority of the disrupted group were functional or atypical null-cell adenomas. The high and low genomic disruption classes did not differ in mean MIB-1 proliferative index. Frequent loss of chromosomes 11 and 1p were observed, as well as significant recurrent amplifications of chromosome 5, 7, 9, 12, and 14q. On the whole, the tumors harbored a low rate of mutations, similar to other benign brain tumors. CONCLUSIONS: Genomic characterization of a large series of sporadic pituitary adenomas reveals two distinct classes of tumor, based on genomic disruption from broad copy-number alterations, and associates with tumor subtype.

BACKGROUND: Brain metastases are the most common intracranial tumors in adults. We have a limited understanding of how brain metastases evolve from their primary tumor. Our objectives were to (1) elucidate the evolutionary patterns leading to brain metastases and (2) identify whether brain metastases are genetically distinct from their primary tumors. METHODS: We subjected 101 matched primary tumors, brain metastases, and normal tissue to whole exome sequencing. We developed novel computational tools to perform an integrative analysis of somatic mutations and copy-number alterations. This analysis allowed us to estimate the clonal architecture of the primary and metastases, and to reconstruct a phylogenetic tree relating the subclones from each patient. RESULTS: Every brain metastasis likely developed from a single clone. The brain metastasis and primary tumor shared a common ancestor yet both the primary tumor and brain metastasis continued to evolve independently. Subclonal mutations in the metastasis by definition occurred within the brain; these mutations displayed different mutational signatures than those acquired in the primary tumor. These contrasts were most pronounced in cases of lung cancer or melanoma, with tobacco and UV signatures prominent in these primaries and nearly absent from mutations acquired after metastasis. In order to understand the molecular drivers of clonal evolution and metastasis, we annotated each subclone with driver mutations identified using large numbers of cancer samples analyzed by the cancer genome atlas consortium. This produced a detailed portrait of each patient's cancer, with nearly every node in each phylogenetic tree associated with at least one known driver. We found novel drivers, many of which are known actionable targets, that were exclusive to brain metastases. CONCLUSIONS: This study sheds light on the evolutionary mechanisms in brain metastases. Our data suggests that single biopsies of primary tumors and metastases may not be sufficient to identify potential therapeutic targets.