Concurrent BRAF/MEK Inhibitors in
            BRAF
            V600–Mutant High-Grade Primary Brain Tumors

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.

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From first symptoms to diagnosis: Initial clinical presentation of primary brain tumors

Clinical and Translational Neuroscience ◽

10.1177/2514183x20968368 ◽

2020 ◽

Vol 4 (2) ◽

pp. 2514183X2096836

Author(s):

B Alther ◽

V Mylius ◽

M Weller ◽

AR Gantenbein

Keyword(s):

Brain Tumors ◽

Clinical Presentation ◽

Personality Change ◽

University Hospital ◽

World Health ◽

Low Grade ◽

High Grade ◽

Primary Brain Tumors ◽

Presenting Symptoms ◽

Time To Diagnosis

Background: Despite modern imaging methods, a long symptom-to-diagnosis interval can be observed in patients with primary brain tumors. Objective: The study evaluated the initial and subsequent clinical presentation of patients with brain tumors in the context of time to diagnosis, localization, histology, and tumor grading. Methods: In this retrospective analysis of 85 consecutive patients with primary brain tumors, we assessed the presenting symptoms and signs. The analyses were based on entries from medical records at the Department of Neurology of Zurich University Hospital between 2005 and 2010. Results: A total of 54 men and 31 women with a mean age at diagnosis of 48 years were included. 60% of the patients present with a malignant tumor (World Health Organization grading III–IV), 24.7% with a benign tumor (I–II), and 15.3% were not classified. The interval between symptom onset and diagnosis varied from 1 day to 96 months (median: 39 days). High-grade tumors (III–IV) were diagnosed significantly earlier than low-grade tumors (II) after the first symptoms occurred (median: 26 vs. 138 days; z = −3.847, p < 0.001). Conclusions: Symptoms with a short symptom-to-diagnosis interval such as nausea/vomiting, seizures, as well as of personality change are assumed to contribute to a faster diagnosis in high-grade tumors. Visual disturbances and headaches, although occurring relatively seldom, did not contribute to a decrease in time to diagnosis and should therefore be considered for further diagnostic workup.

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Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases

Neurosurgical FOCUS ◽

10.3171/2013.12.focus13464 ◽

2014 ◽

Vol 36 (2) ◽

pp. E10 ◽

Cited By ~ 80

Author(s):

Serge Marbacher ◽

Elisabeth Klinger ◽

Lucia Schwyzer ◽

Ingeborg Fischer ◽

Edin Nevzati ◽

...

Keyword(s):

Adverse Effects ◽

Brain Tumors ◽

Brain Metastases ◽

Low Grade ◽

High Grade ◽

Open Resection ◽

Who Grade ◽

Primary Brain Tumors ◽

High Grade Gliomas ◽

Surgical Adjunct

Object The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolevulinic acid (5-ALA)–induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of patients with primary brain tumors and metastases. Methods The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA–guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. Results A total of 458 cases qualified for final analysis. The highest percentage of 5-ALA–positive fluorescence in open resection was found in glioblastomas (96%, n = 99/103). Among other tumors, 5-ALA–positive fluorescence was detected in 88% (n = 21/32) of anaplastic gliomas (WHO Grade III), 40% (n = 8/19) of low-grade gliomas (WHO Grade II), no (n = 0/3) WHO Grade I gliomas, and 77% (n = 85/110) of meningiomas. Among metastases, the highest percentage of 5-ALA–positive fluorescence was detected in adenocarcinomas (48%, n = 13/27). Low rates or absence of positive fluorescence was found among pituitary adenomas (8%, n = 1/12) and schwannomas (0%, n = 0/7). Biopsies of high-grade primary brain tumors showed positive rates of fluorescence similar to those recorded for open resection. No clinical adverse effects associated with use of 5-ALA were observed. Only 1 patient had clinically silent transient elevation of liver enzymes. Conclusions Study findings suggest that the administration of 5-ALA as a surgical adjunct for resection and biopsy of primary brain tumors and brain metastases is safe. In light of the high rate of positive fluorescence in high-grade gliomas other than glioblastomas, meningiomas, and a variety of metastatic cancers, 5-ALA seems to be a promising tool for enhancing intraoperative identification of neoplastic tissue and optimizing the extent of resection.

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Incidence trends in high-grade primary brain tumors in males and females

Oncology Letters ◽

10.3892/ol.2017.5770 ◽

2017 ◽

Vol 13 (4) ◽

pp. 2831-2837 ◽

Cited By ~ 4

Author(s):

Jonas Nilsson ◽

Georg Holgersson ◽

Tobias Carlsson ◽

Roger Henriksson ◽

Stefan Bergström ◽

...

Keyword(s):

Brain Tumors ◽

High Grade ◽

Primary Brain Tumors ◽

Incidence Trends ◽

Males And Females

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CGE19-063: Creating a Clinical-Molecular Database to Study Patients with BRAF V600E-Mutated Brain Tumors

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7137 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. CGE19-063

Author(s):

Yamini V. Ananth ◽

Karisa Schreck

Keyword(s):

Natural History ◽

Brain Tumors ◽

Molecular Data ◽

Age At Diagnosis ◽

Braf V600e ◽

Response To Treatment ◽

High Grade ◽

Primary Brain Tumors ◽

History Of ◽

High Grade Gliomas

Background: Glioblastoma remains incurable, but detailed molecular characterization has revealed different genomic subtypes have differential survival and sensitivity to therapies. Correlating clinical with molecular data has proven challenging, however, limiting the field’s insight into the effect of specific mutations. BRAF V600E, a targetable mutation with important therapeutic implications, is not well studied in adults with high-grade gliomas. With this study we sought to establish a consolidated clinical-molecular database in order to ascertain the range of primary brain tumors with BRAF V600E mutations that occur in adults, and the clinical and histopathological features of these tumors. Methods: We created a secure, web-based database using the REDCap tool. We analyzed data from 29 adults with primary brain tumors containing the BRAF V600E mutation, recording gender, age at diagnosis, tumor pathology, molecular tumor information, dates of surgeries, time to progression, treatments received, response to treatment, and survival. Results: The patient cohort’s median age at diagnosis was 33 ± 3.2 years. These patients were followed for a median of 4.2 ± 1.5 years. Tumor grades ranged from WHO I to IV, with 59% (n=17) of tumors classified as high grade by WHO criteria (III or IV). Of the patients with high-grade gliomas, 60% (n=6) received chemotherapy and radiation within 4 months of diagnosis. Three patients were treated at progression: 1 received standard therapy, the other 2 received an experimental targeted therapy of dabrafenib and trametinib (BRAF/MEK inhibitors). Overall, the high-grade glioma cohort received a median of one treatment (range 0–4) with a median follow up of 1.2 ± 0.9 years. Conclusion: Understanding the natural history of different genomic subtypes of glioblastoma is critical for the appropriate application of novel therapeutics. Here we demonstrate that a clinical-pathological database consisting of clinical and molecular data from patients with an uncommon mutation in brain tumors (BRAF V600E) is useful for understanding the prevalence, distribution, and natural history of this disease. This novel database tool also creates a systematic manner in which to track the clinical outcome in cohorts of patients with specific mutations, which is of broad interest for patients with glioblastoma and other potentially targetable mutations.

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Durable Progression-Free Survival With the Use of BRAF and MEK Inhibitors in Four Cases With BRAF V600E-Mutated Gliomas

Cancer Control ◽

10.1177/10732748211040013 ◽

2021 ◽

Vol 28 ◽

pp. 107327482110400

Author(s):

Michael J. Fusco ◽

Yolanda Piña ◽

Robert J. Macaulay ◽

Solmaz Sahebjam ◽

Peter A. Forsyth ◽

...

Keyword(s):

Brain Tumors ◽

Mapk Pathway ◽

Case Series ◽

Progression Free Survival ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Who Grade ◽

Free Survival ◽

Mek Inhibitors ◽

Primary Brain Tumors

Introduction BRAF V600 E mutations have been identified in a subset of patients with primary brain tumors. Combination therapy with BRAF and Mitogen-activated protein kinase (MEK) inhibitors (BRAF/MEKi) targeting sequential steps in the MAPK pathway has replaced BRAFi monotherapy as the standard of care in multiple tumors with BRAF V600 E mutations, and clinical evidence for this strategy continues to grow in primary brain tumors. Case series We describe four patients with BRAF V600 E mutated gliomas, including a 21-year-old woman with a ganglioglioma WHO grade I, a 19-year-old man with a pleomorphic xanthoastrocytoma WHO grade III, and 21-year-old and 33-year-old women with epithelioid GBM WHO grade IV, who achieved durable progression-free survival with combination BRAF/MEKi. Conclusion Combination of BRAF/MEK inhibition can be a novel, promising approach as targeted therapy in gliomas with BRAF V600 E mutations, especially those that are resistant to standard therapy. Our cases, along with other early reports utilizing dabrafenib/trametinib, highlight the importance of somatic next-generation sequencing, particularly in younger patients. Interim results from clinical trials utilizing dabrafenib/trametinib have been promising thus far, and our case series suggests that durable clinical benefit is possible, even in the setting of glioblastoma, WHO grade IV.

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