Biomarker-based prognostic stratification of young adult glioblastoma

Zhang, Rui Qi; Shi, Zhifeng; Chen, Hong; Chung, Nellie Yuk Fei; Yin, Zi; Li, Kay Ka Wai; Chan, Danny Tat Ming; Poon, Wai Sang; Wu, Jinsong; Zhou, Lei; Chan, Aden Ka Yin; Mao, Ying; Ng, Ho Keung

doi:10.18632/oncotarget.5456

Cited by 43 publications

(31 citation statements)

References 46 publications

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“…Despite the relatively low frequency of BRAF mutations, it is increased among several subsets of adult patients with GBM: approximately 15% of GBM cases in patients aged 17 to 35 years will harbor a BRAF V600E mutation. 15 Remarkably, BRAF mutations in this cohort were found in similar frequency and were mutually exclusive to other common mutations in IDH1 (17%) and H3F3A (19%), suggesting that BRAF-mutated GBM represents a distinct subgroup. Likewise, the incidence of BRAF V600E is approximately 50% in epithelioid GBM (eGBM), a rare variant of IDH wild-type GBM recognized in the revised 2016 WHO classification.…”

supporting

confidence: 49%

“…Several large retrospective studies have attempted to estimate the frequency of BRAF mutations in pediatric and adult primary CNS tumors [11][12][13][14][15] ; for adult GBM, the frequency of these mutations is approximately 1% to 3%. Interestingly, the only missense mutation found to date in adult or pediatric primary CNS tumors is the V600E variant.…”

Section: Incidencementioning

confidence: 99%

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BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

Johanns¹,

Ansstas²,

Dahiya³

2018

J Natl Compr Canc Netw

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Use of small molecule inhibitors specific to activating BRAF V600 mutations first demonstrated efficacy in metastatic melanoma.1 Recently, similar results were observed in patients with BRAF-mutated non-small cell lung cancer, leading to FDA approval in June 2017. 2,3 Furthermore, the observation that combining BRAF inhibition (BRAFi) with MEK inhibition (MEKi) leads to improved efficacy and reduced resistance without increased toxicity has set the bar for any future multidrug combination. 4,5 These observations, along with encouraging early-phase data in other histologies, such as papillary thyroid cancer 6 and hairy cell leukemia, 7 which both have high frequencies of BRAF V600E mutations, have led to increasing interest in exploring the role of BRAFi and MEKi in all BRAF-mutated cancers, regardless of histology.8 However, the lack of efficacy in BRAF-mutated colorectal cancer cautions against the agnostic generalization of results with these agents.For primary central nervous system (CNS) tumors, increasing evidence has suggested that BRAFi therapy may be effective. Preliminary results from a phase I/II study of dabrafenib in relapsed or progressive pediatric BRAF V600E-mutated low-grade gliomas reported an 82% clinical benefit rate (stable disease or better at 6 months) among 32 evaluable subjects.9 A subsequent phase II study is underway evaluating the efficacy of combined BRAFi/MEKi in a similar patient population (ClinicalTrials.gov identifier: NCT02684058). Conversely, the efficacy of these agents in adult patients, particularly those with high-grade gliomas (HGGs; WHO grade III) or glioblastoma (GBM; WHO grade IV), which are more common in adults, remains undefined. Two recent publications in JNCCN-an earlier work by Johanns et al 10 and an article by Schreck et al found elsewhere in this issue describing the successful use of combined BRAFi/MEKi therapy in adults with HGG or GBM-contribute to this growing body of literature, suggesting a therapeutic role for these agents in primary CNS disease, and raise several important clinical considerations. IncidenceSeveral large retrospective studies have attempted to estimate the frequency of BRAF mutations in pediatric and adult primary CNS tumors [11][12][13][14][15] ; for adult GBM, the frequency of these mutations is approximately 1% to 3%. Interestingly, the only missense mutation found to date in adult or pediatric primary CNS tumors is the V600E variant. Despite the relatively low frequency of BRAF mutations, it is increased among several subsets of adult patients with GBM: approximately 15% of GBM cases in patients aged 17 to 35 years will harbor a BRAF V600E mutation. 15 Remarkably, BRAF mutations in this cohort were found in similar frequency and were mutually exclusive to other common mutations in IDH1 (17%) and H3F3A (19%), suggesting that BRAF-mutated GBM represents a distinct subgroup. Likewise, the incidence of BRAF V600E is approximately 50% in epithelioid GBM (eGBM), a rare variant of IDH wild-type GBM recognized in the revised 2016 WHO classif...

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supporting

confidence: 49%

Section: Incidencementioning

confidence: 99%

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

Johanns¹,

Ansstas²,

Dahiya³

2018

J Natl Compr Canc Netw

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“…Controversy exists on whether a BRAF V600E mutation constitutes a favorable biomarker for glioblastoma. A review of young adult glioblastoma patients revealed that those with BRAF mutant tumors had a median OS of 43.2 months compared to their wildtype counterparts with a median OS of 13.6 months [12]. This is supported by the high occurrences of this mutation among lower grade gliomas: 66% in pleomorphic xanthoastrocytomas, 18% in gangliogliomas and 9% in pilocytic astrocytomas [5].…”

Section: Discussionmentioning

confidence: 96%

Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases

Woo

Lam

et al. 2019

Oncotarget

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Background: Up to 15% of young adults with glioblastoma have the activating oncogenic BRAF V600E mutation, an actionable target of the MAPK signal transduction pathway governing tumor cell proliferation. Small molecule inhibitors of BRAF and MEK, a downstream protein immediately following BRAF, have been shown to confer a survival advantage for patients with BRAF V600E mutant advanced melanoma. We describe our experience using this combined target therapy for two patients with BRAF V600E mutant glioblastoma (GBM) as primary treatment due to extenuating clinical circumstances that prohibited the prescription of standard treatment.Case Presentation: The two patients were both 22 years old on presentation. After the initial tumor resection, they both developed rapid deterioration in performance status within a few weeks due to leptomeningeal metastases. In view of the critical condition, BRAF and MEK inhibitors were prescribed as first line treatment. The two patients both achieved dramatic clinical response, which was parallel to the impressive radiological regression of the disease. Unfortunately, the duration of disease control was short as drug resistance developed rapidly. The two patients died 7 and 7.5 month after initial diagnosis of GBM.Conclusions: Primary treatment with inhibitors of BRAF and MEK can lead to tumor regression for patients with BRAF V600E mutant glioblastoma. We therefore recommend that all young GBM patients should undergo BRAF V600E mutation testing, especially for those with unusual aggressive clinical course.

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“…17 Zhang et al and Matthew et al also reported that 16 out of 107 cases of young adult GBM and five out of 10 cases of pediatric secondary GBM exhibited the BRAF V600E mutation and had better prognoses. 18,19 Although detailed histology was not provided, these cases of pediatric GBM with a PXA-like methylation pattern appear to resemble our case. 17 It currently remains unknown whether concurrent BRAF V600E and ATRX mutations are associated with a specific glioma subtype or clinical course.…”

Section: Discussionmentioning

confidence: 50%

“…15,16 Additionally, recent studies revealed a subset of pediatric and young adult GBM showing a higher percentage of the BRAF V600E mutation and taking less malignant courses. [17][18][19] Korshunov et al reported a subgroup of pediatric GBM with PXA or PA-like genome methylation profiles, 40% of which harbored the BRAF V600E mutation, which followed significantly longer courses. 17 Zhang et al and Matthew et al also reported that 16 out of 107 cases of young adult GBM and five out of 10 cases of pediatric secondary GBM exhibited the BRAF V600E mutation and had better prognoses.…”

Section: Discussionmentioning

confidence: 99%

A case of high‐grade astrocytoma with BRAF and ATRX mutations following a long‐standing course over two decades

et al. 2017

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Pediatric high-grade gliomas are rare and occasionally hard to classify. These tumors often feature a well-demarcated histology and are expected to have a better outcome than ordinary diffuse high-grade gliomas in adults. We herein report a case of circumscribed high-grade glioma that showed a distinct molecular profile and followed an excellent course for 26 years. The patient, a 3-year-old boy at onset, presented with a contrast-enhancing mass in the right temporal lobe and underwent resection. Histologically, the tumor mainly consisted of compact bundles of GFAP-positive spindle cells. With its malignant features including brisk mitotic activity and pseudopallisading necrosis, a diagnosis of high-grade astrocytoma was made and adjuvant chemoradiotherapy was administered. After a disease-free period of two decades, the tumor recurred locally. The resected tumor was histologically identical to the primary tumor and additionally contained pleomorphic cells, but lacked eosinophilic granular bodies and reticulin networks. The primary and recurrent tumors both harbored the BRAF V600E mutation, and the recurrent tumor was immunonegative for ATRX. Combined BRAF and ATRX mutations are rare in gliomas, with only a pediatric case of glioblastoma being reported in the literature. However, our case cannot be regarded as glioblastoma because of its well-demarcated histology and excellent course. The distinction of either a diffuse or localized nature in gliomas is important, particularly in children, for predicting prognoses and selecting adjuvant therapies that consequently affect life-long health care. The present case provides novel insights into pediatric high-grade astrocytomas.

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Biomarker-based prognostic stratification of young adult glioblastoma

Cited by 43 publications

References 46 publications

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases

A case of high‐grade astrocytoma with BRAF and ATRX mutations following a long‐standing course over two decades

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