Clinical Outcome of Patients with Epithelioid Glioblastoma Harboring BRAFV600E Mutation; A Single Institution Experience

Abstract

Purpose

Epithelioid glioblastoma (GBM) is a rare variant of GBM. The study aimed to look into clinicopathological details and outcomes of patients with epithelioid GBM harboring BRAFV600E mutation from a single institution.

Methods

Ten cases of epithelioid GBM diagnosed over the past 5 years were reviewed. All patients underwent surgical resection followed by adjuvant treatment as per protocol after initial diagnosis. Of these, seven patients were planned to redo surgery, reradiation, BRAF with MEK inhibitors, and bevacizumab based on clinical condition, magnetic resonance imaging findings, and progression-free survival after their recurrence. Four recurrent patients had received dabrafenib and trametinib.

Results

All tumor locations were supratentorial. The median follow-up was 2.3 years and the median time to recurrence was 19 months from the diagnosis (range 4–36 months). Four recurrent patients received BRAF + MEK inhibitors. One patient who started dabrafenib and trametinib experienced local progression after 33 months, followed by lung and bone metastasis. One patient died due to multiple subacute hemorrhages, who was a known case of congenital vascular malformations, and two patients remained disease-free after a year and 2 years.

Conclusion

Epithelioid GBM is a very rare, but well-documented entity. Therefore, careful preoperative imaging and detailed evaluation of genetic studies including BRAF V600E mutation are necessary for accurate diagnosis and appropriate selection of treatment for epithelioid GBM. Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF V600E mutation-positive recurrent high-grade glioma.

Keywords

epithelioid glioblastoma - BRAF V600E inhibitors

Publikationsverlauf

Eingereicht: 01. April 2024

Angenommen: 26. Juli 2024

Artikel online veröffentlicht:
29. August 2024

• References

• 1 Louis DN, Perry A, Reifenberger G. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131 (06) 803-820
• 2 Nakajima N, Nobusawa S, Nakata S. et al. BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity. Brain Pathol 2018; 28 (05) 663-673
• 3 Chatterjee D, Radotra BD, Aggarwal D, Madan R, Gupta SK. Analysis of 24 cases of epithelioid glioblastoma: experience from a tertiary centre of North India. Ann Diagn Pathol 2021; 50: 151679
• 4 Furuta T, Miyoshi H, Komaki S. et al. Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma. Neuropathology 2018; 38 (03) 218-227
• 5 Alexandrescu S, Korshunov A, Lai SH. et al. Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas–same entity or first cousins?. Brain Pathol 2016; 26 (02) 215-223
• 6 Śmiech M, Leszczyński P, Kono H, Wardell C, Taniguchi H. Emerging BRAF mutations in cancer progression and their possible effects on transcriptional networks. Genes (Basel) 2020; 11 (11) 1342
• 7 Nakagomi N, Sakamoto D, Hirose T. et al. Epithelioid glioblastoma with microglia features: potential for novel therapy. Brain Pathol 2020; 30 (06) 1119-1133
• 8 Kanemaru Y, Natsumeda M, Okada M. et al. Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy. Acta Neuropathol Commun 2019; 7 (01) 119
• 9 Venkatesh A, Joshi A, Allinson K. et al. Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: a case report and literature review. Curr Probl Cancer 2021; 45 (05) 100701
• 10 Di Nunno V, Gatto L, Tosoni A, Bartolini S, Franceschi E. Implications of BRAF V600E mutation in gliomas: molecular considerations, prognostic value and treatment evolution. Front Oncol 2023; 12: 1067252
• 11 Ding Y, Wang Q, Wang F. et al. TTFields prolonged the PFS of epithelioid glioblastoma patient: a case report. Brain Sci 2023; 13 (04) 633
• 12 Sasame J, Ikegaya N, Kawazu M. et al. HSP90 inhibition overcomes resistance to molecular targeted therapy in BRAFV600E-mutant high-grade glioma. Clin Cancer Res 2022; 28 (11) 2425-2439
• 13 Liebelt BD, Boghani Z, Takei H, Fung SH, Britz GW. Epithelioid glioblastoma presenting as massive intracerebral hemorrhage: case report and review of the literature. Surg Neurol Int 2015; 6 (Suppl. 02) S97-S100
• 14 Huang QL, Cao X, Chai X, Wang X, Xiao C, Wang J. The radiological imaging features of easily misdiagnosed epithelioid glioblastoma in seven patients. World Neurosurg 2019; 124: e527-e532
• 15 Wang S, He Q, Zhang Q, Guan B, Zhou X. Clinicopathologic features and prognosis of epithelioid glioblastoma. Int J Clin Exp Pathol 2020; 13 (07) 1529-1539
• 16 Gaillard F. Epithelioid glioblastoma | Radiology Reference Article | Radiopaedia.org. Radiopaedia.
• 17 Zeng Y, Zhu X, Wang Y. et al. Clinicopathological, immunohistochemical and molecular genetic study on epithelioid glioblastoma: a series of fifteen cases with literature review. OncoTargets Ther 2020; 13: 3943-3952
• 18 Khanna G, Pathak P, Suri V. et al. Immunohistochemical and molecular genetic study on epithelioid glioblastoma: series of seven cases with review of literature. Pathol Res Pract 2018; 214 (05) 679-685
• 19 Le BH, Close RA. Imaging and histopathologic nuances of epithelioid glioblastoma. Case Rep Surg 2018; 2018: 1285729
• 20 Pan R, Wang X, Fang R, Xia Q, Wu N, Rao Q. Epithelioid glioblastoma exhibits a heterogeneous molecular feature: a targeted next-generation sequencing study. Front Oncol 2022; 12: 980059
• 21 Ebrahimi A, Korshunov A, Reifenberger G. et al. Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival. Acta Neuropathol Commun 2022; 10 (01) 5
• 22 Korshunov A, Chavez L, Sharma T. et al. Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis. Brain Pathol 2018; 28 (05) 656-662
• 23 Ahmed A, Nobre L, Mason W. et al. Acquired PTEN loss may mediate dabrafenib and trametinib resistance in BRAF V600E-mutated epithelioid glioblastoma: a case report and literature review. EMJ Oncol Oncol 2023;
• 24 Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 2013; 37 (05) 685-698
• 25 Simon M, Hosen I, Gousias K. et al. TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro-oncol 2015; 17 (01) 45-52
• 26 Lu VM, George ND, Brown DA. et al. Confirming diagnosis and effective treatment for rare epithelioid glioblastoma variant: an integrated survival analysis of the literature. World Neurosurg 2019; 131: 243-251.e2
• 27 Tonse R, Gupta T, Epari S. et al. Impact of WHO 2016 update of brain tumor classification, molecular markers and clinical outcomes in pleomorphic xanthoastrocytoma. J Neurooncol 2018; 136 (02) 343-350
• 28 Behling F, Barrantes-Freer A, Skardelly M. et al. Frequency of BRAF V600E mutations in 969 central nervous system neoplasms. Diagn Pathol 2016; 11 (01) 55
• 29 Wan PTC, Garnett MJ, Roe SM. et al; Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004; 116 (06) 855-867
• 30 Ascierto PA, Kirkwood JM, Grob JJ. et al. The role of BRAF V600 mutation in melanoma. J Transl Med 2012; 10 (01) 85
• 31 Touat M, Idbaih A, Sanson M, Ligon KL. Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol 2017; 28 (07) 1457-1472
• 32 Bouchè V, Aldegheri G, Donofrio CA. et al. BRAF signaling inhibition in glioblastoma: which clinical perspectives?. Front Oncol 2021; 11: 772052
• 33 Bautista F, Paci A, Minard-Colin V. et al. Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr Blood Cancer 2014; 61 (06) 1101-1103
• 34 Brown NF, Carter T, Kitchen N, Mulholland P. Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol 2017; 6 (04) 291-296
• 35 Zhang J, Yao TW, Hashizume R. et al. Combined BRAF^V600E and MEK blockade for BRAF^V600E-mutant gliomas. J Neurooncol 2017; 131 (03) 495-505
• 36 Wen PY, Stein A, van den Bent M. et al. Dabrafenib plus trametinib in patients with BRAF^V600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol 2022; 23 (01) 53-64