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Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma

  • Clinical Study
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Abstract

Purpose

Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors.

Methods

We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed.

Results

Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22–69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2–11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7–38.9).

Conclusion

Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

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References

  1. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2020) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro Oncol 22:iv. https://doi.org/10.1093/neuonc/noaa200

    Article  Google Scholar 

  2. Wen PY, Weller M, Lee EQ et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol 22(8):1073–1113. https://doi.org/10.1093/neuonc/noaa106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lamba N, Chukwueke UN, Smith TR et al (2020) Socioeconomic disparities associated with MGMT promoter methylation testing for patients with glioblastoma. JAMA Oncol 6(12):1972–1974. https://doi.org/10.1001/jamaoncol.2020.4937

    Article  PubMed  Google Scholar 

  4. Brennan CW, Verhaak RGW, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462. https://doi.org/10.1016/j.cell.2013.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kleinschmidt-Demasters BK, Aisner DL, Birks DK, Foreman NK (2013) Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 37(5):685–698. https://doi.org/10.1097/PAS.0b013e31827f9c5e

    Article  PubMed  PubMed Central  Google Scholar 

  6. Long GV, Stroyakovskiy D, Gogas H et al (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371(20):1877–1888. https://doi.org/10.1056/NEJMoa1406037

    Article  CAS  PubMed  Google Scholar 

  7. Johanns TM, Ferguson CJ, Grierson PM, Dahiya S, Ansstas G (2018) Rapid clinical and radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated high-grade glioma. JNCCN J Natl Compr Cancer Netw 16(1):4–10. https://doi.org/10.6004/jnccn.2017.7032

    Article  Google Scholar 

  8. Schreck KC, Guajardo A, Lin DDM, Eberhart CG, Grossman SA (2018) Concurrent BRAF/MEK inhibitors in BRAF V600-Mutant high-grade primary brain tumors. JNCCN J Natl Compr Cancer Netw 16(4):343–347. https://doi.org/10.6004/jnccn.2017.7052

    Article  Google Scholar 

  9. Dahiya S, Emnett RJ, Haydon DH et al (2014) BRAF-V600E mutation in pediatric and adult glioblastoma. Neuro Oncol 16(2):318–319. https://doi.org/10.1093/neuonc/not146

    Article  PubMed  Google Scholar 

  10. Andersen BM, Miranda C, Hatzoglou V, Deangelis LM, Miller AM (2019) Leptomeningeal metastases in glioma: the Memorial Sloan Kettering Cancer Center experience. Neurology 92(21):e2483–e2491. https://doi.org/10.1212/WNL.0000000000007529

    Article  PubMed  PubMed Central  Google Scholar 

  11. Vertosick FT, Selker RG (1990) Brain stem and spinal metastases of supratentorial glioblastoma multiforme. Neurosurgery 27(4):516. https://doi.org/10.1097/00006123-199010000-00002

    Article  PubMed  Google Scholar 

  12. Dias-Santagata D, Akhavanfard S, David SS et al (2010) Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2(5):146–158. https://doi.org/10.1002/emmm.201000070

    Article  PubMed  PubMed Central  Google Scholar 

  13. Garcia EP, Minkovsky A, Jia Y et al (2017) Validation of oncopanel a targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch Pathol Lab Med 141(6):751–758. https://doi.org/10.5858/arpa.2016-0527-OA

    Article  CAS  PubMed  Google Scholar 

  14. Brat DJ, Aldape K, Colman H et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139(3):603–608. https://doi.org/10.1007/s00401-020-02127-9

    Article  PubMed  Google Scholar 

  15. Behling F, Barrantes-Freer A, Skardelly M et al (2016) Frequency of BRAF V600E mutations in 969 central nervous system neoplasms. Diagn Pathol. https://doi.org/10.1186/s13000-016-0506-2

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ryall S, Zapotocky M, Fukuoka K et al (2020) Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell 37(4):569-583.e5. https://doi.org/10.1016/j.ccell.2020.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Korshunov A, Chavez L, Sharma T et al (2018) Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis. Brain Pathol 28(5):656–662. https://doi.org/10.1111/bpa.12566

    Article  CAS  PubMed  Google Scholar 

  18. Lu VM, George ND, Brown DA et al (2019) Confirming diagnosis and effective treatment for rare epithelioid glioblastoma variant: an integrated survival analysis of the literature. World Neuroncol. https://doi.org/10.1016/j.wneu.2019.08.007

    Article  Google Scholar 

  19. Mistry M, Zhukova N, Merico D et al (2015) BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 9:1015–1022. https://doi.org/10.1200/JCO.2014.58.3922

    Article  CAS  Google Scholar 

  20. Ellison DW, Hawkins C, Jones DTW et al (2019) cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol 137(4):683–687. https://doi.org/10.1007/s00401-019-01987-0

    Article  CAS  PubMed  Google Scholar 

  21. Ryall S, Zapotocky M, Fukuoka K, Ellison DW, Tabori U, Hawkins Correspondence C (2020) Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell. https://doi.org/10.1016/j.ccell.2020.03.011

    Article  PubMed  PubMed Central  Google Scholar 

  22. Broniscer A, Tatevossian RG, Sabin ND et al (2014) Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol 40(3):327–336. https://doi.org/10.1111/nan.12093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Arita N, Taneda M, Hayakawa T (1994) Leptomeningeal dissemination of malignant gliomas. Incidence, diagnosis and outcome. Acta Neurochir (Wien) 126(24):84–92. https://doi.org/10.1007/BF01476415

    Article  CAS  Google Scholar 

  24. Burger MC, Ronellenfitsch MW, Lorenz NI et al (2017) Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep 38(6):3291–3296. https://doi.org/10.3892/or.2017.6013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hauschild A, Grob JJ, Demidov LV et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365. https://doi.org/10.1016/S0140-6736(12)60868-X

    Article  CAS  PubMed  Google Scholar 

  26. Robert C, Grob JJ, Stroyakovskiy D et al (2019) Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med 381(7):626–636. https://doi.org/10.1056/NEJMoa1904059

    Article  CAS  PubMed  Google Scholar 

  27. Kaley T, Touat M, Subbiah V et al (2018) BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J Clin Oncol 36:3477–3484. https://doi.org/10.1200/JCO.2018.78.9990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kushnirsky M, Feun LG, Gultekin SH, de la Fuente MI (2020) Prolonged complete response with combined dabrafenib and trametinib after BRAF inhibitor failure in BRAF-mutant glioblastoma. JCO Precis Oncol 4:44–50. https://doi.org/10.1200/po.19.00272

    Article  Google Scholar 

  29. Wen P, Alexander S, Yung-Jue B et al (2018) Rare-09. Efficacy and safety of dabrafenib + trametinib in patients with recurrent/refractory braf v600e–mutated high-grade gliomA (HGG). Neuro Oncol 20:238. https://doi.org/10.1093/neuonc/noy148.986

    Article  Google Scholar 

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Funding

No funding was received in support of this study.

Author information

Authors and Affiliations

  1. Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada

    Mary Jane Lim-Fat

  2. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Mary Jane Lim-Fat, Brian M. Andersen, David A. Reardon & Patrick Y. Wen

  3. Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Kun Wei Song, Deborah A. Forst, Justin T. Jordan, Elizabeth R. Gerstner & Isabel Arrillaga-Romany

  4. Department of Neurology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Kun Wei Song & Patrick Y. Wen

  5. Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Mary Jane Lim-Fat, Brian M. Andersen, Deborah A. Forst, Justin T. Jordan, Elizabeth R. Gerstner & Isabel Arrillaga-Romany

  6. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    J. Bryan Iorgulescu

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Contributions

MJL-F, KWS and IA-R contributed to the experimental design, implementation, analysis and interpretation of data, including statistical analysis, writing and revision of the manuscript; JBI and BMA, DAF, ERG, JTJ, DAR and PYW contributed to the analysis and interpretation of data, writing and revision the manuscript.

Corresponding authors

Correspondence to Mary Jane Lim-Fat or Isabel Arrillaga-Romany.

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Conflict of interest

M.J. Lim-Fat; K.W. Song; B.M. Andersen; D.A. Forst; E.R. Gerstner and I. Arrillaga-Romany report no disclosures relevant to the manuscript; J.B. Iorgulescu received support from the NIH (NCI K12CA090354) and Conquer Cancer Foundation/Sontag Foundation Young Investigator Award; J.T. Jordan received honoraria from Elsevier and Consulting for Navio Theragnostics, Recursion Pharmaceuticals, CereXis, Inc, and Health2047, Inc; D.A. Reardon received Research support (paid to DFCI) fromAcerta Phamaceuticals; Agenus; Celldex; EMD Serono; Incyte; Inovio; Midatech; Omniox; Tragara, advisory/consultation (paid to Dr. Reardon): Abbvie; Advantagene; Agenus; Amgen; Bayer; Bristol-Myers Squibb; Celldex; DelMar; EMD Serono; Genentech/Roche; Imvax; Inovio; Merck; Merck KGaA; Monteris; Novocure; Oncorus; Oxigene; Regeneron; Stemline; Taiho Oncology, Inc., Honoraria (paid to Dr. Reardon): Abbvie; Advantagene; Agenus; Bristol-Myers Squibb; Celldex; EMD Serono; Genentech/Roche; Imvax; Inovio; Merck; Merck KGaA; Monteris; Novocure; Oncorus; Oxigene; Regeneron; Stemline; Taiho Oncology, Inc; P.Y. Wen received honoraria from Agios, Astra Zeneca/Medimmune, Beigene, Celgene, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Vascular Biogenics, VBI Vaccines (research support); Agios, Astra Zeneca, Bayer, Blue Earth Diagnostics, CNS Pharmaceuticals, Immunomic Therapeutics, Karyopharm, Kiyatec, Puma, Taiho, Vascular Biogenics, Deciphera, VBI Vaccines, Tocagen, Voyager, QED, Imvax, Elevate Bio (advisory board) and Merck, Prime Oncology (speaker honoraria).

Ethical approval

This study was conducted under a Dana-Farber/Harvard Cancer Center Institutional Review Board protocol. A waiver was granted for informed consent due to its retrospective nature.

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Supplementary file1 (PDF 247 KB)

Representative BRAF V600E immunohistochemistry micrographs of the initial, pre-treatment pathology from 2 GBM patients, which demonstrate variable positive staining (brown) – with (B) 19.8% and (C) 24.3% variant allele frequencies of BRAF V600E on molecular testing. Microvascular proliferation served as internal negative controls. Total magnification 200x.

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Lim-Fat, M.J., Song, K.W., Iorgulescu, J.B. et al. Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma. J Neurooncol 152, 515–522 (2021). https://doi.org/10.1007/s11060-021-03719-5

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