Dabrafenib in BRAFV600E mutant pilocytic astrocytoma in a pediatric patient

Abstract

Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system tumors. They constitute around 30% of all primary central nervous tumors in the pediatric age group. Their clinical behavior may vary but most of them are indolent and do not undergo malignant transformations compared with their adult counterparts. PAs are primarily treated with surgery and in cases of progression; chemotherapy may be needed. They usually carry a good prognosis, with a 10-year survival rate of 90%. BRAFV600E mutations have been identified in approximately 9–15% of patients with PA. These relatively high mutation frequencies in PA open avenues for treatment using targeted therapies such as BRAFV600E inhibitors (e.g., dabrafenib). There have been a few published case reports and case series showing clinical benefits with BRAF inhibitors in BRAF-positive tumors. We report a case of successful treatment of BRAFV600E immunopositive optic pathway PA in a child with dabrafenib.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Ostrom QT, de Blank PM, Kruchko C, Petersen CM, Liao P, Finlay JL, Stearns DS, Wolff JE, Wolinsky Y, Letterio JJ, Barnholtz-Sloan JS (2015) Alex’s Lemonade Stand Foundation infant and childhood primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-Oncology 16(Suppl 10):x1–x36. https://doi.org/10.1093/neuonc/nou327

    Article  PubMed  Google Scholar 

  2. 2.

    Rickert CH, Paulus W (2001) Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification. Child’s Nerv Syst : ChNS : Off J Int Soc Pediatr Neurosurg 17:503–511. https://doi.org/10.1007/s003810100496

    CAS  Article  Google Scholar 

  3. 3.

    Banan R, Hartmann C (2017) The new WHO 2016 classification of brain tumors—what neurosurgeons need to know. Acta Neurochir 159:403–418. https://doi.org/10.1007/s00701-016-3062-3

    Article  PubMed  Google Scholar 

  4. 4.

    Burkhard C, Di Patre PL, Schuler D, Schuler G, Yasargil MG, Yonekawa Y, Lutolf UM, Kleihues P, Ohgaki H (2003) A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 98:1170–1174. https://doi.org/10.3171/jns.2003.98.6.1170

    Article  PubMed  Google Scholar 

  5. 5.

    Koeller KK, Rushing EJ (2004) From the archives of the AFIP: pilocytic astrocytoma: radiologic-pathologic correlation. Radiographics 24:1693–1708. https://doi.org/10.1148/rg.246045146

    Article  PubMed  Google Scholar 

  6. 6.

    Collins VP, Jones DT, Giannini C (2015) Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol 129:775–788. https://doi.org/10.1007/s00401-015-1410-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Faulkner C, Ellis HP, Shaw A, Penman C, Palmer A, Wragg C, Greenslade M, Haynes HR, Williams H, Lowis S, White P, Williams M, Capper D, Kurian KM (2015) BRAF fusion analysis in pilocytic astrocytomas: KIAA1549-BRAF 15-9 fusions are more frequent in the midline than within the cerebellum. J Neuropathol Exp Neurol 74:867–872. https://doi.org/10.1097/nen.0000000000000226

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Mansur DB, Rubin JB, Kidd EA, King AA, Hollander AS, Smyth MD, Limbrick DD, Park TS, Leonard JR (2011) Radiation therapy for pilocytic astrocytomas of childhood. Int J Radiat Oncol*Biol*Phys 79:829–834. https://doi.org/10.1016/j.ijrobp.2009.11.015

    Article  PubMed  Google Scholar 

  9. 9.

    Lassaletta A, Scheinemann K, Zelcer SM, Hukin J, Wilson BA, Jabado N, Carret AS, Lafay-Cousin L, Larouche V, Hawkins CE, Pond GR, Poskitt K, Keene D, Johnston DL, Eisenstat DD, Krishnatry R, Mistry M, Arnoldo A, Ramaswamy V, Huang A, Bartels U, Tabori U, Bouffet E (2016) Phase II weekly vinblastine for chemotherapy-naive children with progressive low-grade glioma: a Canadian pediatric brain tumor consortium study. J Clin Oncol 34:3537–3543. https://doi.org/10.1200/jco.2016.68.1585

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Peyssonnaux C, Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62

    CAS  Article  Google Scholar 

  11. 11.

    Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW, Sidransky D (2003) BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95:625–627. https://doi.org/10.1093/jnci/95.8.625

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954. https://doi.org/10.1038/nature00766

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Hawkins C, Walker E, Mohamed N, Zhang C, Jacob K, Shirinian M, Alon N, Kahn D, Fried I, Scheinemann K, Tsangaris E, Dirks P, Tressler R, Bouffet E, Jabado N, Tabori U (2011) BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17:4790–4798. https://doi.org/10.1158/1078-0432.ccr-11-0034

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A, Serre D, Hauser P, Garami M, Bognar L, Hanzely Z, Montes JL, Atkinson J, Farmer JP, Bouffet E, Hawkins C, Tabori U, Jabado N (2009) Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 101:722–733. https://doi.org/10.1038/sj.bjc.6605179

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677. https://doi.org/10.1158/0008-5472.can-08-2097

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Myung JK, Cho H, Park CK, Kim SK, Lee SH, Park SH (2012) Analysis of the BRAF(V600E) mutation in central nervous system tumors. Transl Oncol 5:430–436. https://doi.org/10.1593/tlo.12328

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405. https://doi.org/10.1007/s00401-011-0802-6

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry R, Guerreiro Stucklin A, Zhukova N, Arnoldo A, Ryall S, Ling C, McKeown T, Loukides J, Cruz O, de Torres C, Ho C-Y, Packer RJ, Tatevossian R, Qaddoumi I, Harreld JH, Dalton JD, Mulcahy-Levy J, Foreman N, Karajannis MA, Wang S, Snuderl M, Nageswara Rao A, Giannini C, Kieran M, Ligon KL, Garre ML, Nozza P, Mascelli S, Raso A, Mueller S, Nicolaides T, Silva K, Perbet R, Vasiljevic A, Faure Conter C, Frappaz D, Leary S, Crane C, Chan A, Ng H-K, Shi Z-F, Mao Y, Finch E, Eisenstat D, Wilson B, Carret AS, Hauser P, Sumerauer D, Krskova L, Larouche V, Fleming A, Zelcer S, Jabado N, Rutka JT, Dirks P, Taylor MD, Chen S, Bartels U, Huang A, Ellison DW, Bouffet E, Hawkins C, Tabori U (2017) Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol 35:2934–2941. https://doi.org/10.1200/JCO.2016.71.8726

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Menzies AM, Long GV, Murali R (2012) Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Design, Dev Ther 6:391–405. https://doi.org/10.2147/dddt.s38998

    CAS  Article  Google Scholar 

  20. 20.

    Kieran MW, Bouffet E, Broniscer A, Cohen KJ, Geoerger B, Hansford JR, Hingorani P, Aerts I, Andre N, Bertozzi-Salamon A-I, Dunkel IJ, Hummel TR, Leary S, Moreno L, Russo MW, Tseng L, Dasgupta K, Nebot N, Whitlock J, Hargrave DR (2018) Efficacy and safety results from a phase I/IIa study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed refractory low-grade glioma. J Clin Oncol 36:10506–10506. https://doi.org/10.1200/JCO.2018.36.15_suppl.10506

    Article  Google Scholar 

  21. 21.

    Olow A, Mueller S, Yang X, Hashizume R, Meyerowitz J, Weiss W, Resnick AC, Waanders AJ, Stalpers LJA, Berger MS, Gupta N, James CD, Petritsch CK, Haas-Kogan DA (2016) BRAF status in personalizing treatment approaches for pediatric gliomas. Clin Cancer Res :Off J Am Assoc Cancer Res 22:5312–5321. doi:https://doi.org/10.1158/1078-0432.CCR-15-1101

    CAS  Article  Google Scholar 

  22. 22.

    Bautista F, Paci A, Minard-Colin V, Dufour C, Grill J, Lacroix L, Varlet P, Valteau-Couanet D, Geoerger B (2014) Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr Blood Cancer 61:1101–1103. https://doi.org/10.1002/pbc.24891

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Robinson GW, Orr BA, Gajjar A (2014) Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 14:258–258. https://doi.org/10.1186/1471-2407-14-258

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bavle A, Jones J, Lin FY, Malphrus A, Adesina A, Su J (2017) Dramatic clinical and radiographic response to BRAF inhibition in a patient with progressive disseminated optic pathway glioma refractory to MEK inhibition. Pediatr Hematol Oncol 34:254–259. https://doi.org/10.1080/08880018.2017.1360971

    Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to F. Mustansir.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mustansir, F., Mushtaq, N. & Darbar, A. Dabrafenib in BRAFV600E mutant pilocytic astrocytoma in a pediatric patient. Childs Nerv Syst 36, 203–207 (2020). https://doi.org/10.1007/s00381-019-04346-2

Download citation

Keywords

  • BRAFV600E
  • Pilocytic astrocytoma
  • Dabrafenib treatment