Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent

Journal of Translational Medicine

Angela Mastronuzzi⁷  Elisabetta Ferretti^1,10  Franco Locatelli⁸  Antonella Cacchione⁷  Giuseppe Bianco²  Loredana Moi⁴  Manuela Badiali^1,11  Manila Antonelli³  Felice Giangaspero⁹  Conor Mallucci¹  Benedetta Pettorini¹  Lorenzo Figà-Talamanca⁶  Andrea Carai⁵  Francesca del Bufalo⁷ 

[1] Paediatric Neurosurgery Department, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK;Pharmacy Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, Rome, 00165, Italy;Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, Rome, 00161, Italy;Public Health, Clinic and Molecular Medicine Department, Microcitemico Children’s Hospital, Via Jenner s/n 09121, Cagliari, Italy;Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’ Onofrio 4, Rome, 00165, Italy;Department of Radiology, Unit of Neuroradiology, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’ Onofrio 4, Rome, 00165, Italy;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, Rome, 00165, Italy;University of Pavia, Strada Nuova, Pavia, 27100, Italy;Neuromed Institute, IRCCS, Via Atinense 18, Isernia, 86077, Pozzilli, IS, Italy;Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, Rome, 00161, Italy;Bone Marrow Transplantation Unit, Microcitemico Children’s Hospital, Via Jenner s/n 09121, Cagliari, Italy

关键词: Vemurafenib;    BRAF V600E;    MAP Kinase pathway;    Ganglioglioma;    Low Grade Glioma;   

Others  :  1146576
DOI  :  10.1186/s12967-014-0356-1

 received in 2014-08-27, accepted in 2014-12-04,  发布年份 2014

【 摘 要 】

Background

Ganglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. LGGs not amenable of complete resection (CR) represent a challenging subgroup where traditional treatments often fail. Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively.

Case presentation

We report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery. After multiple relapse, BRAF status was analyzed by immunohistochemistry and sequencing showing a BRAFV600E mutation. Treatment with Vemurafenib as single agent was started. For the first time, a radiological and clinical response was obtained after 3 months of treatment and sustained after 6 months.

Conclusion

Our experience underline the importance of understanding the driver molecular alterations of LGG and suggests a role for Vemurafenib in the treatment of pediatric GG not amenable of complete surgical resection.

【 授权许可】

   
2014 del Bufalo et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008, 118:1739-1749.
• [2]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: Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 2009, 101:722-733.
• [3]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: Analysis of BRAFV600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011, 121:397-405.
• [4]Nicolaides TP, Li H, Solomon DA, Hariono S, Hashizume R, Barkovich K, Baker SJ, Paugh BS, Jones C, Forshew T, Hindley GF, Hodgson JG, Kim JS, Rowitch DH, Weiss WA, Waldman TA, James CD: Targeted therapy for BRAFV600E malignant astrocytoma. Clin Cancer Res 2011, 17:7595-7604.
• [5]Robinson GW, Brent AO, Gajjar A: Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 2014, 14:258. BioMed Central Full Text
• [6]Bautista F, Paci A, Minard-Colin V, Dufour C, Grill J, Lacroix L, Varlet P, Valteau-Couanet D, Georerger B: Vemurafenib in pediatric patients with BRAFV600E mutated high grade gliomas. Pediat Blood Cancer 2014, 61:1101-1103.
• [7]Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008, 68:8673-8677.
• [8]Dahiya S, Haydon DH, Alvarado D, Gurnett CA, Gutmann DH, Leonard JR: BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol 2013, 125:901-910.
• [9]Walker DA, Liu J, Kieran M, Jabado N, Picton S, Packer R, St Rose C: CPN Paris 2011 Conference Consensus Group: A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro Oncol 2013, 15:462-468.
• [10]Stokland T, Liu JF, Ironside JW, Ellison DW, Taylor R, Robinson KJ, Picton SV, Walker DA: A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). Neuro Oncol 2010, 12:1257-1268.
• [11]Terashima K, Chow K, Jones J, Ahern C, Jo E, Ellezam B, Paulino AC, Okcu MF, Su J, Adesina A, Mahajan A, Dauser R, Whitehead W, Lau C, Chintagumpala M: Long-term outcome of centrally located low-grade glioma in children. Cancer 2013, 119:2630-2638.
• [12]Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, Lazarus KH, Packer RJ, Prados M, Sposto R, Vezina G, Wisoff JH, Pollack IF: Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J Clin Oncol 2012, 30:2641-2647.
• [13]Packer RJ: Radiation Therapy for Pediatric Low-Grade Gliomas: Survival and Sequelae. Curr Neurol Neurosci Rep 2010, 10:10-13.
• [14]Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA: Phase II trial of conformal radiation therapy for pediatric low-grade gliomas. J Clin Oncol 2009, 27:3598-3604.
• [15]Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X: Late effects of conformal radiation therapy for pediatric patients with low grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009, 27:3691-3697.
• [16]Deshmukh H, Yeh TH, Yu J, Sharma MK, Perry A, Leonard JR, Watson MA, Gutmann DH, Nagarajan R: High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene 2008, 27:4745-4751.
• [17]Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 2008, 67:878-887.
• [18]Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, Resnick AC, Sutton LN, Storm PB, Shaikh TH, Biegel JA: Duplication of 7q34 in pediatric low-grade astrocytomas detected by high density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 2009, 19:449-458.
• [19]Janzarik WG, Kratz CP, Loges NT, Olbrich H, Klein C, Schafer T, Scheurlen W, Roggendorf W, Weiller C, Niemeyer C, Korinthenberg R, Pfister S, Omran H: Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 2007, 38:61-63.
• [20]Marko NF, Weil RJ: The molecular biology of WHO grade I astrocytomas. Neuro Oncol 2012, 14:1424-1431.
• [21]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 JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer. Nature 2002, 417:949-954.
• [22]Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, Orisme W, Punchihewa C, Parker M, Qaddoumi I, Boop FA, Lu C, Kandoth C, Ding L, Lee R, Huether R, Chen X, Hedlund E, Nagahawatte P, Rusch M, Boggs K, Cheng J, Becksfort J, Ma J, Song G, Li Y, Wei L, Wang J, Shurtleff S, Easton J, Zhao D, Fulton RS, Fulton LL, Dooling DJ, Vadodaria B, Mulder HL, Tang C, Ochoa K, Mullighan CG, Gajjar A, Kriwacki R, Sheer D, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Baker SJ, Ellison DW: St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project..Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013, 45:602-612.
• [23]Chappé C, Padovani L, Scavarda D, Forest F, Nanni-Metellus I, Loundou A, Mercurio S, Fina F, Lena G, Colin C, Figarella-Branger D: Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF mutation and expression. Brain Pathol 2013, 23:574-583.
• [24]Koelsche C, Wöhrer A, Jeibmann A, Schittenhelm J, Schindler G, Preusser M, Lasitschka F, von Deimling A, Capper D: Mutant BRAFV600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 2013, 125:891-900.
• [25]Donson AM, Kleinschmidt-DeMasters BK, Aisner DL, Bemis LT, Birks DK, Levy JM, Smith AA, Handler MH, Foreman NK, Rush SZ: Pediatric Brainstem Gangliogliomas Show BRAF(V600E) Mutation in a High Percentage of Cases. Brain Pathol 2014, 24:173-183.
• [26]Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF: Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 2012, 14:777-789.
• [27]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: BRAFKIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 2011, 17:4790-4798.
• [28]Jeuken JW, Wesseling P: MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential. J Pathol 2010, 222:324-328.
• [29]Cin H, Meyer C, Herr R, Janzarik WG, Lambert S, Jones DT, Jacob K, Benner A, Witt H, Remke M, Bender S, Falkenstein F, Van Anh TN, Olbrich H, von Deimling A, Pekrun A, Kulozik AE, Gnekow A, Scheurlen W, Witt O, Omran H, Jabado N, Collins VP, Brummer T, Marschalek R, Lichter P, Korshunov A, Pfister SM: Oncogenic FAM131B-BRAF fusion resulting from 7q34deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 2011, 121:763-774.
• [30]Lin A, Rodriguez FJ, Karajannis MA, Williams SC, Legault G, Zagzag D, Burger PC, Allen JC, Eberhart CG, Bar EE: BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol 2012, 71:66-72.
• [31]Vemurafenib FDA approval and full prescribing information [http://www.cancer.gov/cancertopics/druginfo/fda-vemurafenib]
• [32]West ES, Williams VL, Morelli JG: Vemurafenib-induced neutrophlic panniculitis in a child with a brainstem glioma.Pediatr Dermatol 2014. doi:10.1111/pde.12316
• [33]Rush S, Foreman N, Liu A: Brainstem ganglioglioma successfully treated with vemurafenib. J Clin Oncol 2013, 31:e159-e160.
• [34]Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010, 363:809-819.
• [35]Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. New Engl J Med 2012, 366:707-714.
• [36]Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA: MEK1 mutations confer resistance to MEK and B‑RAF inhibition. Proc Natl Acad Sci 2009, 106:20411-20416.
• [37]Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D: Dermatologic Cooperative Oncology Group of Germany (DeCOG): The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 2014, 4:94-109.
• [38]Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB: RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011, 480:387-390.
• [39]Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D’Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M: Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF‑1R/PI3K. Cancer Cell 2010, 18:683-695.