Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations.

As the field of neuro-oncology makes headway in uncovering the key oncogenic drivers in pediatric glioma, the role of precision diagnostics and therapies continues to rapidly evolve with important implications for the standard of care for clinical management of these patients. Four studies at major academic centers were published in the last year outlining the clinically integrated molecular profiling and targeting of pediatric brain tumors; all four demonstrated the feasibility and utility of incorporating sequencing into the care of children with brain tumors, in particular for children and young adults with glioma. Based on synthesis of the data from these studies and others, we provide consensus recommendations for the integration of precision diagnostics and therapeutics into the practice of pediatric neuro-oncology. Our primary consensus recommendation is that next-generation sequencing should be routinely included in the workup of most pediatric gliomas.

[1]  David T. W. Jones,et al.  EWSR1‐PATZ1 gene fusion may define a new glioneuronal tumor entity , 2018, Brain pathology.

[2]  P. Robertson,et al.  CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response , 2018, Acta Neuropathologica Communications.

[3]  David T. W. Jones,et al.  Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial , 2018, Cancer cell.

[4]  A. Chinnaiyan,et al.  Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors. , 2018, JCO precision oncology.

[5]  J. Ojemann,et al.  Year 1 in the Molecular Era of Pediatric Brain Tumor Diagnosis: Application of Universal Clinical Targeted Sequencing in an Unselected Cohort of Children. , 2018, JCO precision oncology.

[6]  M. Chintagumpala,et al.  A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas , 2018, Pediatric blood & cancer.

[7]  Rachel A. Kudgus,et al.  A phase 1 study of the c‐Met inhibitor, tivantinib (ARQ197) in children with relapsed or refractory solid tumors: A Children's Oncology Group study phase 1 and pilot consortium trial (ADVL1111) , 2017, Pediatric blood & cancer.

[8]  Kun Mu,et al.  Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma , 2017, Cancer cell.

[9]  A. Chinnaiyan,et al.  Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors. , 2017, Translational research : the journal of laboratory and clinical medicine.

[10]  James Suh,et al.  Comprehensive Genomic Profiling of 282 Pediatric Low‐ and High‐Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures , 2017, The oncologist.

[11]  A. Chinnaiyan,et al.  Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event , 2017, npj Precision Oncology.

[12]  P. Robertson,et al.  Identification and targeting of an FGFR fusion in a pediatric thalamic “central oligodendroglioma― , 2018 .

[13]  W. Vandertop,et al.  A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma , 2017, Journal of Neuro-Oncology.

[14]  K. Ligon,et al.  Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Mariella G. Filbin,et al.  Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors , 2017, Neuro-oncology.

[16]  Robert J. Lonigro,et al.  Integrative Clinical Genomics of Metastatic Cancer , 2017, Nature.

[17]  P. Northcott,et al.  Genomic Analysis of Childhood Brain Tumors: Methods for Genome-Wide Discovery and Precision Medicine Become Mainstream. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  A. Ferrari,et al.  Front‐line window therapy with cisplatin in patients with primary disseminated Ewing sarcoma: A study by the Associazione Italiana di Ematologia ed Oncologia Pediatrica and Italian Sarcoma Group , 2017, Pediatric blood & cancer.

[19]  I. Pollack,et al.  A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study. , 2017 .

[20]  T. MacDonald,et al.  A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high‐grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study , 2017, Pediatric blood & cancer.

[21]  P. Wen,et al.  A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma , 2017, Oncotarget.

[22]  Jindong Chen,et al.  Immune Checkpoint in Glioblastoma: Promising and Challenging , 2017, Front. Pharmacol..

[23]  Levi Garraway,et al.  Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden , 2017, Genome Medicine.

[24]  G. Mason,et al.  Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report. , 2017, Journal of neurosurgery. Pediatrics.

[25]  D. Ziegler,et al.  Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models , 2017, PloS one.

[26]  Arie Perry,et al.  Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy , 2016, Neuro-oncology.

[27]  David T. W. Jones,et al.  Pediatric high-grade glioma: biologically and clinically in need of new thinking , 2016, Neuro-oncology.

[28]  Marilyn M. Li,et al.  Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. , 2017, The Journal of molecular diagnostics : JMD.

[29]  M. Prados,et al.  Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas , 2017, Journal of Neuro-Oncology.

[30]  Roland Eils,et al.  Recurrent MET fusion genes represent a drug target in pediatric glioblastoma , 2016, Nature Medicine.

[31]  B. Geoerger,et al.  CNS tumoursThe first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas , 2016 .

[32]  D. Merico,et al.  Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  Chris Jones,et al.  Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma , 2016, Oncotarget.

[34]  I. Pollack,et al.  Nonrandomized comparison of neurofibromatosis type 1 and non–neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low‐grade glioma: A report from the Children's Oncology Group , 2016, Cancer.

[35]  J. McPherson,et al.  Coming of age: ten years of next-generation sequencing technologies , 2016, Nature Reviews Genetics.

[36]  P. Burger,et al.  Management of pediatric intracranial low-grade gliomas: long-term follow-up after radiation therapy , 2016, Child's Nervous System.

[37]  D. Ferguson,et al.  ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma , 2016, Science Translational Medicine.

[38]  H. Gan,et al.  Prolonged disease control with MEK inhibitor in neurofibromatosis type I‐associated glioblastoma , 2016, Journal of clinical pharmacy and therapeutics.

[39]  Somak Roy,et al.  Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. , 2016, Neuro-oncology.

[40]  Roland Eils,et al.  New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs , 2016, Cell.

[41]  J. MacKeigan,et al.  Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. , 2015, Neuro-oncology.

[42]  J. Ptak,et al.  Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord , 2015, Proceedings of the National Academy of Sciences.

[43]  M. Sahin,et al.  Tuberous sclerosis complex. , 2015, Pediatric clinics of North America.

[44]  Nicholas J. Wang,et al.  Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma , 2015, Nature Medicine.

[45]  D. Merico,et al.  BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  K. Kurian,et al.  Current Understanding of BRAF Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas , 2015, Front. Oncol..

[47]  R. Riccardi,et al.  Temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: a broken promise? , 2015, Journal of chemotherapy.

[48]  P. Anderson Futility versus utility of marrow assessment in initial Ewing sarcoma staging workup , 2014, Pediatric blood & cancer.

[49]  E. Roach,et al.  Tuberous sclerosis complex. , 2015, Handbook of clinical neurology.

[50]  A. Gajjar,et al.  Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy , 2014, BMC Cancer.

[51]  Amar Gajjar,et al.  The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma , 2014, Nature Genetics.

[52]  David T. W. Jones,et al.  Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. , 2013, Cancer cell.

[53]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[54]  D. Kirsch,et al.  PD-0332991, a CDK4/6 Inhibitor, Significantly Prolongs Survival in a Genetically Engineered Mouse Model of Brainstem Glioma , 2013, PloS one.

[55]  Y. Miyakita,et al.  Secondary hematological malignancies associated with temozolomide in patients with glioma. , 2013, Neuro-oncology.

[56]  D. Brat,et al.  PDGFRA Amplification is Common in Pediatric and Adult High‐Grade Astrocytomas and Identifies a Poor Prognostic Group in IDH1 Mutant Glioblastoma , 2013, Brain pathology.

[57]  Roland Eils,et al.  Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma , 2013, Nature Genetics.

[58]  B. Garcia,et al.  Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma , 2013, Science.

[59]  Heather L. Mulder,et al.  Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas , 2013, Nature Genetics.

[60]  E. Thiele,et al.  Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial , 2013, The Lancet.

[61]  K. Ligon,et al.  BRAF Duplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper , 2012, Journal of neuropathology and experimental neurology.

[62]  I. Pollack,et al.  Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. , 2012, Neuro-oncology.

[63]  Rebecca A. Ihrie,et al.  Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy , 2012, Proceedings of the National Academy of Sciences.

[64]  David T. W. Jones,et al.  Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma , 2012, Nature.

[65]  T. Tihan,et al.  Pathologic Characteristics of Pediatric Intracranial Pilocytic Astrocytomas and Their Impact on Outcome in 3 Countries: A Multi-institutional Study , 2012, The American journal of surgical pathology.

[66]  L. Garraway,et al.  Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. , 2011, The Journal of molecular diagnostics : JMD.

[67]  R. McLendon,et al.  Altered Telomeres in Tumors with ATRX and DAXX Mutations , 2011, Science.

[68]  H. Zentgraf,et al.  Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody , 2011, Acta Neuropathologica.

[69]  J. Wisoff,et al.  Primary Neurosurgery for Pediatric Low-Grade Gliomas: A Prospective Multi-Institutional Study From the Children's Oncology Group , 2011, Neurosurgery.

[70]  Daniel J Brat,et al.  Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group. , 2011, Neuro-oncology.

[71]  Kirsten Schmieder,et al.  Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma , 2011, Acta Neuropathologica.

[72]  A. Byars,et al.  Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. , 2010, The New England journal of medicine.

[73]  G. Armstrong Long-term survivors of childhood central nervous system malignancies: the experience of the Childhood Cancer Survivor Study. , 2010, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[74]  M. Prados,et al.  Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. , 2010, Cancer research.

[75]  M. Belvin,et al.  RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth , 2010, Nature.

[76]  C. Kramm,et al.  Intensive chemotherapy improves survival in pediatric high‐grade glioma after gross total resection: results of the HIT‐GBM‐C protocol , 2010, Cancer.

[77]  N. Turner,et al.  Fibroblast growth factor signalling: from development to cancer , 2010, Nature Reviews Cancer.

[78]  Thomas E Merchant,et al.  Brain tumors across the age spectrum: biology, therapy, and late effects. , 2010, Seminars in radiation oncology.

[79]  T. Merchant,et al.  Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  David T. W. Jones,et al.  Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. , 2008, Cancer research.

[81]  S. Jóźwiak,et al.  Tuberous sclerosis , 2008, The Lancet.

[82]  P. Houghton,et al.  Phase I study of everolimus in pediatric patients with refractory solid tumors. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[84]  D. Louis WHO classification of tumours of the central nervous system , 2007 .

[85]  D. Hargrave,et al.  Diffuse brainstem glioma in children: critical review of clinical trials. , 2006, The Lancet. Oncology.

[86]  E. Thiele,et al.  Subependymal giant cell tumors in tuberous sclerosis complex , 2004, Neurology.

[87]  G. Almouzni,et al.  Histone H3.1 and H3.3 Complexes Mediate Nucleosome Assembly Pathways Dependent or Independent of DNA Synthesis , 2004, Cell.

[88]  M. Prados,et al.  Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen , 1997, Journal of Neuro-Oncology.

[89]  Audrey E. Evans,et al.  The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: Results of a randomized trial , 1989, Journal of Neuro-Oncology.

[90]  H. Winn Youmans Neurological Surgery , 2003 .

[91]  Hitoshi Takahashi,et al.  Clinicopathological study of diffuse type brainstem gliomas: analysis of 40 autopsy cases. , 2002, Neurologia medico-chirurgica.

[92]  David J. Kwiatkowski,et al.  Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[93]  M. Cartmill,et al.  Diffuse brain stem glioma A review of stereotactic biopsies , 1999, Child's Nervous System.

[94]  M. Berger,et al.  Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group trial no. CCG-945. , 1998, Journal of neurosurgery.

[95]  M. Ewen,et al.  Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. , 1993, Genes & development.

[96]  W. Whisler,et al.  Youmans' Neurological Surgery: , 1990 .

[97]  J. Higginson,et al.  International Agency for Research on Cancer. , 1968, WHO chronicle.