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Cancer Cell. 2018 May 14;33(5):829-842.e5. doi: 10.1016/j.ccell.2018.04.004.

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.

Author information

1
Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK.
2
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Roche Innovation Center, New York, NY, USA.
4
Department of Radiology, Oncology and Anatomic-Pathology Sciences, Sapienza University, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy.
5
Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
6
DGNN Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
7
UCL Great Ormond Street Institute of Child Health, London, UK; Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
8
Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, Marseille, France.
9
Nottingham University Hospitals, Nottingham, UK.
10
The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11
The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
12
The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
13
Pediatric Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.
14
Centro di Neuro-Oncologia, Istituto Giannina Gaslini, Genoa, Italy.
15
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
16
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Institute of Neuropathology, Berlin, Germany; Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
17
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
18
Department of Neurosurgery, Brain Tumor Center Amsterdam, VU Medical Center, Amsterdam, the Netherlands.
19
Genentech, South San Francisco, CA, USA.
20
Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France.
21
Sainte-Anne Hospital, Paris-Descartes University, Paris, France.
22
Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK. Electronic address: chris.jones@icr.ac.uk.

Abstract

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01390948.

KEYWORDS:

CD8; H3F3A; MAPK; hypermutator; immune; pediatric high-grade glioma

PMID:
29763623
PMCID:
PMC5956280
DOI:
10.1016/j.ccell.2018.04.004
[Indexed for MEDLINE]
Free PMC Article

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