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

Alan Mackay; Anna Burford; Valeria Molinari; David T W Jones; Elisa Izquierdo; Jurriaan Brouwer-Visser; Felice Giangaspero; Christine Haberler; Torsten Pietsch; Thomas S Jacques; Dominique Figarella-Branger; Daniel Rodriguez; Paul S Morgan; Pichai Raman; Angela J Waanders; Adam C Resnick; Maura Massimino; Maria Luisa Garrè; Helen Smith; David Capper; Stefan M Pfister; Thomas Würdinger; Rachel Tam; Josep Garcia; Meghna Das Thakur; Gilles Vassal; Jacques Grill; Tim Jaspan; Pascale Varlet; Chris Jones

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

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

Authors

Alan Mackay¹, Anna Burford¹, Valeria Molinari¹, David T W Jones², Elisa Izquierdo¹, Jurriaan Brouwer-Visser³, Felice Giangaspero⁴, Christine Haberler⁵, Torsten Pietsch⁶, Thomas S Jacques⁷, Dominique Figarella-Branger⁸, Daniel Rodriguez⁹, Paul S Morgan⁹, Pichai Raman¹⁰, Angela J Waanders¹¹, Adam C Resnick¹², Maura Massimino¹³, Maria Luisa Garrè¹⁴, Helen Smith¹⁵, David Capper¹⁶, Stefan M Pfister¹⁷, Thomas Würdinger¹⁸, Rachel Tam¹⁹, Josep Garcia¹⁵, Meghna Das Thakur¹⁹, Gilles Vassal²⁰, Jacques Grill²⁰, Tim Jaspan⁹, Pascale Varlet²¹, Chris Jones²²

Affiliations

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.

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Bevacizumab / therapeutic use*
CD8-Positive T-Lymphocytes
Chemoradiotherapy / methods*
Child
Child, Preschool
DNA Polymerase III / genetics
Female
Glioma / genetics
Glioma / immunology
Glioma / pathology
Glioma / therapy*
Humans
Male
Mutation*
Neoplasm Grading
Neurofibromin 1 / genetics
Proto-Oncogene Proteins B-raf / genetics
Survival Analysis
Temozolomide / therapeutic use*

Substances

Neurofibromin 1
Bevacizumab
BRAF protein, human
Proto-Oncogene Proteins B-raf
DNA Polymerase III
Temozolomide

Associated data

ClinicalTrials.gov/NCT01390948

Grants and funding

23536/CRUK_/Cancer Research UK/United Kingdom