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

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 CapperStefan M. Pfister, Thomas Würdinger, Rachel Tam, Josep Garcia, Meghna Das Thakur, Gilles Vassal, Jacques Grill, Tim Jaspan, Pascale Varlet, Chris Jones

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

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. In a pediatric high-grade non-brainstem glioma cohort, Mackay et al. show that hypermutator tumors and those resembling pleomorphic xanthoastrocytoma are highly infiltrated by CD8⁺ lymphocytes and benefit from the addition of bevacizumab, whereas the histone H3 subgroups are immune cold and have a poor outcome.

Original language	English
Pages (from-to)	829-842.e5
Journal	Cancer Cell
Volume	33
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2018.04.004
Publication status	Published - May 14 2018

Keywords

CD8
H3F3A
hypermutator
immune
MAPK
pediatric high-grade glioma

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccell.2018.04.004

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Mackay, A., Burford, A., Molinari, V., Jones, D. T. W., Izquierdo, E., Brouwer-Visser, J., Giangaspero, F., Haberler, C., Pietsch, T., Jacques, T. S., Figarella-Branger, D., Rodriguez, D., Morgan, P. S., Raman, P., Waanders, A. J., Resnick, A. C., Massimino, M., Garrè, M. L., Smith, H., ... Jones, C. (2018). Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell, 33(5), 829-842.e5. https://doi.org/10.1016/j.ccell.2018.04.004

Mackay, A, Burford, A, Molinari, V, Jones, DTW, Izquierdo, E, Brouwer-Visser, J, Giangaspero, F, Haberler, C, Pietsch, T, Jacques, TS, Figarella-Branger, D, Rodriguez, D, Morgan, PS, Raman, P, Waanders, AJ, Resnick, AC, Massimino, M, Garrè, ML, Smith, H, Capper, D, Pfister, SM, Würdinger, T, Tam, R, Garcia, J, Thakur, MD, Vassal, G, Grill, J, Jaspan, T, Varlet, P & Jones, C 2018, 'Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial', Cancer Cell, vol. 33, no. 5, pp. 829-842.e5. https://doi.org/10.1016/j.ccell.2018.04.004

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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. In a pediatric high-grade non-brainstem glioma cohort, Mackay et al. show that hypermutator tumors and those resembling pleomorphic xanthoastrocytoma are highly infiltrated by CD8+ lymphocytes and benefit from the addition of bevacizumab, whereas the histone H3 subgroups are immune cold and have a poor outcome.",

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AU - Mackay, Alan

AU - Burford, Anna

AU - Molinari, Valeria

AU - Jones, David T.W.

AU - Izquierdo, Elisa

AU - Brouwer-Visser, Jurriaan

AU - Giangaspero, Felice

AU - Haberler, Christine

AU - Pietsch, Torsten

AU - Jacques, Thomas S.

AU - Figarella-Branger, Dominique

AU - Rodriguez, Daniel

AU - Morgan, Paul S.

AU - Raman, Pichai

AU - Waanders, Angela J.

AU - Resnick, Adam C.

AU - Massimino, Maura

AU - Garrè, Maria Luisa

AU - Smith, Helen

AU - Capper, David

AU - Pfister, Stefan M.

AU - Würdinger, Thomas

AU - Tam, Rachel

AU - Garcia, Josep

AU - Thakur, Meghna Das

AU - Vassal, Gilles

AU - Grill, Jacques

AU - Jaspan, Tim

AU - Varlet, Pascale

AU - Jones, Chris

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

Abstract

Keywords

ASJC Scopus subject areas

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