jueves, 1 de noviembre de 2018

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

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. 2018 May 14; 33(5): 829–842.e5.
PMCID: PMC5956280
PMID: 29763623

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

Alan Mackay,1,2 Anna Burford,1,2 Valeria Molinari,1,2 David T.W. Jones,3,4 Elisa Izquierdo,1,2 Jurriaan Brouwer-Visser,6 Felice Giangaspero,7,8 Christine Haberler,9,10 Torsten Pietsch,11 Thomas S. Jacques,12,13 Dominique Figarella-Branger,14 Daniel Rodriguez,15 Paul S. Morgan,15 Pichai Raman,16,17 Angela J. Waanders,16,18 Adam C. Resnick,16,17,18 Maura Massimino,19 Maria Luisa Garrè,20 Helen Smith,21 David Capper,22,23,24 Stefan M. Pfister,3,4,5 Thomas Würdinger,25 Rachel Tam,26 Josep Garcia,21 Meghna Das Thakur,26 Gilles Vassal,27 Jacques Grill,27 Tim Jaspan,15 Pascale Varlet,28 and Chris Jones1,2,29,∗
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Summary

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.
Keywords: immune, CD8, MAPK, hypermutator, H3F3A, pediatric high-grade glioma

Significance

We validate in the prospective clinical trial setting the biological and clinical diversity of pediatric high-grade glioma previously described in large retrospective series, underpinned by detailed pathological and radiological analysis. Although adding bevacizumab (BEV) to standard temozolomide/radiotherapy did not improve survival across the whole cohort, we identify disease subgroups with MAPK activation to harbor an enhanced CD8+ T cell immune response, which may derive benefit from the addition of BEV. If confirmed in another study, this would represent a useful predictive biomarker for this regimen in these tumors, and points the way for therapeutic strategies for subgroups of children with high-grade glioma.

Introduction

High-grade gliomas (HGGs) in children, like their adult counterparts, continue to have a bleak prognosis, with a median overall survival (OS) of 9–15 months (, , ). Recent integrated molecular-profiling initiatives have shown that pediatric HGGs (pHGGs) are biologically distinct from their adult counterparts, with subgroups of the disease marked by recurrent mutations in genes encoding histone H3 variants having different age of incidence, anatomical location, clinical outcome, and a range of biological parameters (, , , , , , ). Histone wild-type (WT) tumors have widely differing mutational burdens, ranging from infant cases (<3 years) driven by single gene fusion events through to patients with biallelic mismatch repair deficiency harboring some of the highest mutational rates in human cancer (, , , ).
The rapid advances in our understanding of pHGGs have come predominantly from the accumulation of numerous disparate retrospective collections, a reflection of the rarity of the disease. Clinical trial cohorts with ancillary biomarker analyses have been relatively limited in their scope, and historically have focused on single-marker analyses. These include the Children's Oncology Group ACNS0126 (radiotherapy [RT]/temozolomide [TMZ]) () and ACNS0423 (RT/TMZ followed by TMZ and lomustine) () studies, which report on the frequency and clinical correlations of O6-methylguanine-DNA methyltransferase (MGMT) expression (ACNS0126) (, ), IDH1 mutation (ACNS0423) (), as well as phosphorylated Akt expression () and microsatellite instability (both) (). The CCG-945 study (“8 in 1” chemotherapy) () reported on the prognostic significance of p53 expression/mutation (), in addition to the presence/absence of 1p19q co-deletion ().
This last study () also highlighted the critical importance of pathological review in the diagnosis of pHGG, and subsequent interpretation of clinical trial results (, ), particularly in midline locations (). It has subsequently become clear that numerous histological subtypes of HGG can harbor distinct genetic drivers and have considerably better clinical outcomes, such as BRAF_V600E mutations in epithelioid glioblastoma (GBM), anaplastic ganglioglioma, and anaplastic pleomorphic xanthoastrocytoma (PXA) (); in the latter two categories, this mutation is also found in lower-grade entities lacking obvious anaplasia. Additional histone WT cases of otherwise uncontroversial HGGs have been found to be biologically and clinically more similar to several types of low-grade glioma (LGG) and PXA (), highlighting the importance of an integrated diagnosis combining molecular and histological features.
The HERBY trial (study BO25041; clinicaltrials.gov NCT01390948) was a phase II, open-label, randomized, multicenter, comparator study of the addition of the anti-angiogenic agent bevacizumab (BEV) to RT and TMZ in patients between the ages of 3 and 18 years with newly diagnosed non-brainstem HGG (). Central confirmation of HGG diagnosis was mandatory before randomization, followed by consensus review by five independent expert neuropathologists. Real-time panel radiological assessment was also incorporated. An exploratory endpoint of the study was to establish a biospecimen repository for correlative molecular profiling. In addition to its role in tumor angiogenesis, vascular endothelial growth factor (VEGF) restricts immune cell activity, and BEV has been demonstrated to facilitate recruitment of T cells to infiltrate tumors (), as well as increase the ratio of CD8+CD3+ T cells in adult GBM specimens (). We therefore also sought to explore the immune profile of cases within the HERBY cohort.

Results

The Translational Research Cohort Is Representative of the Whole Clinical Trial Population

The total HERBY cohort comprised 121 randomized patients at diagnosis (3–18 years) plus 3 infant cases (<3 years) at relapse. Of these, 113 patients consented to the translational research program (Table S1). Tumor tissue was collected from either resection (n = 93) or biopsy (n = 20), although 24 cases failed to provide sufficient quantity or quality of sample for molecular analysis. For the remaining 89 cases, material was available in the form of either fresh-frozen material (n = 36), formalin-fixed paraffin-embedded pathology specimens (n = 79), or both (n = 26). These were subjected to Sanger sequencing for H3F3A (n = 89), exome sequencing (n = 86), Illumina 450k methylation BeadChip profiling (n = 74), CD8 immunohistochemistry (n = 70), methylation-specific PCR for MGMT promoter methylation (n = 36), a capture-based sequencing panel for common fusion gene detection (n = 68), and RNA sequencing (RNA-seq) (n = 20) (Figure 1A).

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