Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

Bouffet, Éric; Larouche, Valérie; Campbell, Brittany; Merico, Daniele; Borja, Richard de; Aronson, Melyssa; Durno, Carol; Krueger, Joerg; Cabric, Vanja; Ramaswamy, Vijay; Zhukova, Nataliya; Mason, Gary; Farah, Roula; Afzal, Samina; Yalon, Michal; Rechavi, Gideon; Magimairajan, Vanan; Walsh, Michael F.; Constantini, Shlomi; Dvir, Rina; Elhasid, Ronit; Reddy, Alyssa; Osborn, Michael; Sullivan, Michael J.; Hansford, Jordan R.; Dodgshun, Andrew; Klauber-DeMore, Nancy; Peterson, Lindsay L.; Patel, Sunil; Lindhorst, Scott; Atkinson, Jeffrey; Cohen, Zane; Laframboise, Rachel; Dirks, Peter B.; Taylor, Michael D.; Malkin, David; Albrecht, Steffen; Dudley, Roy; Jabado, Nada; Hawkins, Cynthia; Shlien, Adam; Tabori, Uri

doi:10.1200/jco.2016.66.6552

Cited by 708 publications

(603 citation statements)

References 28 publications

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“…1). Whether these highly mutated tumours respond to immune checkpoint inhibitors, as described for paediatric glioblastoma, should be of clinical interest 13 .…”

Section: Mutation Frequencies Across Cancer Typesmentioning

confidence: 99%

“…3b, c). Both groups are clinically relevant: patients with constitutional MMR deficiency could be candidates for immune checkpoint inhibition 13 (Figs 1, 3b, c). Carriers of TP53 germline mutations (Li-Fraumeni syndrome), here most common in adrenocortical carcinomas, hypodiploid B-ALL, SHH medulloblastomas, and K27wt high-grade gliomas, are at a 50% risk for early-onset cancer compared to 1% overall, and are susceptible to treatmentinduced secondary oncogenesis 2,[20][21][22] (Fig.…”

Section: Germline Variants In Cancer Predisposition Genesmentioning

confidence: 99%

“…1). Whether these highly mutated tumours respond to immune checkpoint inhibitors, as described for paediatric glioblastoma, should be of clinical interest 13 .As in previous reports, the somatic mutation burden increased with patient age (R = 0.39, P = 2.9 × 10 −6 ), except in Burkitt's lymphoma (immunoglobulin hypermutation) and tumours with 'kataegis' events of localized hypermutation at double-stranded breakpoints 14,15 (Extended Data Fig. 1e, f).…”

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confidence: 99%

“…It also highlights the need for personalized profiling for each patient, both to increase diagnostic accuracy and to exploit the potential for potentially more effective and less harmful precision therapies. This may also transcend the direct targeting of genes or pathways, for example, through immune checkpoint inhibition in hypermutated tumours 13 or through PARP inhibition in genomically unstable ('BRCAness') tumours 48 . It is hoped that ongoing personalized medicine approaches for patients at relapse will give initial information on the use and effectiveness of such targeted drugs (for example, in the clinical trials pedMATCH-NCT03155620; eSMART-NCT02813135; INFORM 19 ).…”

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confidence: 99%

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The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

1,108

1,156

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The landscape of genomic alterations across childhood cancers a list of authors and affiliations appears at the end of the paper. OPENPan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.Cure rates for childhood cancers have increased to about 80% in recent decades, but cancer is still the leading cause of death by disease in the developed world among children over one year of age 1,2 . Furthermore, many children who survive cancer suffer from long-term sequelae of surgery, cytotoxic chemotherapy, and radiotherapy, including mental disabilities, organ toxicities, and secondary cancers 3 . A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets. The compendium of genetic alterations presented here is available to the scientific community at http://www.pedpancan.com.This integrative analysis includes 24 types of cancer and covers all major childhood cancer entities, many of which occur exclusively in children 8 (Fig. 1, Supplementary Table 1). Ninety-five per cent of the patients in this study were diagnosed during childhood or adolescence (aged 18 years or younger) and 5% as young adults (up to 25 years) (Extended Data ...

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“…1). Whether these highly mutated tumours respond to immune checkpoint inhibitors, as described for paediatric glioblastoma, should be of clinical interest 13 .…”

Section: Mutation Frequencies Across Cancer Typesmentioning

confidence: 99%

Section: Germline Variants In Cancer Predisposition Genesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

1,108

1,156

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show abstract

“…*P < 0.05, **P < 0.01, ***P < 0.0001, and NS, P > 0.05. Recent studies have demonstrated that mutation load levels within tumors such as GBMs are associated with response to immunotherapy (55,56). As the decreased cytotoxic T lymphocyte (CTL) signature in IDH-MUT compared with IDH-WT cases could be due to differences in mutation load, we compared the mutation load levels in TCGA data.…”

Section: Discussionmentioning

confidence: 99%

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

Kohanbash¹,

Carrera²,

Shrivastav³

et al. 2017

Journal of Clinical Investigation

326

277

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Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

et al. 2019

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IMPORTANCE Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-totreat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. OBJECTIVE To assess the feasibility of identifying potentially actionable mutations using nextgeneration sequencing-based assays in a clinically relevant time frame. DESIGN, SETTING, AND PARTICIPANTS This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. MAIN OUTCOMES AND MEASURES Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. RESULTS A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. CONCLUSIONS AND RELEVANCE Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, (continued) Key Points Question Can genome sequencing facilitate the molecular profiling of the patient's tumor to identify actionable and targetable alterations? Findings In this diagnostic study of 62 consecutive pediatric patients with hard-to-treat cancer who were enrolled in the TRICEPS study, incorporating multimodal genomic sequencing, including RNA sequencing, into the management of refractory or relapsed childhood and adolescent cancers identified potentially actionable alterations in 54 (87%)...

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Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

Abstract: This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

Cited by 708 publications

References 28 publications

The landscape of genomic alterations across childhood cancers

The landscape of genomic alterations across childhood cancers

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

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