Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience

Pfaff, Elke; Damaty, Ahmed El; Balasubramanian, Gnana Prakash; Blattner-Johnson, Mirjam; Worst, Barbara C.; Stark, Sebastian; Witt, Hendrik; Pajtler, Kristian W.; Tilburg, Cornelis M. van; Witt, Ruth; Milde, Till; Jakobs, Martin; Fiesel, Petra; Frühwald, Michael C.; Driever, Pablo Hernáiz; Thomale, Ulrich W.; Schuhmann, Martin U.; Metzler, Markus; Bochennek, Konrad; Simon, Thorsten; Dürken, Matthias; Karremann, Michael; Knirsch, Stephanie; Ebinger, Martin; Bueren, André O. von; Pietsch, Torsten; Herold‐Mende, Christel; Reuß, David; Kiening, Karl; Lichter, Peter; Eggert, Angelika; Kramm, Christof M.; Pfister, Stefan M.; Jones, David; Bächli, Heidi; Witt, Olaf

doi:10.1016/j.ejca.2019.03.019

Cited by 56 publications

(37 citation statements)

References 30 publications

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“…In contrast to a recently published study in DIPG (30) our study cohort was restricted to H3K27M glioma (8/10 H3F3A, 2/10 HIST1H3B), also including a thalamic and a spinal case. Comparable to previous studies, 50% of tumors harbored a mutation in TP53 (29,30). By comprehensive molecular profiling, we detected targetable alterations in 90% (9/10) of the tumors, which is comparable to previous results from the INFORM study.…”

Section: Discussionsupporting

confidence: 86%

“…Recent high-throughput studies led to the conclusion that despite shared H3K27M mutation, these entity comprises multiple different molecular subgroups (8,19). Being controversially discussed some years ago, biopsy of DMGs has been shown to be safe, which we could also confirm in our case series (29,30). Hence, personalized treatment approaches based on comprehensive molecular profiling are considered a particularly promising treatment approach (27).…”

Section: Discussionsupporting

confidence: 70%

“…Several previous studies assessed the potential of molecular approaches in H3K27M glioma (4,8,18,29); however, data on the clinical impact is limited (30). In contrast to a recently published study in DIPG (30) our study cohort was restricted to H3K27M glioma (8/10 H3F3A, 2/10 HIST1H3B), also including a thalamic and a spinal case.…”

Section: Discussionmentioning

confidence: 99%

“…As pediatric tumors harbor much less mutations than do adult cancers, precision targeted therapy is likely to be more effective against these tumors than standard population-based approaches (27,28). This has been corroborated by a recent prospective analysis confirming the presence of potentially targetable alterations in 76% of H3K27M-positive pontine gliomas (29). Additionally, a recently reported pilot study for DIPG has also reported feasibility of personalized treatment recommendations (30).…”

Section: Introductionmentioning

confidence: 85%

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Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

et al. 2020

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Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either Gojo et al.Personalized Treatment of H3K27M Glioma miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

See 2 more Smart Citations

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

et al. 2020

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“…Several recent observational studies have suggested that brainstem biopsy in pediatric patients is relatively safe, with a metanalysis of 735 patients demonstrating a weighted average proportion of 6.7% for overall morbidity, 0.6% for permanent morbidity, and 0.6% for mortality [31]. A prospective phase II clinical trial in which biopsy of presumed DIPG was mandated reported no biopsy-attributed deaths, and only one patient of 50 (2%) experienced a persistent neurologic deficit after biopsy [32], with similar outcomes being observed in two recent prospective studies mandating biopsy [25,33]. The risks of biopsy may vary by lesion location, among other host, tumor, and technical factors, and the safety profile of biopsy for patients with aDIPG has not been specifically reported.…”

Section: Discussionmentioning

confidence: 79%

Clinical, imaging, and molecular analysis of pediatric pontine tumors lacking characteristic imaging features of DIPG

Chiang

Diaz

Makepeace

et al. 2020

acta neuropathol commun

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Diffuse intrinsic pontine glioma (DIPG) is most commonly diagnosed based on imaging criteria, with biopsy often reserved for pontine tumors with imaging features not typical for DIPG (atypical DIPG, 'aDIPG'). The histopathologic and molecular spectra of the clinical entity aDIPG remain to be studied systematically. In this study, thirty-three patients with newly diagnosed pontine-centered tumors with imaging inconsistent with DIPG for whom a pathologic diagnosis was subsequently obtained were included. Neoplasms were characterized by routine histology, immunohistochemistry, interphase fluorescence in situ hybridization, Sanger and next-generation DNA/ RNA sequencing, and genome-wide DNA methylome profiling. Clinicopathologic features and survival outcomes were analyzed and compared to those of a contemporary cohort with imaging features consistent with DIPG (typical DIPG, 'tDIPG'). Blinded retrospective neuroimaging review assessed the consistency of the initial imagingbased diagnosis and correlation with histopathology. WHO grade II-IV infiltrating gliomas were observed in 54.6% of the cases; the remaining were low-grade gliomas/glioneuronal tumors or CNS embryonal tumors. Histone H3 K27M mutation, identified in 36% of the cases, was the major prognostic determinant. H3 K27M-mutant aDIPG and H3 K27M-mutant tDIPG had similar methylome profiles but clustered separately from diffuse midline gliomas of the diencephalon and spinal cord. In the aDIPG cohort, clinicoradiographic features did not differ by H3 status, yet significant differences in clinical and imaging features were observed between aDIPG without H3 K27M mutation and tDIPG. Neuroimaging review revealed discordance between the classification of aDIPG and tDIPG and did not correlate with the histology of glial/glioneuronal tumors or tumor grade. One patient (3.1%) developed persistent neurologic deficits after surgery; there were no surgery-related deaths. Our study demonstrates that surgical sampling of aDIPG is well-tolerated and provides significant diagnostic, therapeutic, and prognostic implications, and that neuroimaging alone is insufficient to distinguish aDIPG from tDIPG. H3 K27M-mutant aDIPG is epigenetically and clinically similar to H3 K27M-mutant tDIPG.

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The Promise and the Reality of Genomics to Guide Precision Medicine in Pediatric Oncology: The Decade Ahead

Evans

Pui

Yang

2019

Clin Pharma and Therapeutics

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Much has been written about the promise of "precision medicine", especially in oncology, where somatic mutations can influence the response of cancer cells to "targeted therapy". There have been successful examples of targeted therapy improving the outcome of some childhood cancers, such as the addition of an ABL class tyrosine kinase inhibitor to conventional chemotherapy substantially improving the cure rate for patients with BCR-ABL1 positive acute lymphoblastic leukemia. Although there are other mutations serving as putative targets in various childhood leukemias and solid tumors, effective targeted therapy has yet to be established for them in prospective clinical trials. There are also uncertainties about which "targeted therapy" to use when patients have multiple targetable genomic lesions in their cancer cells, given the paucity of data upon which to develop evidence-based guidelines for selecting and integrating targeted agents for individual patients. There are also multiple examples of inherited germline variants for which evidence-based guidelines have been developed by CPIC to guide the selection and dosing of medications in children with cancer. Clinical pharmacology is poised to play a critical role in both the discovery and development of new targeted anticancer agents and their evidence-based translation into better treatment for children with cancer. To embrace these challenges and opportunities of "precision medicine", clinical and basic pharmacologists must expand the depth of our science and the bandwidth of our translational capacity, if we are to optimize precision medicine and advance the treatment of cancer in children and adults.

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Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience

Cited by 56 publications

References 30 publications

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

Clinical, imaging, and molecular analysis of pediatric pontine tumors lacking characteristic imaging features of DIPG

The Promise and the Reality of Genomics to Guide Precision Medicine in Pediatric Oncology: The Decade Ahead

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