Molecular diagnostics enables detection of actionable targets: the Pediatric Targeted Therapy 2.0 registry

Ecker, Jonas; Selt, Florian; Sturm, Dominik; Sill, Martin; Korshunov, Andrey; Hirsch, Steffen; Capper, David; Dikow, Nicola; Sutter, Christian; Müller, Carina; Sigaud, Romain; Eggert, Angelika; Simon, Thorsten; Niehues, Tim; Deimling, Andreas von; Pajtler, Kristian W.; Tilburg, Cornelis M. van; Jones, David; Sahm, Felix; Pfister, Stefan M.; Witt, Olaf; Milde, Till

doi:10.1016/j.ejca.2022.11.015

Cited by 11 publications

(4 citation statements)

References 25 publications

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“…We, therefore, recommend genetic counseling and testing for pediatric patients with H3 wild-type HGG (in addition to existing guidelines 33 , 34 ). The clinical information retrieved through national study headquarters indicates that most patients were not known or suspected to carry pathogenic constitutional variants, similarly to previous observations beyond patients with CNS tumors 35 , 36 . This highlights the importance of diligent consultation of patients and their families, considering that more than 95% of study participants and parents elected to be informed about constitutional pathogenic variants detected by NGS.…”

Section: Discussionsupporting

confidence: 67%

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Sturm

Capper

Andreiuolo

et al. 2023

Nat Med

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The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

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Section: Discussionsupporting

confidence: 67%

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Sturm

Capper

Andreiuolo

et al. 2023

Nat Med

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“…This study is one of the first with the largest patient cohort to report a comprehensive outcome analysis of PGT, evaluating both response rates and survival outcomes with extended follow-up for children on a precision medicine trial. The clinical uptake for those have received a PGT recommendation (43%) is, to our knowledge, the highest amongst pediatric precision oncology studies [2][3][4][5]8,14,15 .…”

Section: Discussionmentioning

confidence: 94%

Precision-guided treatment improves outcomes for children with high-risk cancers

Ziegler,

Lau,

Khuong-Quang

et al. 2023

Preprint

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Recent reports have shown that precision medicine can identify new treatment strategies for childhood cancer patients. However, it remains unclear which patients will benefit most from precision-guided treatment (PGT). Here we report 384 consecutive high-risk childhood cancer patients (with an expected cure rate of <30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Program PRISM trial. A total of 256 (67%) patients received PGT recommendations, of whom 110 (43%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% vs. 12%; P=0.049) or targeted agents not guided by molecular findings (26% vs. 5.2%; P=0.003). PGT based on Tier 1 evidence, PGT targeting fusions or commenced prior to disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers.

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“…Informed consent for sample collection, use of material and clinical data was obtained within the study S-304/2014 (V2/V3), approved by the institutional review board of the University of Heidelberg. The primary patient tumor material was molecularly analyzed (DNA-methylation and gene panel sequencing) within the PTT2.0 study [ 15 ] or the LOGGIC Core co-clinical biobank [ 16 ]. Methylation scores were obtained via the brain tumor classifiers (V11b4, 12.3 or 12.5) ( www.molecularneuropathology.org ).…”

Section: Methodsmentioning

confidence: 99%

Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow

Selt,

El Damaty,

Schuhmann

et al. 2023

J Neurooncol

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Purpose Although pediatric low-grade gliomas (pLGG) are the most common pediatric brain tumors, patient-derived cell lines reflecting pLGG biology in culture are scarce. This also applies to the most common pLGG subtype pilocytic astrocytoma (PA). Conventional cell culture approaches adapted from higher-grade tumors fail in PA due to oncogene-induced senescence (OIS) driving tumor cells into arrest. Here, we describe a PA modeling workflow using the Simian Virus large T antigen (SV40-TAg) to circumvent OIS. Methods 18 pLGG tissue samples (17 (94%) histological and/or molecular diagnosis PA) were mechanically dissociated. Tumor cell positive-selection using A2B5 was perfomed in 8/18 (44%) cases. All primary cell suspensions were seeded in Neural Stem Cell Medium (NSM) and Astrocyte Basal Medium (ABM). Resulting short-term cultures were infected with SV40-TAg lentivirus. Detection of tumor specific alterations (BRAF-duplication and BRAF V600E-mutation) by digital droplet PCR (ddPCR) at defined time points allowed for determination of tumor cell fraction (TCF) and evaluation of the workflow. DNA-methylation profiling and gene-panel sequencing were used for molecular profiling of primary samples. Results Primary cell suspensions had a mean TCF of 55% (+/− 23% (SD)). No sample in NSM (0/18) and ten samples in ABM (10/18) were successfully transduced. Three of these ten (30%) converted into long-term pLGG cell lines (TCF 100%), while TCF declined to 0% (outgrowth of microenvironmental cells) in 7/10 (70%) cultures. Young patient age was associated with successful model establishment. Conclusion A subset of primary PA cultures can be converted into long-term cell lines using SV40-TAg depending on sample intrinsic (patient age) and extrinsic workflow-related (e.g. type of medium, successful transduction) parameters. Careful monitoring of sample-intrinsic and extrinsic factors optimizes the process.

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Molecular diagnostics enables detection of actionable targets: the Pediatric Targeted Therapy 2.0 registry

Cited by 11 publications

References 25 publications

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Precision-guided treatment improves outcomes for children with high-risk cancers

Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow

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