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Int J Cancer. 2019 Mar 12. doi: 10.1002/ijc.32258. [Epub ahead of print]

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

Author information

1
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
2
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
3
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
4
Center for Data-Driven Discovery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5
Translational Genomic Research Institute (TGEN), Phoenix, AZ, USA.
6
Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC, USA.
7
Brain Tumor Institute, Children's National Health System, Washington, DC, USA.
8
Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
9
Division of Neurosurgery, Children's National Health System, Washington, DC, USA.
10
University of California San Diego, San Diego, CA, USA.
11
Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR, USA.
12
Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
13
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
14
Children's Brain Tumor Tissue Consortium, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
15
College of Pharmacy, University of Texas Health Science Center, San Antonio, TX, USA.
16
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Abstract

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.

KEYWORDS:

circulating tumor DNA; diffuse intrinsic pontine glioma; genomics-guided clinical trial; next generation sequencing; precision medicine

PMID:
30861105
DOI:
10.1002/ijc.32258

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