Format

Send to

Choose Destination
Clin Cancer Res. 2018 Dec 1;24(23):5850-5859. doi: 10.1158/1078-0432.CCR-18-1345. Epub 2018 Oct 15.

Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy.

Author information

1
Rese arch Center for Genetic Medicine, Children's National Health System, Washington, D.C.
2
Institute for Biomedical Sciences, George Washington University School of Medicine and Health Sciences, Washington, D.C.
3
Center for Cancer and Blood Disorders, Children's National Health System, Washington D.C.
4
Brain Tumor Institute, Children's National Health System, Washington, D.C.
5
Departments of Neurology, Pediatrics and Neurosurgery, University of California, San Francisco School of Medicine, San Francisco, California.
6
Division of Neurosurgery, Children's National Health System, Washington, D.C.
7
Department of Neurological Surgery and Pediatrics, University of California San Francisco, San Francisco, California.
8
Pediatric Hematology-Oncology and Neurology, UCSF Benioff Children's Hospital, San Francisco, California.
9
Department of Neurosciences, UC San Diego School of Medicine, La Jolla, California.
10
National Cancer Institute, NIH, Bethesda, Maryland.
11
Department of Radiology, University of California, San Francisco School of Medicine, San Francisco, California.
12
Translational Genomics Research Institute, Phoenix, Arizona.
13
Center for Data-Driven Discovery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
14
Rese arch Center for Genetic Medicine, Children's National Health System, Washington, D.C. jnazarian@childrensnational.org.
15
Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C.

Abstract

PURPOSE:

Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy.

EXPERIMENTAL DESIGN:

We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data.

RESULTS:

H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients.

CONCLUSIONS:

Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center