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

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.

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

“…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).…”

“…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). Although multiple interventional molecular matching studies are ongoing (NCT01182350, NCT02233049), evidence for the clinical benefit of this approach in H3K27M glioma is still lacking.…”

“…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.…”

Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

“…For example, integration of international pHGG genomic datasets in PedcBioPortal from the CBTTC (this study), the Herby Trial, Pacific Neuro-Oncology (PNOC) 003 clinical trial and International HGG consortium results in over 1500 cases of pHGG and diffuse intrinsic pontine glioma (DIPG). 1,28,29 These datasets are expected to increase, lending statistical power to analysis of subsets of pHGG to advance discoveries and collaborations. For example, the second release of data for the CBTTC/PBTA is expected in 2019 and will include additional paired diagnosis and relapse specimens.…”

PhISCS-BnB: A Fast Branch and Bound Algorithm for the Perfect Tumor Phylogeny Reconstruction Problem

“…Better understanding of SCS data may lead to better treatments or better strategies for drug develop-331 331 ment. In current treatment strategies, mutation sequencing data are presented to tumor boards to decide 332 332 the course of treatment (Mueller et al, 2019). In that clinical context, the rapid availability of phylogenetic problems.…”