Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Cassie Kline, Payal Jain, Lindsay Kilburn, Erin R Bonner, Nalin Gupta, John R Crawford, Anu Banerjee, Roger J Packer, Javier Villanueva-Meyer, Tracy Luks, Yalan Zhang, Madhuri Kambhampati, Jie Zhang, Sridevi Yadavilli, Bo Zhang, Krutika S Gaonkar, Jo Lynne Rokita, Adam Kraya, John Kuhn, Winnie Liang, Sara Byron, Michael Berens, Annette Molinaro, Michael Prados, Adam Resnick, Sebastian M Waszak, Javad Nazarian, Sabine Mueller

TLDR

  • PNOC003 is a study that looked at children and young adults with a type of brain tumor called diffuse intrinsic pontine glioma (DIPG). The study wanted to see if taking a specific type of medicine (called FDA-approved drugs) and doing a specific type of test (called circulating tumor DNA) could help predict how long these patients would live. The study also looked at the genetic makeup of the tumors and found that certain genetic changes were associated with worse outcomes. The study highlights the importance of doing a biopsy (a small sample of the tumor) before starting treatment to identify these genetic changes and make personalized treatment recommendations.

Abstract

PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Patients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.

Overview

  • PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
  • Patients were enrolled on the basis of imaging consistent with DIPG and biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN).
  • The primary objective of the study is to determine the clinical utility of upfront treatment-naïve biopsy in identifying clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.

Comparative Analysis & Findings

  • H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome.

Implications and Future Directions

  • The study highlights the importance of upfront treatment-naïve biopsy in identifying clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs. The findings suggest that H3K27M-mutant ctDNA, TP53 mutations, and genome instability are important prognostic biomarkers for H3K27-altered DIPGs. The study also demonstrates the utility of molecular tumor board recommendations in personalized treatment for DIPGs. Future research should focus on validating these findings in larger cohorts and exploring the potential of these biomarkers for predicting response to treatment and overall survival in DIPG patients.
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