AI Article Synopsis
- PNOC003 is a multicenter trial focusing on personalized treatment for children and young adults diagnosed with diffuse intrinsic pontine glioma (DIPG), utilizing various molecular analyses and FDA-approved drugs after radiotherapy.
- Of the 38 enrolled patients, 28 were evaluated, with 19 following the recommended treatment; overall survival for all patients was an average of 13.1 months, with factors like TP53 mutations impacting survival rates.
- The study highlights the importance of upfront biopsy for understanding molecular alterations and prognostic markers in patients with H3K27-altered DIPGs, providing valuable insights for future treatments.
Article Abstract
Purpose: PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
Patients And Methods: 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).
Results: 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.
Conclusions: Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475246 | PMC |
| http://dx.doi.org/10.1158/1078-0432.CCR-22-0803 | DOI Listing |
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