Upfront biology-guided therapy in diffuse intrinsic pontine glioma: therapeutic, molecular, and biomarker outcomes from PNOC003
Clinical cancer research : an official journal of the American Association for Cancer Research
BACKGROUND: PNOC003 is a multi-center precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). METHODS: Patients (3-25 years) were enrolled based on imaging consistent with DIPG. Biopsy tissue was collected for whole exome and mRNA sequencing. After radiation therapy (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 mo (95% 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 a negative association between TP53 status and clinical outcome. CONCLUSION: Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.
Kline, Cassie; Jain, Payal; Kilburn, Lindsay; Bonner, Erin R.; Gupta, Nalin; Crawford, John R.; Banerjee, Anu; Packer, Roger J.; Villanueva-Meyer, Javier; Luks, Tracy; Zhang, Yalan; Kambhampati, Madhuri; Zhang, Jie; Yadavilli, Sridevi; Zhang, Bo; Gaonkar, Krutika S.; Rokita, Jo Lynne; Kraya, Adam; Kuhn, John; Liang, Winnie; Byron, Sara; Berens, Michael; Molinaro, Annette; Prados, Michael; Resnick, Adam; Waszak, Sebastian M.; Nazarian, Javad; and Mueller, Sabine, "Upfront biology-guided therapy in diffuse intrinsic pontine glioma: therapeutic, molecular, and biomarker outcomes from PNOC003" (2022). GW Authored Works. Paper 1281.