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.

中文翻译：

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弥漫性内源性脑桥胶质瘤的前期生物学引导治疗：PNOC003 的治疗、分子和生物标志物结果

目的：PNOC003 是一项针对新诊断的弥漫性内质性脑桥胶质瘤 (DIPG) 的儿童和年轻人的多中心精准医学试验。患者和方法：患者（3-25 岁）根据与 DIPG 一致的影像学特征入组。收集活检组织进行全外显子组和 mRNA 测序。放射治疗 (RT) 后，根据分子肿瘤委员会的建议，为患者分配最多四种 FDA 批准的药物。纵向测量 H3K27M 突变体循环肿瘤 DNA (ctDNA)。使用全基因组测序和 DNA 甲基化分析对肿瘤组织和匹配的原代细胞系进行了表征。如果适用，结果会在儿童脑肿瘤网络 (CBTN) 的独立队列中得到验证。结果：在 38 名入组患者中，28 名患者（中位年龄 6 年，10 名女性）由分子肿瘤委员会审查。其中 19 人遵循了治疗建议。中位总生存期 (OS) 为 13.1 个月 [95% 置信区间 (CI)，11.2–18.4]，遵循建议的患者与未遵循建议的患者之间没有差异。60% 的测试病例在基线时检测到 H3K27M 突变体 ctDNA，并且与 RT 反应和生存相关。建立了 11 种细胞系，显示原发肿瘤中关键体细胞驱动基因改变的 100% 保真度。在 H3K27 改变的 DIPG 中，TP53 突变与较差的 OS 相关（TP53mut 11.1 mo；95% CI，8.7–14；TP53wt 13.3 mo；95% CI，11.8–NA；P = 3.4e−2）、基因组不稳定（P = 3.1e−3) 和 RT 电阻 (P = 6.4e−4)。CBTN 队列证实了 TP53 突变状态、基因组不稳定性和临床结果之间的关联。结论：