Clinical and Genomic Characteristics of Adult Diffuse Midline Glioma

Abstract

Purpose: The treatment outcomes and genomic profiles of diffuse midline glioma (DMG) in adult patients are rarely characterized. We performed a retrospective study to evaluate the clinicogenomic profiles of adult patients with brain DMG.

Materials and methods: Patients aged ≥ 18 years diagnosed with brain DMG at Seoul National University Hospital were included. The clinicopathological parameters, treatment outcomes, survival, and genomic profiles using 82-gene targeted next-generation sequencing (NGS) were analyzed. The 6-month progression-free survival (PFS6) after radiotherapy and overall survival (OS) were evaluated.

Results: Thirty-three patients with H3-mutant brain DMG were identified. The median OS from diagnosis was 21.8 months (95% confidence interval [CI], 13.2 to not available [NA]) and involvement of the ponto-medullary area tended to have poor OS (median OS, 20.4 months [95% CI, 9.3 to NA] vs. 43.6 months [95% CI, 18.2 to NA]; p=0.07). Twenty-four patients (72.7%) received radiotherapy with or without temozolomide. The PFS6 rate was 83.3% (n=20). Patients without progression at 6 months showed significantly prolonged OS compared with those with progression at 6 months (median OS, 24.9 months [95% CI, 20.4 to NA] vs. 10.8 months [95% CI, 4.0 to NA]; p=0.02, respectively). Targeted NGS was performed in 13 patients with DMG, among whom nine (69.2%) harbored concurrent TP53 mutation. Two patients (DMG14 and DMG23) with PIK3CAR38S+E545K and KRASG12A mutations received matched therapies. Patient DMG14 received sirolimus with a PFS of 8.4 months.

Conclusion: PFS6 after radiotherapy was associated with prolonged survival in adult patients with DMG. Genome-based matched therapy may be an encouraging approach for progressive adult patients with DMG.

Keywords: Concurrent chemoradiotherapy; Diffuse midline glioma; Targeted sequencing.

Fig. 1

Genomic landscape of adult patients with DMG obtained by targeted NGS. The landscape plot shows the genomic landscape of adult patients with DMG obtained by targeted NGS. The annotations with corresponding colors are described at the bottom. At the top of the plot, the bar plot shows the PFS of CCRT with TMZ of each patient with a cross mark depicting events. The dashed line crosses y-axis at 6 months. Below the bar plot is a tile plot that depicts the clinical features of each patient. The numbers at the bottom of the plots are the index numbers of the patients. Paired NGS samples at the time of diagnosis and progression after CCRT with TMZ were obtained from patient DMG31 (samples DMG31 and DMG31-1). CCRT, concurrent chemoradiotherapy; DMG, diffuse midline glioma; GTR, gross total resection; MAPK, mitogen-activated protein kinase; NGS, next-generation sequencing; NTR, near-total resection; PFS, progression-free survival; PFS6, 6-month progression-free survival; PI3K, phosphatidylinositol-3 kinase; RTK, receptor tyrosine kinase; STR, subtotal resection; TMZ, temozolomide.

Fig. 2

Kaplan-Meier curves for the OS from diagnosis of all patients with DMG patients included in the study. (A) The Kaplan-Meier curve shows the overall survival of all patients with DMG. (B) The Kaplan-Meier curves show the overall survival of all patients with DMG according to ponto-medullary involvement. The blue line represents patients without ponto-medullary involvement; the red line represents patients with ponto-medullary involvement. The risk tables are below each plot, and p-values by the log-rank test are annotated in each plot. Censored data are depicted by vertical marks. DMG, diffuse midline glioma; OS, overall survival.

Fig. 3

Kaplan-Meier survival curves for the OS from diagnosis of patients according to PFS6 status from radiotherapy. The Kaplan-Meier curves show the OS from diagnosis of patients who received radiotherapy. The blue line represents patients without progression at 6 months after radiotherapy initiation; the red line represents patients whose diseases had progressed at 6 months. The risk tables are below each plot, and p-values by the log-rank test are annotated in each plot. Censored data are depicted by vertical marks. OS, overall survival; PFS6, 6-month progression-free survival.

Fig. 4

History and images of patient DMG14 with PIK3CA mutation. Integrative genomics viewer, and MRI images of patient DMG14 with PIK3CA mutation who received sirolimus. The numbers above the timeline show months from the initiation of surgery. CCRT, concurrent chemoradiotherapy; GTR, gross total resection; MRI, magnetic resonance imaging; RT, radiotherapy; TMZ, temozolomide.