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. 2025 May 7;7(1):vdaf092.
doi: 10.1093/noajnl/vdaf092. eCollection 2025 Jan-Dec.

Identifying targetable alterations predictive of distant progression in glioblastoma patients undergoing standard therapy

Shivani Chiranth  1 , Vincent Fougner  1   2 , Ib Jarle Christensen  1 , Anouk Kirsten Trip  1   3 , Terkel Christiansen  1   2 , Dorte Schou Nørøxe  1   2 , Christina Westmose Yde  4 , Anne Kiil Berthelsen  2 , Benedikte Hasselbalch  1   2 , Ulrik Lassen  1   2 , Hans Skovgaard Poulsen  1 , Thomas Urup  1   2
Affiliations

Identifying targetable alterations predictive of distant progression in glioblastoma patients undergoing standard therapy

Shivani Chiranth et al. Neurooncol Adv. .

Abstract

Background: Infiltrative growth is a hallmark of glioblastoma (GBM) and is a major factor in therapeutic failure. Distant progression is a surrogate marker for infiltrative growth and genetic variants predictive of distant progression may serve as novel treatment targets. The aim was to identify clinical, molecular, radiographic, and genetic factors associated with distant progression in GBM patients.

Methods: From our prospective database, all consecutive GBM IDH wild type patients receiving standard therapy (Stupp regimen) from 2016 to 2021 at Rigshospitalet (Denmark) were included. Distant progression was defined as a new contrast-enhancing lesion > 2 cm from the initial lesion. Clinical, molecular, radiographic, and genomic covariates were assessed for association with time to distant progression using Cox analysis.

Results: This single-center study included 353 patients, of whom 303 patients had radiographic progression. Distant progression was found in 66 patients (22%) and was associated with poor post-progression survival (P < .001). Unmethylated MGMT (hazard ratio [HR]: 2.54, 95% confidence interval [CI]: 1.62-3.97, P < .001), and multicentric disease at diagnosis (HR: 2.32, 95% CI: 1.28-4.20, P = .005) were associated with a shorter time to distant progression. In patients with a genomic tumor profile (n = 204), the NF1 gene alteration was identified as an independent predictor of distant progression (HR: 3.48, 95% CI: 1.48-8.21, P = .004) and poor survival.

Conclusion: Distant progression is an aggressive progression pattern associated with a poor prognosis. Unmethylated MGMT, multicentric disease, and NF1 alteration independently predict distant progression. NF1 alteration may serve as a predictive biomarker for targeted treatment.

Keywords: IDHwt glioblastoma; distant progression; glioma migration; invasion; progression pattern.

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Conflict of interest statement

Benedikte Hasselbalch: Advisory board member at Servier Nordics. The other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Kaplan–Meier curve showing the association between progression pattern and post-progression survival. The median post-progression survival for local progression and distant progression is shown.
Figure 2.
Figure 2.
The 4 common glioblastoma signaling pathways and candidate genetic alterations belonging to them. The frequency of alterations identified in analyzed samples is also shown as a percentage.
Figure 3.
Figure 3.
(A) Kaplan–Meier curve showing the association between progression-free survival and NF1 gene status. (B) Kaplan–Meier curve showing the association between overall survival and NF1 gene status. The median progression-free survival and overall survival for both groups are shown. In multivariate analysis adjusted for known prognostic factors such as, age, ECOG performance status, multicentric disease, corticosteroid use, resection versus biopsy and, MGMT status, loss-of-function NF1 alteration remained independently associated with a poor OS (hazard ratio: 2.0, 95% confidence interval): 1.2–3.3, P = .008).
See this image and copyright information in PMC

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