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. 2025 Jul 2;15(7):713.
doi: 10.3390/brainsci15070713.

Biomolecular Predictors of Recurrence Patterns and Survival in IDH-Wild-Type Glioblastoma: A Retrospective Analysis of Patients Treated with Radiotherapy and Temozolomide

Paolo Tini  1 , Flavio Donnini  1 , Francesco Marampon  2 , Marta Vannini  1 , Tommaso Carfagno  1 , Pierpaolo Pastina  1 , Giovanni Rubino  1 , Salvatore Chibbaro  3 , Alfonso Cerase  4 , Giulio Bagnacci  5 , Armando Perrella  5 , Maria Antonietta Mazzei  5 , Alessandra Pascucci  6 , Vincenzo D'Alonzo  6 , Anna Maria Di Giacomo  6 , Giuseppe Minniti  2   7
Affiliations

Biomolecular Predictors of Recurrence Patterns and Survival in IDH-Wild-Type Glioblastoma: A Retrospective Analysis of Patients Treated with Radiotherapy and Temozolomide

Paolo Tini et al. Brain Sci. .

Abstract

Background and aim: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with poor prognosis despite maximal surgical resection, radiotherapy (RT), and temozolomide (TMZ) per the Stupp protocol. IDH-wild-type GBM, the predominant molecular subtype, frequently harbors EGFR amplification and is resistant to therapy, while MGMT promoter methylation predicts improved TMZ response. This study aimed to assess the prognostic impact of EGFR and MGMT status on survival and recurrence patterns in IDH-wild-type GBM.

Materials and methods: We retrospectively analyzed 218 patients with IDH-wild-type GBM treated at the Azienda Ospedaliero-Universitaria Senese (2016-2024). All patients underwent maximal safe surgical resection whenever feasible. The cohort includes patients who received gross total resection (GTR), subtotal resection (STR), or biopsy only, depending on tumor location and clinical condition, followed by intensity-modulated RT (59.4-60 Gy) with concurrent and adjuvant TMZ. EGFR amplification was assessed via FISH/NGS and immunohistochemistry; MGMT promoter methylation was determined using methylation-specific PCR. Progression-free survival (PFS), overall survival (OS), and recurrence patterns (in-field, marginal, out-field) were evaluated using Kaplan-Meier, Cox regression, and logistic regression analyses.

Results: Among patients (64.7% male; mean age 61.8), 58.7% had EGFR amplification and 49.1% showed MGMT methylation. Median OS and PFS were 14 and 8 months, respectively. EGFR non-amplified/MGMT methylated tumors had the best outcomes (OS: 22.0 months, PFS: 10.5 months), while EGFR-amplified/MGMT unmethylated tumors fared worst (OS: 10.0 months, PFS: 5.0 months; p < 0.001). MGMT methylation was an independent positive prognostic factor (HR: 0.48, p < 0.001), while EGFR amplification predicted worse survival (HR: 1.57, p = 0.02) and higher marginal recurrence (OR: 2.42, p = 0.01).

Conclusions: EGFR amplification and MGMT methylation significantly influence survival and recurrence dynamics in IDH-wild-type GBM. Incorporating these biomarkers into treatment planning may enable tailored therapeutic strategies, potentially improving outcomes in this challenging disease. Prospective studies are needed to validate biomolecularly guided management approaches.

Keywords: EGFR; MGMT; glioblastoma; pattern of recurrence; radiotherapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pattern of relapse classification. Recurrence patterns were evaluated by co-registering follow-up MRI scans with RT treatment plans using RayStation® software (RaySearch Laboratories AB, Stockholm, Sweden) and were categorized based on spatial distribution in relation to the 95% isodose line. Spatial recurrence: (A) in-field; (B) marginal; (C) Out-field. Green: PTV; Red: RELAPSE.
Figure 2
Figure 2
Kaplan–Meier curves for progression-free survival (PFS) across EGFR/MGMT molecular subgroups. Progression-free survival curves stratified by combined EGFR amplification (amplified vs. non-amplified) and MGMT promoter methylation (methylated vs. unmethylated) status. log-rank test: p < 0.001.
Figure 3
Figure 3
Kaplan–Meier curves for overall survival (OS) across EGFR/MGMT subgroups. Overall survival curves stratified by combined EGFR amplification (amplified vs. non-amplified) and MGMT promoter methylation (methylated vs. unmethylated) status. Log-rank test: p < 0.001.
See this image and copyright information in PMC

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