Purpose: Clinicians recognise significant inter-patient variability in tumour response to radiotherapy, even within the same tumour type. Glioblastoma (GBM) is relatively radioresistant and demonstrates heterogeneous treatment responses despite standardised therapy. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) assessment of intracellular manganese (Mn) has previously been associated with radiosensitivity. This study aimed to identify a predictive biomarker of radioresistance in GBM.
Methods and Materials: Protocols [2024/ETH01069; 2025/PID00420] analysed data from up to 60 GBM patients across two institutions using strict eligibility criteria. All patients were deceased, underwent >90% resection, had high Karnofsky performance scores, IDH-negative tumours, and received standard Stupp treatment (60 Gy radiotherapy in 30 fractions with temozolomide). Histopathology specimens were analysed using LA-ICP-MS to quantify intra-tumoural Mn, iron (Fe), copper (Cu), and zinc (Zn). Associations between metal concentrations, overall survival (OS), and age were assessed using linear regression, Kaplan-Meier analysis, and Cox regression. Established molecular prognostic markers were evaluated. To assess measurement reliability, select tumours were analysed using formalin-fixed paraffin-embedded (FFPE) tissue and compared with matched fresh frozen biobank specimens.
Results: Of the metals analysed, only Mn concentration was significantly associated with OS. Preliminary analysis demonstrated median survival of 21.7 months in patients with low Mn scores (≤0.3279 ppm), compared with 10.7 months in those with higher Mn scores (>0.3279 ppm). MGMT promoter methylation was associated with improved survival and correlated with intra-tumoural Mn (p=0.05). Mn measurements demonstrated strong concordance between FFPE and fresh frozen tissue. Patients requiring repeat surgery for recurrence exhibited higher Mn scores.
Conclusion: An intra-tumoural Mn threshold has been identified in GBM and may provide a clinically useful biomarker to guide treatment decisions. FFPE tissue appears equivalent to fresh frozen tissue for analysis, facilitating broader implementation. Analysis continues and more data will be presented. Further validation studies and analysis of additional solid cancers are ongoing.