PATH-10. PTEN homozygous deletion is a negative prognostic factor in Tumor Treating Fields-treated glioblastoma, IDH wildtype patients

Abstract INTRODUCTION Tumor Treating Fields (TTFields) are an adjunctive treatment for glioblastoma, isocitrate dehydrogenase wildtype (IDH wt). TTFields indication is not standardized; patient selection is mostly based on a high KPS. Objective: This study aims to identify molecular biomarkers guiding clinical decisions on TTFields initiation. Patients & methods: A retrospective analysis was conducted on 64 patients with newly diagnosed glioblastoma, IDH wt treated with surgery, radiochemotherapy, followed by TTFields. Clinical data (e.g. extent of resection, survival data) were collected. Tumors underwent TSO500 DNA/RNA sequencing and methylation profiling (EPIC). Alterations were analyzed for association with overall survival using Kaplan-Meier as well as univariate and multivariate Cox models. Methylation class, tumor mutional burden, and signaling pathway activation (e.g. PI3K/AKT/mTOR pathway) were also assessed for associations with overall survival. Two TTFields-naïve glioblastoma, IDH wt cohorts served as controls (combined n=175). RESULTS Molecular profiling revealed 25 alterations occurring in at least 5 patients (e.g., mutations: PTEN, EGFR, deletions: PTEN, CDKN2A/B; amplifications: EGFR). Univariate analyses showed preoperative KPS and MGMT promoter methylation as protective, while EGFR amplification, CDKN2A/B, and PTEN homozygous deletions were linked to worse survival in the TTFields treated cohort. Multivariate analysis confirmed KPS and MGMT as protective and PTEN homozygous deletion as a significant risk factor for worse outcome (HR: 3.86, 95% CI: 1.51–9.87, p=0.0049). Comparative analysis with TTFields-naïve cohorts showed no link between PTEN homozygous deletion and worse outcomes, with homozygous deletion rates comparable across cohorts (controls: 7%, TTFields: 11%). CONCLUSION Alongside established protective outcome factors MGMT and KPS, in our cohort of glioblastoma, IDH wt patients treated with TTFields, PTEN homozygous deletion was significantly associated with worse survival. PTEN deletion status may thus predict reduced benefit from TTFields, warranting testing before treatment initiation.