PTEN homozygous deletion is a negative prognostic factor in tumor treating fields‐treated glioblastoma, IDH wildtype patients

Abstract Tumor treating fields (TTFields) are a treatment for glioblastoma, isocitrate dehydrogenase wildtype (GBM, IDH wt) that improves survival, but no validated biomarkers exist to identify patients likely to benefit. This study aims to identify molecular biomarkers guiding clinical decisions on TTFields initiation. Eighty gliomas treated with surgery, radiochemotherapy, and TTFields were reassessed using DNA methylation profiling and TSO500 DNA/RNA panel sequencing, identifying 64 highly characteristic GBM, IDH wt with comprehensive molecular data. Alterations present in ≥5 cases were analyzed for association with survival using Kaplan–Meier and Cox models. Two TTFields‐naïve GBM, IDH wt cohorts ( n = 175) served as controls. For 18 cases, post‐treatment tissue from a second surgery was profiled. Twenty‐four alterations occurred in ≥5 patients. Univariate analyses showed KPS and MGMT promoter methylation as protective, while EGFR amplification, CDKN2A/B loss, and homozygous PTEN deletion were linked to worse survival with TTFields. Multivariate analysis confirmed KPS and MGMT as protective and homozygous PTEN deletion as a risk factor (median OS 368 vs. 603 days; HR 3.86, p = 0.0049). In TTFields‐naïve cohorts, homozygous PTEN deletion was not associated with outcome, and frequencies were comparable (controls 7%, TTFields 11%). Post‐TTFields GBM, IDH wt did not acquire hypermutation or other recurrent molecular alterations. Alongside the established factors MGMT and KPS, PTEN homozygous deletion was associated with worse survival in GBM, IDH wt patients treated with TTFields. Homozygous PTEN deletion may be associated with reduced benefit from TTFields and should be further investigated as a predictive biomarker for TTFields treatment.