BIOM-64. ALTERATIONS IN MDM2/4-TP53 AXIS PREDICT RESPONSE TO TUMOR TREATING FIELD (TTF) THERAPY IN IDH WILD TYPE GLIOBLASTOMA

Abstract BACKGROUND Tumor Treating Field (TTF) therapy exerts antineoplastic effects through application of alternating electrical fields that disrupt mitotic machinery and induce DNA damage and activation of cell cycle checkpoints. However, despite extensive utilization in clinical practice for the management of glioblastoma, molecular markers for TTF sensitivity have proven elusive. METHODS To assess impact of molecular alterations on TTF response, we evaluated our institutional cohort of IDH wild type glioblastomas (n=449) for whom chromosomal microarray data was available. RESULTS A total of 142 patients were found to have undergone TTF treatment (31.6%) with improved overall survival (OS) (p=0.0049, univariate analysis). We assessed TTF treatment responses when stratified by alterations in the MDM2/4-TP53 axis, as well as the CDK4/6-RB1 axis, given well-described roles for these pathways on cellular responses to DNA damage and mitotic stressors. On univariate analysis, MDM2/4 amplified tumors treated with TTFs demonstrated significantly improved OS compared to untreated tumors (p=0.0012), and while MDM2/4-unaltered, TP53 intact tumors showed OS benefit from TTFs (p=0.0192), TP53-altered tumors did not demonstrate such benefit (p=0.6591). We confirmed these findings with multivariate Cox regression after adjusting for age and sex, where TTF therapy improved OS in MDM2/4 amplified tumors (HR 0.3881, p=0.0062) and a signal towards improved OS was seen in TP53 intact tumors (HR 0.7552, p=0.0509) but no such benefit was seen in TP53-altered tumors (HR 1.0025, p=0.9916). TTF therapy appeared to demonstrate improved OS in CDK4/6 amplified tumors (p=0.0116) on univariate analysis, with continued signal towards this effect on multivariate Cox regression (HR 0.5975, p=0.0870). CONCLUSIONS TP53 intact status and MDM2/4 amplification may represent previously unappreciated molecular markers for sensitivity to TTF therapy in IDH wild type glioblastoma. Confirmatory work with multi-institutional collaborations and evaluation of other potential prognostic factors are currently underway.