Genomic Alterations Predictive of Rapid Early Tumor Progression in IDH-Wild type GBM

Introduction: Glioblastoma IDH-WT (IDH-WT GBM) is the most common malignant primary brain tumor. Despite multimodal treatments following surgery, most GBM patients experience recurrence. For newly-diagnosed GBM, rapid early tumor progression (REP) may occur in 50% of the cases. Genetic characteristics predictive of REP in GBM have not been previously described.

Methods: We identified 282 patients from our institutional database, all diagnosed with IDH-wild type (IDH-WT) GBM. Patients underwent Next-Generation Sequencing targeting 205 tumor-associated genes. Patients who had an MRI within 48 hours following surgery and a second MRI before starting chemoradiotherapy were included. REP was characterized as early tumor progression per RANO criteria before initiation of adjuvant chemoradiotherapy. The study focused on outcomes such as progression-free survival (PFS) and overall survival (OS).

Results: Thirty-eight IDH-WT GBM patients met the inclusion criteria. From these, 17 patients had REP and 21 without REP (45% of patients). The median PFS was 8.3 months (95% CI: 4.8-11.8 months) in the non-REP group, and 6.4 months(95% CI=4.1-8.6 months) in the REP group, log-rank p=0.020. There were no significant differences in OS (median OS in REP was 20.1 months [95% CI 8.7-31.4], and 22 months [16.7-27.2] in the non-REP group, p= >0.05). Univariate and multivariate analyses on PFS revealed four mutations associated high risk of progression: KMT2C (MLL3) HR=11.7(95%CI=2.11-65.36, p=0.005); NF1 HR=3.7(1.00-13.79,p=0.050); PTPN11 HR=17.9(95%CI=1.63-198.46); TP53 HR=5.16 (95%CI=1.65-16.12,p=0.005).

Conclusion : This pilot study provides novel insights into the genetic characteristics of REP in IDH-WT GBM. Notably, patients in the non-REP group exhibited higher PFS. Specific gene mutations including KMT2C(MLL3), NF1, PTPN11, and TP53 were found to increase the risk of REP. These mutations could serve as potential prognostic markers or therapeutic targets for this aggressive form of GBM.