P06.07.B IDENTIFYING TARGETABLE ALTERATIONS PREDICTIVE OF DISTANT PROGRESSION IN GLIOBLASTOMA PATIENTS UNDERGOING STANDARD THERAPY
Authors: S Chiranth, V Fougner, I Christensen, A Trip, T Christiansen, D Nørøxe, C Yde, A Berthelsen, B Hasselbalch, U Lassen, H Poulsen, T Urup
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Infiltrative growth is a hallmark of glioblastoma (GBM) and is a major factor in therapeutic failure. Genetic variants predictive of distant progression may serve as novel treatment targets. The aim was to identify clinical, molecular and genetic factors associated with distant progression in GBM patients treated with standard therapy. MATERIAL AND METHODS From our prospective database, all consecutive IDH wild type GBM patients administered standard therapy (radiation therapy with concomitant + adjuvant temozolomide) from 2016 to 2021 at Rigshospitalet (Denmark) were included. The progression pattern was reviewed, and distant progression was defined as a new contrast-enhancing tumor &amp;gt; 2 cm from the initial lesion. Clinical and molecular data were retrieved from our database, while radiographic data came from the baseline MRI scans. Genomic tumor profiling (whole-exome, whole-genome, or targeted panel sequencing) was performed in selected patients. Genetic factors comprised pathogenic and likely-pathogenic genetic variants present in &amp;gt; 5% of cases. From univariate Cox regression analysis, covariates associated with time to distant progression (p &amp;lt; 0.20) were considered for multivariate analysis. RESULTS The study included 353 patients of whom 303 patients (86%) had radiographic disease progression. Distant progression was found in 66 (22%) patients with a median time to distant progression of 8.8 months. Of these patients, 29 patients had more than one new contrast enhancing lesion (range 1-5). The median distance between the primary and distant recurrent tumor was 4 cm (range: 2.1-50). Comparing the progression pattern with post-progression survival, patients with distant progression were significantly associated with a poor prognosis (p &amp;lt; 0.001). In 204 patients a genomic tumor profile was performed. This subgroup did not differ significantly from the total study cohort in terms of baseline factors, prognosis, or progression pattern. By univariate analysis of the total cohort, multifocal disease (p = 0.17), unmethylated MGMT (p = 0.003), unresected tumors (p = 0.07) and the lack of P53 protein expression by immunohistochemistry (p = 0.02) were associated with a shorter time to distant progression. In multivariate analysis adjusted for known independent prognostic factors, unmethylated MGMT was the only factor associated with a higher risk of distant progression (HR: 2.72, 95% CI: 1.52 - 4.89, p &amp;lt; 0.001). By univariate analysis of the genomic cohort, NF1 mutation was the only gene variant associated with a higher risk of distant progression (p = 0.003). NF1 remained significant in multivariate analysis adjusted for known prognostic factors (HR: 3.22, 95% CI: 1.37-7.61, p = 0.008). CONCLUSION Unmethylated MGMT and NF1 mutation independently predict distant progression. These factors suggest a migratory phenotype that may be susceptible to targeted treatment.