Molecular profiling in targeted therapy of gliomas in a community setting.

Abstract

e14030 Background: In the 2021 WHO Classification for gliomas, molecular characteristics are mandatory for classification. However, there is not enough data to support the use of comprehensive molecular analysis in glioma patients and the association between different biomarkers and outcome is still under investigation. As more targeted therapies are approved in solid tumors, the need to detect predictive biomarkers in central nervous system tumors is urgent considering their prognosis. Methods: We performed a retrospective review of 61 patients with malignant gliomas treated between 2012 and 2024. Formalin- Fixed Paraffin Embedded (FFPE) tumor samples were collected, and molecular profiling was performed using two different multigene panels. In the first panel DNA was extracted from the samples and the Oncomine Comprehensive Assay Plus was used for the analysis of 513 genes. In the second panel DNA was extracted from FFPE samples and targeted-capture sequencing was performed using a 1021 gene panel (Oncology Multi-Gene Variant Assay). The analysis included detection of SNVs (Single Nucleotide Variants), CNVs (Copy Number Variants), SVs (Structural Variants) as well as assessment of TMB and MSI status and in some cases PD-L1 status. We analyzed genomic profile in association with histology, clinical characteristics, treatment. Results: 33 patient samples were analyzed using the 513 gene panel and 28 with the 1021 gene panel. Histologies were 43 glioblastomas, 3 astrocytomas grade 3, 5 astrocytomas grade 2, 5 oligodendrogliomas grade 3, 1 oligodendroglioma grade 2, 3 astrocytomas IDH-mutant grade 4 and 1 diffuse glioma H3 G34. In 6,5% of the patients analyzed no gene aberration was found. The most common genes affected were TERT promoter mutation (44%), TP53 mutation (41%), PTEN mutation (31%), IDH1 mutation (21%), EGFR amplification (21%), NF1 mutation (16%) and ATRX loss (11%). A targetable biomarker was found in 60% of the patients analyzed: IDH1 (21%), NF1 (16%), PDL1 (11%), TMB high (10%), LOH (10%), PIK3CA (8%), FGFR3 fusion (5%), BRAF (3%), RAD51C (3%), TSC2 (3%) and BRCA2 (1%). Accordingly, 11 patients received targeted therapy: 3 patients olaparib (RAD51C, BRCA2, H3.3 G34), 2 pembrolizumab (TMB high), 1 ivosidenib (IDH1), 1 selumetinib (NF1), 1 alpelisib (PIK3CA), 1 erdafitinib (FGFR3), 1 trametinib (NF1) and 1 dabrafenib/trametinib (BRAF) and then everolimus (TSC2). Mean duration of treatment on targeted therapy was 4.7 months, ranging from 1 month up to 16 months (olaparib). 7 out of the 11 patients who received targeted therapy were glioblastomas. Although it is a rather small number of patients, median overall survival was 15.6 months for glioblastomas who didn’t receive targeted therapy versus 31 months for glioblastomas who received a targeted agent. Conclusions: Molecular profiling nowadays is not only mandatory in glioma classification but can also provide additional therapies in patients with limited options.