297P The genetic profile of primary and recurrent gliomas: A mono-institutional experience using next-generation sequencing

The use of next-generation sequencing (NGS) tests is currently increasing in neuro-oncology, to identify alterations of cancer-related genes and establish a better personalized glioma treatment. However, the genetic profile may change during glioma progression. Here we analyzed the difference between matched primary and recurrent gliomas by extensive NGS. From Nov 2019 to Jan 2022, at Veneto Institute of Oncology in Padua, we collected glioma FFPE blocks at initial surgery and at recurrence. NGS was performed using FoundationOne®CDx assay. We identified 46 samples from 23 pts who underwent surgery twice. According to WHO 2021 classification, samples were classified into: 1) IDH-wildtype glioblastoma (GBM) (n=36); 2) IDH-mutant astrocytoma (n=2 Grade 2, n=5 G3 and n=1 G4); 3) IDH-mutant 1p/19q co-deleted oligodendroglioma (n=1 G2, n=1 G3). In 3 pts an evolution to higher histological grade was detected. All pts received TMZ with or without RT after the 1st surgery. NGS was successfully performed in 44/46 gliomas, while data were not reported due to sample failure in 2 cases, both among first resections. Recurrent gliomas exhibited de novo mutation in 7 pts: TP53 (4/23; 17.4%), PTEN loss (4/23; 17.4%) and NF1 alterations (6/23; 26%). Alterations such as TERT mutation (18/21), CDKN2A (14/21) CDKN2B (12/21) MTAP loss (6/21), BRCA2 (4/21) and PIK3CA mutation (2/21) were early events observed in initial samples maintained at recurrence; 2 and 4 pts have lost CDKN2A loss and EGFR mutation/amplification/fusion during progression, respectively. In one GBM, a BRCA2 germline mutation (Q2354*) was recognized; another GBM pt had a conserved BRAF V600E somatic mutation; both pts benefited from target therapy as a consequence of NGS. Median tumor mutational burden (TMB) was 1.68 (0-6.30) and 14.9 (0-129.8) mutations/megabase in initial and subsequent resection, respectively. By extensive NGS, we observed 3 de novo gene alterations in 7 (30.4%) recurrent tumor patients; 6 (26%) patients showed loss of genetic alterations during progression. High TMB in second samples is consistent with reports of treatment-induced hypermutagenesis. We showed that NGS should be performed both at diagnosis and at relapse.