P12.47.B MOLECULAR PROFILING OF GLIOMAS: INSIGHTS INTO RADIONECROSIS AND PSEUDOPROGRESSION THROUGH NEXT-GENERATION SEQUENCING

Abstract BACKGROUND High-grade gliomas are the most common and aggressive primary tumors of the central nervous system (CNS), posing significant diagnostic and therapeutic challenges due to their molecular heterogeneity. Next-generation sequencing (NGS) has improved diagnostic accuracy by identifying actionable genetic alterations. However, post-treatment effects such as radionecrosis and pseudoprogression may complicate disease monitoring by mimicking tumor recurrence. This study aimed to evaluate associations between specific genetic alterations identified by NGS and the development of treatment-related effects. MATERIAL AND METHODS This retrospective study included 192 patients with high-grade gliomas treated with radiotherapy between 2018 and 2023 at a Brazilian cancer center. NGS results were available for 20 patients with radionecrosis and 20 patients of a control group. Patients were grouped based on the presence or absence of post-treatment effects, radionecrosis or pseudoprogression and the groups were matched by irradiation volume. Genetic alterations and clinical outcomes were extracted from electronic medical records. Fisher’s exact test and nominal regression models were used to identify associations between molecular alterations and post-treatment effects. Statistical significance was defined as p<0.05. RESULTS Among 192 patients, 46 (23.9%) experienced post-treatment effects. Of the 20 patients with NGS data, 15 developed radionecrosis, 8 pseudoprogression, and 3 both. Although no statistically significant associations were found using Fisher’s test, TERT promoter mutations (c.1-124C>T) and EGFR amplification were the most frequent alterations in radionecrosis (n=9 and n=8, respectively). In pseudoprogression, TERT mutations (n=6), EGFR amplification (n=4), PTEN (n=4), and NF1 mutations (n=2) were identified. Nominal regression revealed significant associations between radionecrosis and EGFR amplification (p=0.004), MDM4 amplification (p=0.019), PTEN mutation (p=0.034), and SEC16A: : NOTCH1 fusion (p=0.019). Temporal analysis showed that pseudoprogression occurred earlier (median onset: 147 days), whereas radionecrosis was more delayed (200-500 days post-RT). CONCLUSION NGS provides valuable insights into the molecular landscape of high-grade gliomas and may help identify patients at risk for treatment-related effects. Understanding the genomic profile associated with radionecrosis and pseudoprogression can inform follow-up strategies and minimize misdiagnosis. These preliminary findings warrant validation in larger prospective cohorts to better elucidate the clinical relevance of these molecular alterations.