Anatomical-molecular interaction in glioblastoma: subventricular zone involvement and MGMT-related survival benefit.

PURPOSE: Both MGMT promoter methylation and subventricular zone (SVZ) involvement influence glioblastoma prognosis. We investigated whether SVZ involvement modifies the prognostic impact of MGMT promoter methylation. METHODS: We retrospectively analysed 117 adults with IDH-wildtype glioblastoma (CNS WHO 2021) treated with chemoradiotherapy (Stupp protocol) between 2019 and 2024. MGMT methylation was assessed by pyrosequencing (cut-off ≥10%). SVZ involvement was defined as overlap between the gross tumour volume and a 5-mm expansion from the lateral ventricular walls, including temporal horns. Overall (OS) and progression-free survival (PFS) were analysed using multivariable Cox models with an MGMT × SVZ interaction term and two sensitivity analyses. RESULTS: SVZ involvement occurred in 45 patients (38%). Median PFS and OS were 11 and 15 months. Median OS was 32 months in MGMT-methylated/SVZ-negative vs 13 months in MGMT-methylated/SVZ-positive cases (pairwise log-rank p=0.001). On multivariable analysis, MGMT methylation remained protective (HR 0.50, p=0.008), whereas SVZ involvement lost independent significance (p=0.16). The MGMT × SVZ interaction was significant for OS (HR 2.62, 95% CI 1.12-5.40; p=0.020) but not PFS (p=0.42), persisting across sensitivity analyses. Recurrences were predominantly in-field (72.0-81.8%). CONCLUSION: SVZ involvement attenuates the survival benefit conferred by MGMT methylation, supporting combined anatomical-molecular stratification. Given the cohort size and lack of PFS effect, these findings are hypothesis-generating and do not justify modifying radiotherapy target volumes based on SVZ involvement alone.