| Summary: | Introduction: Recent studies suggest an overrepresentation of <i>MGMT</i> promoter methylated tumors in females with <i>IDH</i>wt glioblastoma (GBM) compared to males, with a subsequent better response to alkylating treatment. Methods: To reveal sex-bound associations that may have gone unnoticed in the original analysis, we re-analyzed two previously published clinical cohorts. One was the multicenter Nordic trial of elderly patients with GBM, randomizing patients into three different treatment arms, including 203 cases with known <i>MGMT</i> promoter methylation status. The other was a population-based study of 179 patients with <i>IDH</i>wt GBM, receiving concomittant radiotherapy and chemotherapy with temozolomide. Cohorts were stratified by sex to test the hypothesis that female sex in combination with <i>MGMT</i> promoter methylation constitutes a subgroup with more favorable outcome. Results: There was a significantly larger proportion of <i>MGMT</i> promoter methylation and better outcome for female patients with <i>MGMT</i> promoter methylated tumors. Results were confirmed in 257 TCGA-derived <i>IDH</i>wt GBM with known sex and <i>MGMT</i> status. Conclusions: These results confirm that patient sex in combination with <i>MGMT</i> promoter methylation is a key determinant in GBM to be considered prior to treatment decisions. Our study also illustrates the need for stratification to identify such sex-bound associations.
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