Sex differences in the incidence and outcome of human disease are broadly recognized, but in most cases, not sufficiently understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that standard therapy is more effective in female compared to male GBM patients. We then applied a computational algorithm to linked GBM transcriptome and outcome data and identified sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling are the critical determinants of survival for male and female patients, respectively. The clinical utility of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses and that improved outcomes for all patients might be accomplished by tailoring treatment to sex differences in molecular mechanisms.

Glioblastoma (GBM) is the most aggressive primary brain tumor and can have cystic components, identifiable through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7–23% of GBMs and report mixed results regarding their prognostic impact. Using our retrospective cohort of 493 patients with first-diagnosis GBM, we carried out an exploratory analysis on this potential link between cystic GBM and survival. Using pretreatment MRIs, we manually identified 88 patients with GBM that had a significant cystic component at presentation and 405 patients that did not. Patients with cystic GBM had significantly longer overall survival and were significantly younger at presentation. Within patients who received the current standard of care (SOC) ( N = 184, 40 cystic), we did not observe a survival benefit of cystic GBM. Unexpectedly, we did not observe a significant survival benefit between this SOC cystic cohort and patients with cystic GBM diagnosed before the standard was established ( N = 40 with SOC, N = 19 without SOC); this significant SOC benefit was clearly observed in patients with noncystic GBM ( N = 144 with SOC, N = 111 without SOC). When stratified by sex, the survival benefit of cystic GBM was only preserved in male patients ( N = 303, 47 cystic). We report differences in the absolute and relative sizes of imaging abnormalities on MRI and the prognostic implication of cysts based on sex. We discuss hypotheses for these differences, including the possibility that the presence of a cyst could indicate a less aggressive tumor.

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Lacunarity, a quantitative morphological measure of how shapes fill space, and fractal dimension, a morphological measure of the complexity of pixel arrangement, have shown relationships with outcome across a variety of cancers. However, the application of these metrics to glioblastoma (GBM), a very aggressive primary brain tumor, has not been fully explored. In this project, we computed lacunarity and fractal dimension values for GBM-induced abnormalities on clinically standard magnetic resonance imaging (MRI). In our patient cohort (n = 402), we connect these morphological metrics calculated on pretreatment MRI with the survival of patients with GBM. We calculated lacunarity and fractal dimension on necrotic regions (n = 390), all abnormalities present on T1Gd MRI (n = 402), and abnormalities present on T2/FLAIR MRI (n = 257). We also explored the relationship between these metrics and age at diagnosis, as well as abnormality volume. We found statistically significant relationships to outcome for all three imaging regions that we tested, with the shape of T2/FLAIR abnormalities that are typically associated with edema showing the strongest relationship with overall survival. This link between morphological and survival metrics could be driven by underlying biological phenomena, tumor location or microenvironmental factors that should be further explored.