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Glioblastoma Pathway Signatures, Treatment Responses Differ Between Male, Female Patients

NEW YORK (GenomeWeb) – A team led by researchers at Washington University has identified molecular features that differ between glioblastoma (GBM) brain tumors of males and females and may be used to better tailor treatment.

As they reported online yesterday in Science Translational Medicine, the researchers used available transcriptome data from the Cancer Genome Atlas project — along with magnetic resonance imaging-based tumor growth profiling and survival data for more than 60 individuals with GBM — to track growth trajectories, molecular features, and treatment response patterns in tumors from male and female GBM patients.

In particular, the team found that female GBM patients are often more prone to respond to a standard therapeutic approach involving chemotherapy and radiation after surgery. On the molecular side, the gene expression results highlighted differences in integrin signaling and cell cycle pathways in tumors from male and female participants.

"It is our expectation that this study could have an immediate impact on the care of patients with glioblastoma and further research, as the findings indicate we should be stratifying male and female glioblastoma into risk groups and evaluating the effectiveness of treatment in a sex-specific manner," co-corresponding author Joshua Rubin, a pediatrics and neuroscience researcher at Washington University, said in a statement.

Building from epidemiological data pointing to sex-related differences in GBM prevalence and survival, the team set out to document tumor features that might contribute to such discrepancies, with tumor growth velocity profiling in 40 male and 23 female patients with serial MRI measurements available.

"The biology of sex differences and its applications in medicine are highly relevant, but almost always ignored, aspects of personalized treatments," Rubin said, explaining that "you can look at tumor growth velocity while patients are undergoing treatment and derive a value for how fast their tumors are growing" as a means of evaluating treatment effectiveness.

Although the available imaging data pointed to similar pre-treatment tumor growth trajectories in male and female patients, for example, the team saw more dramatic tumor shrinkage in females after treatment with surgery, focal irradiation, and systemic chemotherapy using a drug called temozolomide.

Using statistical algorithms, meanwhile, the researchers compared gene expression features in GBM tumors profiled for TCGA, uncovering 10 transcriptome-based tumor subtypes with distinct gene activity and survival features — results verified with data from three independent cohorts. Half of the expression clusters were more common in male GBM patients, they reported, while the remaining five subtypes tended to appear in female patients with the malignant brain tumor.

By incorporating survival data, the team saw that male GBM patients typically had better outcomes when their tumors contained alterations that dialed down cell cycle progression, while outcomes improved in female patients when gene expression profiles corresponded to reduced integrin signaling and tumor invasiveness.

"[A]lthough it is not yet possible to ascribe a specific fraction of the survival differences between male and female patients with GBM to any of the sex differences we describe," the authors concluded, "the current study does suggest that greater precision in the stratification of patients with GBM may be achieved through sex-specific molecular subtyping and that improvements in GBM outcome might be possible with sex-specific approaches to treatment, including blocking cell cycle progression in male patients and targeting integrin signaling in female patients."