It is widely appreciated that sex differences play a role in both the incidence of and treatment outcomes of many diseases, including some cancers. New research provides an understanding of this phenomenon for glioblastoma (GBM), the most common malignant brain tumor, through the identification of sex-specific molecular pathways. This work not only helps to explain why men die of GBM brain cancer at a higher rate than women, but may also help improve outcomes for patients by pursuing sex-specific approaches to treatment.
Not only is the incidence of GBM different between males and females, but, recent work in the GBM field suggests that patient outcomes vary as well, with female sex associated with longer survival. A collaborative team of researchers at the Washington University School of Medicine, Translational Genomics Research Institute (TGen), Mayo Clinic, Cleveland Clinic, and Case Western Reserve University, report findings in a study published in Science Translational Medicine, entitled, “Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data,” that could lead to tailored drug treatments. More specifically, treatments designed for men and women based on their sex-specific molecular subtype.
“This is a large leap forward in the field,” noted Quinn Ostrom, Ph.D., postdoctoral associate at the Duncan Cancer Center at the Baylor College of Medicine, who was not involved in this paper but has collaborated with Rubin, the senior author, in the past. She told Clinical OMICs that, “It has long been observed that there is a female survival advantage in GBM, but the mechanism through which sex confers this survival advantage has not been known” and that “this analysis by Yang et al. demonstrates that there are identifiable biological differences between males and females with GBM that contribute to these differences.”
To do this, the group of Joshua Rubin, M.D., Ph.D., professor of pediatrics in hematology and oncology at the Washington University in St. Louis School of Medicine and senior author on the study, performed quantitative analyses of therapeutic responses in male and female patients with GBM using an MRI-based imaging method. By calculating tumor growth velocities of 63 GBM patients (40 males and 23 females) every two months, the researchers found that standard therapy is more effective in females compared with male patients with GBM.
“The males did not respond as well, and we wanted to understand why, so we looked at the underlying genetics of patients’ tumors,” said Rubin in the press release associated with the study.
To do this, the researchers applied a computational algorithm to male and female GBM transcriptome data and identified sex-specific gene expression patterns of GBM. They determined that survival in males is correlated with the regulation of cell division through the expression of cell cycle regulators and the critical determinant in females was expression of integrin signaling pathway components to regulate invasiveness.
The clinical relevance of these molecular signatures was further established through in vitro drug screens that looked at the effect of four commonly used chemotherapy drugs on gene expression in a panel of male and female patient-derived GBM cell lines. Both sexes showed a clear correlation.
Rubin said that the impetus for studying sex differences in GBM comes from his own neuro-oncology practice, where he sees that improvements in GBM treatments are among the most pressing unmet needs in neuro-oncology. Although Rubin expected to find sex differences, he was surprised by how well each evaluation complemented the others, noting that “it made for a coherent story that increased my confidence in it.”
Ostrom’s prior work, including a paper published on Jan. 1 in Neuro-oncology entitled, “Sex-specific gene and pathway modeling of inherited glioma risk,” on which Rubin is also an author, focuses on the identification of genetic differences between males and females in susceptibility to glioma.
One of the most exciting aspects of this work, according to Ostrom, is the finding of sex difference in treatment response as measured via MRI imaging. She explained that, “the results of gene expression analyses further suggest that females have increased sensitivity to chemotherapy.”
Taken together, the work suggests that there are both substantial incidence (risk of disease) and survival (clinical outcomes) differences by sex and that sex affects both susceptibility to this disease as well as the disease process in individuals who develop these tumors.
In Ostrom’s own research, analyzing epidemiological data derived from state cancer registries, they have shown that sex differences in survival are largest when the dataset is limited only to those that have received chemotherapy and radiation. These new findings suggest to her that the sex difference they have seen in those analyses may be due to biological treatment response that varies by sex. She was surprised to see that there were no differences in survival by tumor growth velocity in males, especially considering that there are nearly twice as many males included in this study. These sex differences in treatment response have the potential to have significant clinical implications, and should be a topic for future study.
Rubin is excited to be providing a strong rationale for prospectively evaluating sex differences in response to standard and novel treatments for GBM and possibly other cancers. The results also suggest to him that diagnostic criteria and disease response measures might need to be tailored to the sex of the patients and that lab-based investigations of cancer biology should be designed to detect sex differences in mechanisms and response to therapeutics. His hope is that this work will change the way that doctors think about treating GBM and other cancers in a sex-specific way, improving outcomes for all.
Rubin’s team is actively pursuing both clinical and lab-based investigations with a large focus on sex differences in epigenetics and metabolism, the latter providing the rationale for a new clinical trial they opened using ketogenic diet and chemotherapy for children with recurrent brain tumors. In the trial, they will be collecting data to determine whether there are differences in ketosis and disease response in boys and girls.
“It is highly likely that by conducting experiments that do not incorporate sex, researchers are missing potentially important findings if these biological mechanisms vary by sex,” noted Ostrom. She hopes that this work will encourage people to consider the importance of sex in disease processes, noting that we are limiting ourselves by thinking of sex differences as being largely attributable to differences in circulating sex hormones, because there are numerous ways that sex affects biology—all of which are important to consider.
