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If someone were to ask you whether biological sex is related to the risk of cancer, you would might say yes–cis men can suffer from prostate and testicular cancer while cis women may suffer from cervical and ovarian cancer (and are at higher risk of breast cancer). Those all seem obvious; however, there are more substantial differences. Liver cancer, for example, affects men at a higher rate than women (2:1 vs 7:1, respectively) due to numerous factors, including both lifestyle and hormones. Moreover, the gender disparities extend from diagnosis into survival; men have worse overall prognoses than women, including worse overall survival.
Recently, a study by researchers at Washington University of St. Louis sought to examine the impacts of biological sex on brain cancer occurrence, response to treatment, and survival. Men are 1.6-fold more likely to be diagnosed with glioblastoma than women, and these differences can be further broken down by subtype; “classical” glioblastoma occurs at equal rates among men and women, but mesenchymal, proneural, and neural glioblastoma are all twice as likely to occur in men than in women. In this study, researchers studied sex-related differences using patient data, cell lines derived from both males and females, and computational programs. Because sex-related differences are seen in both adults and children, it is unlikely that these differences can be linked to sex hormones, which most people would consider the obvious explanation. Other diseases, such as asthma, have similar differences between sexes that cannot be clearly linked to hormones.
Patients in this study were treated with the standard of care therapy. For glioblastoma, that means focal radiation (i.e., radiation sharply focused on the tumor) and temozolomide chemotherapy. The results showed that females responded more positively to this standard of care than men did. Prior to treatment, the tumors were growing at similar rates in males and females; after treatment the tumors began to grow more slowly and the rate of survival increased in females. There was no improvement in overall survival among males, even in patients with decreased tumor growth.
By looking more closely at gene expression and mutated proteins in both male-derived and female-derived glioblastoma cells, researchers were able to narrow down some of the sex-related differences in tumor growth. For example, mutations in the protein IDH1 are used to predict treatment responses and patient outcomes; however, when considering sex, the researchers found that IDH1 mutations were predictive of positive outcomes in men but not in women. However, the sample size for women was very small, and thus, a larger sample may lead to results similar to those in the male sample. Larger studies are needed to better understand the underlying mechanism of this effect. Another striking result was that sex-related differences not only play a role in how genes were expressed but also in how the proteins in cells react to treatment. Cell-cycle proteins were produced at similar levels in both male- and female-derived glioblastoma cells, but these proteins responded to treatment differently in male- and female-derived cells. In fact, these findings suggest that while female-derived glioblastoma cells respond well to temozolomide, male-derived glioblastoma cells respond better to a different chemotherapeutic, etoposide. The results also showed that when male cancer cells were transplanted into female mice, the resulting tumors grew more slowly than the same tumors in male mice, but responded to etoposide better than temozolomide. This finding indicated that the mechanisms of drug resistance and response rates are cell-dependent, but systemic biological effects, like sex-related factors, can also impact growth rate. More research is necessary to fully understand the intricacies of these interactions and to identify additional biomarkers that, when combined with sex-related differences and a molecular understanding of cancer cells, can help doctors choose the most effective medicines for their particular patient (i.e., personalized or precision medicine).
This study lays a strong foundation for future research on sex-related differences in cancer treatment, but the findings do not fully clarify how biological sex can impact cancer incidence, growth, and therapy. Further studies will be needed before clinicians can effectively use biological sex as an indicator for therapy. Future studies will also likely need to be done in more rigorous tumor models; this study used a notoriously poor method of measuring tumor growth, choosing to implant cells in mouse flanks rather than their brains, where the tumors would naturally grow. This change in cancer cell environment can change their behavior, so these findings will need to be confirmed in studies that use these cell lines in the brain. In addition, this study, like most biomedical studies, focused on cisgendered people, or people whose gender identification matches that which they were assigned at birth from an examination of their external sexual organs.
Yang, W., Warrington, N. M., Taylor, S. J., Whitmire, P., Carrasco, E., Singleton, K. W., et al. (2019). Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Science translational medicine, 11(473), eaao5253.
Image created from stock photos from Pixabay.