Tumour variance between sexes
New research suggests using gender-based approaches to diagnosis and treatment of cancers
HAVE you ever wondered why, in most species, males are larger than females? It’s an aspect of biology determined by evolution, but what does it mean for human health and disease? What are the implications of needing one chart to describe normal growth in boys, and another to describe normal growth in girls? Why are there two normals for growth and does it matter for a disease of growth like cancer?
I’m a paediatric brain tumour doctor and scientist, and am interested in developing new treatments for glioblastoma (GBM) and other malignant brain tumours. Glioblastoma is the most common tumour and killed the late US senators John McCain and Ted Kennedy, and also Beau Biden III, the eldest offspring of former US vice -president Joe Biden.
In this new year, about 22 000 Americans will develop GBM and nearly the same number will die from it. While GBM occurs in both males and females, we can reliably predict that of the 22 000 new cases, 8 500 will be in females, while the remaining 13500 cases will be in males. Moreover, the female GBM patients can be expected to survive, on average, about six months longer than the male patients.
My colleagues and I wondered whether basic differences in biology might explain why males were more vulnerable to these malignant brain tumours and why their survival time was shorter than that of females.
We hypothesised that if there were differences between the male and female versions of GBM, we might be able to generate new, sex-specific approaches to treatment that would improve outcomes for everyone.
Many human diseases exhibit substantial sex differences in their frequency and severity. Autoimmune disorders such as systemic Lupus erythematosus occur nine times more frequently in females than in males, and psychiatric diseases such as depression occur nearly twice as frequently in females compared to males. The implications of sex differences in cancer have not been extensively investigated in clinical or laboratory research.
While there is a great interest in developing more personalised approaches to cancer treatment, a patient’s sex, a key feature of personalisation, has not yet been incorporated into this paradigm. In our recent study in Science Translational Medicine, my collaborators and I provide what we think is compelling evidence that patients’ genders should be incorporated into treatments for GBM and more thoroughly investigated.
In our study, we sought to determine whether differences in survival for males and females with GBM were a consequence of different responses to the standard treatment of surgery, radiation and temozolomide chemotherapy. If this was so, we wanted to explore whether there were sex-specific mechanisms that contributed to treatment response and survival in males and females.
We analysed standard magnetic resonance images – or MRIs – of 371 patients’ brains taken during treatment at the Mayo Clinic. We measured how the tumour proliferated and grew, and how it invaded and spread into the surrounding brain tissue. Both proliferation and invasion killed the patient.
We found that in female patients, radiation and chemotherapy treatment slowed tumour proliferation, but not in male patients. Male tumours continued to grow at the same rate. We also found that tumour proliferation predicted survival for both males and females, but invasion only affected survival for females.
We concluded that female patients’ better response to standard treatment for GBM and better survival might be determined in a sex-specific fashion by invasion, in addition to proliferation. However, survival in male patients appeared to be only influenced by proliferation.
We next sought to identify what caused these differences. One way to understand cancer biology is to look at the differences between the genes that cancer cells use to grow and respond to radiation and chemotherapy. We can then compare these genes to those that normal cells use.
The genes are the tools that cells use for these functions. If researchers can identify the tools that cancers use to grow, we can try to design treatments to disable them.
To do this, we took advantage of a large amount of publicly available data from the Cancer Genome Atlas, the Rembrandt study and two additional databases on cancer gene activity, which geneticists refer to as gene expression. Then, using a specialised kind of maths known as Joint and Individual Variance Explained, we found significant differences in the activities of genes in male and female glioblastoma.
We think it is important that we discovered that some genes had different effects on survival in male and female patients. For instance, when the levels of a gene called CCNB2 were low in males, they survived longer. This was not the case for females. In females, when levels of a gene known as PCDHB were low, females survived longer. This was not the case for males. This suggests that it is essential that researchers study the impact of drugs on male and female cells separately, for GBM and possibly other cancers.
We are intrigued that male survival is significantly determined by genes that control rates of cell division, whereas female survival is significantly determined by genes that can regulate the ability of a cancer cell to migrate to a different area of the brain. This suggests that some types of drugs that target how cancer cells divide might work better in males, whereas drugs that inhibit cancer cells from spreading to distant organs might be more effective in females.
Finally, we asked whether the levels of gene expression mattered for how the cancer cells responded to chemotherapy in a dish. This is important because it might help researchers, including our team, to design treatments for patients by screening large numbers of drugs to find the ones to which they are most sensitive.
We found that the low levels of genes involved in proliferation were linked to longer survival in male patients and greater sensitivity to chemotherapy in a dish. Similarly, we found that low levels of genes involved in cell migration were associated with longer survival in female patients and increased sensitivity to the same chemotherapy in a dish.
Together, these results suggest that it may be possible to improve outcomes for all GBM patients, and possibly other cancers, by using sexbased approaches to diagnosis and treatment. That’s because many cancers are more common in males and it is possible that for each of these cancers, sex-specific approaches would be beneficial.
We believe this should be evaluated in prospective clinical trials of standard and novel therapeutics. We have just begun a clinical trial in which we are gathering data about sex differences in metabolism and response to a ketogenic diet in which tumours are starved of glucose in children with relapsed brain tumours. We are also actively working to determine when, during normal development, sex differences in risk for cancer and sensitivity to treatment arise.
Many human diseases exhibit substantial sex differences in their frequency and severity. Professor Joshua Rubin Washington University, St Louis