Research recently released by Washington University School of Medicine in St. Louis has confirmed long-held beliefs that cancer development and treatment varies for men and women, particularly in glioblastomas. The findings showed that tailored treatment of glioblastoma, the most common malignant brain tumor, based on sex-specific molecular signatures improves outcomes for both men and women. By specifying treatment, researchers found a nearly tripled rate of survival for females, from the typical 1 year to 3 years, and a lengthened survival rate for males, from 12 months to 18 months.
Glioblastomas, which have an average survival of 14 months, are diagnosed nearly twice as often in men than women and are most frequently diagnosed in patients over 50. Current typical treatment, which is found to be more effective for women than men, includes surgery, followed by chemotherapy and radiation; however, recurrent tumors within 6 months post-treatment are common. But despite the research results showing better survival rates with sex-specific treatment, acceptance by the medical community for the relevance of sex in diagnosis and treatment remains a challenge.
To understand sex differences in tumor treatment, researchers measured tumor growth velocity in standard MRI scans every 2 months during treatment. Researchers then applied statistical algorithms to distinguish male- or female-specific gene expression patterns that corresponded to differences in survival rates for men and women. Though initial tumor growth velocities were similar between women and men, only women showed steady and significant decline in tumor growth after treatment with temozolomide, the most commonly used chemotherapy drug in glioblastoma treatment, researchers reported.
Though the research proved promising results, study co-senior author Joshua B. Rubin, MD, PhD, Professor of Pediatrics and of Neuroscience, and Co-Leader of the Solid Tumor Therapeutics Program at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, said the biology of sex differences and its applications in medicine are highly relevant, but almost always ignored aspects of personalized treatments.
“To appropriately perform laboratory and clinic-based experiments to determine the possibility of sex differences requires work beyond what most think,” he stated. For instance, when reviewing grants from the NIH, people often address sex as a biological variable and require an equal number of male and female mice. “That answer is wholly inadequate,” he said. “If you want to look at the effect of sex and its potential modifications, the question becomes how many mice you need to see the interaction; having five mice of one sex and five of another is not adequate.”
However, performing adequate studies is a tremendous expense because experiments tend to be quite large. “By underpowering lab studies, researchers see results suggesting there is no sex difference, which propagates the idea that sex doesn't matter in cancer treatments and that is far from what an epidemiological study would say,” Rubin noted. “Conducting clinical trials that are powered to detect sex differences will demonstrate the value in it, but the burden is on us to prove it.”
Improved Survival Rates
Despite roadblocks, research continues to show promise. Researchers found that the tumors of patients with glioblastoma cluster into 10 distinct subtypes distinguished by gene activity and survival—five for tumors in men and five in females. According to the research, females with tumors in one cluster survived longer than females with tumors in any of the other four clusters, at just over 3 years compared to just over 1 year.
Researchers similarly identified a male cluster with a longer survival rate of just over 18 months compared to just over 12 months for men in the other four clusters. Additional research showed that even genes activated at similar levels in tumors in females and males resulted in substantial sex-specific survival rates.
The research also found that tumors from glioblastoma were not affected by sex hormones, but instead identified genetic pathways that correlated with longest survival. Researchers performed in vitro drug screens, wherein four relatively common chemotherapy drugs where examined to identify how the expression of genes correlated with response to those drugs. For men, survival was found to be dependent on regulating cell division, suggesting that drugs that block cell-cycle progression would be most effective, while female survival was dependent on regulating invasiveness, suggesting that drugs targeting integrin signaling would be most effective.
Though research demonstrates the relevance of sex differences in cancer treatment, Rubin said it could be years before it is accepted by the larger medical community and used to inform treatment options.
“Any time we observe a sex difference in survival, it's reasonable to ask whether treatment should be tailored to patient sex,” he said. “I see the kind of work we are doing now as impacting on that globally, but we also need to build on work from other diseases, such as autoimmune diseases that are much more common in women and cardiovascular disease that is more common in men.”
However, sex-specific treatments can't be incorporated until clinical trials are completed, and though Rubin believes such trials will happen, it may take time before the research is accepted by the larger medical community. “The oncology community is not particularly receptive [to sex-specific research], but with some convincing, I hope people will be more willing to at least accept that experiments need to be done.”
Kelly Wolfgang is a contributing writer.