Uterine microbiome may explain racial disparity in endometrial cancer mortality
Uterine microbial diversity appeared higher among Black women diagnosed with endometrial cancer compared with their white counterparts, according to study results.
The findings, presented at the virtual American Association for Cancer Research Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, also showed distinct microbiota profiles between endometrial cancers of Black women with obesity and white women with obesity.
“[Black] women suffer a 55% higher overall mortality from endometrial cancer compared with white women,” Gabrielle M. Hawkins, MD, fellow in gynecologic oncology at The University of North Carolina at Chapel Hill, said during a presentation. “Potential biological causes for this disparity in Black women include a higher risk for more lethal tumor histology, molecular subtypes such as TP53 mutations, and higher rates of obesity and diabetes. However, we hypothesized that another biological factor driving this racial disparity could be the uterine microbiome, as it is thought to have a complex role in human health and disease, including obesity and cancer.”
Microbe-driven cancer previously has been described, including the roles of Helicobacter pylori in gastric cancer and HPV in cervical, anal, and head and neck cancers.
“Microbial organisms shape the tumor microenvironment by modulating many of the hallmarks of cancer, such as resisting cell death, avoiding immune destruction, activating invasion and metastases, in addition to others,” Hawkins added. “Racial differences have been shown for both the gut and vaginal microbiomes. However, little is known about the racial differences in the uterine microbiome and its impact on the pathogenesis of endometrial cancer.”
For this reason, Hawkins and colleagues assessed the microbiota of endometrial cancer for variations by race. They analyzed banked tumor specimens of postmenopausal Black women (n = 23) and white women (n = 72) undergoing hysterectomy for early-stage endometrioid endometrial cancer, stratified as obese (BMI 30kg/m²) or nonobese (BMI < 30kg/m²).
The researchers used bacterial 16S rRNA high-throughput sequencing to characterize endometrial cancer microbiota and the web-based tool MicrobiomeAnalyst to analyze data. They also assessed the microbial component of endometrioid endometrial cancers included in The Cancer Genome Atlas database.
Results of the database analysis showed endometrial cancers of Black women had higher microbial diversity than those of white women.
Researchers also found that among those with obesity, Black women had higher Lactobacillus acidophilus abundance in tumors, but lower abundance of Dietzia (P < .001) and Geobacillus (P < .001). Compared with nonobese white women, obese white women had increased microbial diversity (P < .001) and abundance of Firmicutes (P = .014) and OD1 (P = .006) in tumors. Among obese women, tumors of Black women had higher microbial diversity (P < .001) and increased abundance of Firmicutes, Cyanobacteria and OD1 phyla compared with tumors of white obese women (P < .001).
“Microbial diversity was higher in endometrial cancers from Black women vs. white women in both our institutional data and The Cancer Genome Atlas database subset,” Hawkins said. “Distinct microbiota profiles were found between endometrial cancers of obese Black women vs. obese white women, and two bacterial enzymes and several metabolic pathways were differentially expressed according to race. Thus, these pathways are worthy of further exploration as potential microbiome-related targets in the prevention of endometrial cancer.”
Hawkins acknowledged limitations of the study, including the use of banked tumor specimens, which can raise concerns for specimen contamination, the use of different methodologies for microbial assessment and the small sample size, which included fewer Black women than white women.
“Therefore, we are in the process of implementing a prospective study that controls the collection and processing of endometrial cancer specimens in a sera fashion that includes a planned sample size of 150 Black women and 150 white women,” Hawkins added. “We are also expanding our cohort beyond early-stage disease to advanced-stage disease, as this is what ultimately accounts for death in Black women with endometrial cancer.”
Perspective
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Beginning with the publication of the Human Microbiome Project in 2012, it has been widely accepted that the composition of the microbiome in tissue contributes significantly to pathologic processes. Gynecologic cancers are no exception.
Compared with other cancers, the microbiome has been underexplored as a contributing factor in endometrial cancer, the most common gynecologic cancer, in addition to racial differences that play an important role in the development and course of this disease. Indeed, although more white women are diagnosed with endometrial cancer, it kills twice as many Black women. Studies thus far have been limited by low sample sizes, with many composed entirely of specimens from white women.
Hawkins and colleagues addressed racial disparities in endometrial cancer by evaluating the uterine microbiome. Using institutional samples of early-stage disease vs. benign controls, the group identified greater microbial diversity in endometrial cancer from Black women and distinct microbiota in Black women with obesity, a group known to be especially disproportionately affected by endometrial cancer.
This work on the role of the microbiome in the development of endometrial cancer opens the possibility of early intervention to prevent or screen for disease. Late diagnosis of Black women is thought to contribute to higher mortality. Microbiome biomarkers, thus, offer the tantalizing future possibility of modified screening mechanisms to identify at-risk women. Proinflammatory environments, such as those caused by shifts in the microbiome, are well-known hallmarks of cancer development. Mounting evidence in the field suggests NSAID use may reduce the risk for endometrial cancer. Data such as those presented by Hawkins and colleagues invite us to question the intriguing interplay between the uterine microbiome and the anti-inflammatory, antimicrobial properties of these commonly used drugs in cancer prevention.
Additionally, interventions like probiotic use and microbial transplant are actively being explored for vaginal health but could translate to beneficial health outcomes higher in the reproductive tract than the uterus.
Studies of other tissue microbiomes, such as the gut, have demonstrated that the microbiome can affect levels of estrogen, a key driver of endometrial cancer. Estrogen is, in fact, found in higher levels in obese women who are at greater risk for endometrial cancer and is a potential contributor to racial disparity in the disease, as greater rates of obesity exist in the Black population.
Moreover, for women already diagnosed with endometrial cancer — particularly Black women, who are often diagnosed at later stages with more aggressive subtypes — the relationship between the microbiome and immunotherapy may influence disease treatment. It is clear from studies on the gut microbiome that bacterial populations influence response to anticancer treatment from drugs such as immune checkpoint inhibitors, including toxicity.
Further, modulating the microbiome prior to therapy can optimize patients for improved response. What role the uterine microbiome may play as we combat endometrial cancer with new immunotherapies is a provocative clinical question.
The investigators take an important step toward equity in endometrial cancer research by considering the uterine microbiome in terms of race and comorbidities, such as obesity. Their work has potential far-reaching implications for women with endometrial cancer as we work toward elimination of disparities in prevention, diagnosis and treatment for a cancer that disproportionately impacts Black women.
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Hawkins G, et al. Abstract PR-07. Presented at: American Association for Cancer Research Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved (virtual); Oct. 2-4, 2020.