Evidence shows that breast cancer risk and outcomes vary significantly across races and ethnicity, and understanding why these disparities exist is critical for the improvement of patient care, outcomes, and quality of life.
Recent research demonstrated that the microbiome and immune microenvironments of breast tumors vary significantly among women of different races, according to senior study author Dipali Sharma, PhD, Professor of Oncology in the Women's Malignancies Disease Group with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and a John Fetting Fund for Breast Cancer Prevention researcher. These findings, which were recently published in npj Breast Cancer, have potential clinical implications for the prediction of disease progression and/or response to treatment (2023; https://doi.org/10.1038/s41523-023-00505-6).
White women have the highest lifetime risk of breast cancer incidence (13%) when compared with American Indian and Alaska Native (8%), Asian & Pacific Islander (11%), Black (12%), and Hispanic (11%) women, according to Sharma and colleagues, who noted that the risk of breast cancer among younger Black women-under the age of 45 years-is higher versus their age-matched White counterparts. While the incidence of breast cancer among Asian women has historically been lower than their Western counterparts, the research team noted an exponential increase in Asia and Southeast Asia in recent years.
"Breast cancer-related mortality has been on a decline for the past several decades, but Black women are at a 40 percent higher risk of dying because of breast cancer," emphasized Sharma, while discussing her team's research with Oncology Times. "Black women are likely to develop a more aggressive form of breast cancer-triple-negative breast cancer-at a younger age," she said. "This disparity in breast cancer-related mortality prompted us to examine factors other than cancer cells themselves. Since the breast harbors rich microbiota, we aimed to examine the microbial population in breast tumors from women of different races."
Study Details
Genomic and metagenomic data was examined from The Cancer Genome Atlas (TCGA) cohort, which included 1,018 breast cancer patients from different races-Asian (65 patients), Black (257 patients), and White (696 patients). TCGA data includes self-reported race groups in the U.S.
"Self-reported race in the U.S. is largely associated with socioeconomic status, geographic location, and access to health care among other factors; and has been used by multiple studies to determine the biological differences among race groups," Sharma and colleagues stated. Among the TCGA Asian dataset, the study authors reported that 74 percent of samples were collected in Vietnam, 9 percent in the U.S., and 3 percent in Pakistan. The remaining 15 percent were gathered from repositories around the U.S.
"In the TCGA Black dataset, only two out of 257 Black breast cancer patients were Hispanic, which accounts for less than 0.8 percent of the sample population," they noted. "Hence, we consider this dataset to be a fair representation of the non-Hispanic Black group."
Data showed unique cellular, microbial, and genomic features among the breast tumors of Asian, Black, and White women. These findings, according to the study authors, could potentially help personalize care and/or predict disease progression.
Sharma and colleagues analyzed the specific 64-cell signatures of breast tumors among the patients using a web-based tool. This analysis revealed distinct, statistically significant variations among races in 11 of the cell types. The study authors observed the most distinct difference between tumors from Black and White women. Comparatively, the tumors of Asian and Black women had the least pronounced differences.
"The tumors from Black women had significantly higher levels of activated dendritic cells, B cells, epithelial cells, megakaryocyte-erythroid progenitors (MEP), mesenchymal stem cells, sebocytes, and Th1 cells, and significantly lower proportions of endothelial cells, hematopoietic stem cells, and smooth muscle cells compared to the tumors from White women," Sharma and her team reported. "The only significant difference between the tumors from Asian and Black women was the higher proportion of smooth muscle cells in the Asian group in comparison to the Black group."
Additionally, the researchers found a significantly lower proportion of hematopoietic stem cells in tumors from Asian women when compared with White women. Conversely, MEPs and Th1 cells were significantly higher in tumors from Asian women. Other observations showed that interferon gamma was higher among tumors from Asian women and CXCL9, which plays a role in immune activation, was overexpressed in tumors from Black women.
Sharma and colleagues also examined the microbiota among these tumors and found that the breast tumor microbes of Asian women did not differ significantly when compared to either their Black or White counterparts. However, the data revealed significantly diverse microbe compositions among breast tumors from Black and White women.
"Acinetobacter, Citrobacter, Enterobacter, Staphylococcus, Paracoccus, and Akkermansia were differentially abundant in breast tumors from Black women compared to the White group whereas Actinomyces and Veillonella were plentiful in breast tumors from White women in comparison to Black women," the study authors stated.
Among Asian women, potential race-specific microbial biomarkers of breast cancer identified by the researchers correlated with genes involved in tumor aggressiveness, blood vessel growth, tumor cell migration and metastasis, and the cancer pathways GLI1 and Notch. Pseudomonas and Methylobacter were recognized as microbial biomarkers.
"The role of microbiota in breast cancer is only starting to be revealed and the racial differences have hardly been considered. The microbiome is cumulatively shaped by various environmental, lifestyle, dietary, disease, and treatment-associated factors," Sharma and investigators explained. "It is important to note that Asian, Black, and White women face different socioenvironmental stressors (e.g., poverty, racism, discrimination, etc.) in the U.S.
"It is plausible that these differences in exposures may have consequences in differences in the tumor microenvironment," they suggested. "Microbiota is an important regulator of immunity, hormone metabolism, and energetics and a dysbiosis significantly impacts cancer risk, shapes the tumor microenvironment, and determines therapy response."
Importantly, the researchers also found that several oncogenic pathways were significantly upregulated in tumors from Black women, including phosphatidylinositol signaling, mTOR signaling, calcium signaling, and phosphotransferase system.
"ABC transporters were also upregulated in tumors from Black women, which are known to be responsible for the development of chemotherapy resistance in breast cancers," Sharma and colleagues wrote. "Surprisingly, VEGF signaling was downregulated in the same set. Two important oncogenic pathways, Notch and WNT, were also found to be upregulated in tumors from Black women (though not statistically significant)."
In an analysis of gene expression profiles, the researchers identified 394 differentially expressed genes between breast tumors from Asian women versus Black women. The same examination identified 381 and 127 differentially expressed genes to be significantly different between Black women versus White women and Asian women versus White women Sharma and colleagues uncovered, respectively.
When looking at the connection between genes and microbial biomarkers, the study authors found that the gene GLI1 has a positive correlation with the bacteria Terrabacter in tumors from Asian and Black women. The gene showed a negative correlation with Succinomonas in tumors from both races. "These results indicate a possible role of intratumor microbiota in tumor vasculogenesis and thus warrant further investigation," Sharma and colleagues noted.
By investigating the metabolic features of intratumoral microbes, the researchers found a "significant differential enrichment of environmental information processing pathways, oncogenic pathways, and lipid metabolism pathways."
"Concomitantly investigating tumor-centric, tumor immune microenvironment-related, and microbial alterations, our study provides a comprehensive understanding of racial disparities in breast cancer and warrants further exploration," the investigators concluded.
Sharma acknowledged that sample size is a significant limitation, and larger studies need to be conducted to identify key microbes of importance. The Johns Hopkins-led research team plans to validate their findings in a larger cohort of patients. Additional investigative aims include gaining a better understanding of the impact microbes in breast tumors have on disease progression, as well as developing microbe-based biomarkers, according to Sharma. "The study paves the path for further explorations as we try to understand this whole network more mechanistically," she said.
Clinical Significance
Despite significant and ongoing therapeutic advancements in breast cancer, racial disparities in clinical outcomes remain a challenge that must be addressed.
"The factors governing racial disparities in breast cancer are multifactorial and can include socioeconomic status, access to primary care, timely referrals, and health and nutrition," Sharma said, in a statement. "However, it is important to identify additional modifiers for these differences. Our study demonstrates that the microbiome and immune microenvironments of breast tumors also vary significantly among women of different ethnicities and could potentially be used as biomarkers to predict disease progression or response to treatment."
This is the first study that shows the differential enrichment of microbes in breast tumors from women of different races, according to Sharma, who noted that "most research projects aiming to understand racial disparity in cancer have focused on tumor-related changes, but this research looks beyond the tumor cells and identifies differential enrichment of residential bacteria.
"Moving forward, we can plan studies encompassing tumor-centric changes, as well as tumor microenvironment-related changes, including resident microbes, to provide a more comprehensive picture of the key processes related to tumor initiation and development in women of different races," she told Oncology Times, while noting that the overall aim is to "develop microbe-based biomarkers for breast cancer initiation and progression and explain the higher burden of breast cancer in Black women."
Catlin Nalley is a contributing writer.
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