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Bacteria & Breast Cancer

The Evidence Is Mounting

Perron, Michelle

doi: 10.1097/01.COT.0000529889.79612.75

In the decade since the NIH centralized efforts to understand the power of the human microbiome, discoveries have ranged from the anticipated to the surprising. One of the latter was described recently in a study of breast tissue, oral cavity, and urinary tract microbiomes in patients with and without breast cancer (Oncotarget 2017;8(50):88122-88138).

The authors, who are based at the Cleveland Clinic Genomic Medicine Institute, the Taussig Cancer Institute's Comprehensive Breast Cancer Program, and Pathology and Laboratory Medicine Institute, found that local breast microbiota differ among patients with and without breast cancer, and that these microbiota exist as far away from the breast as the urinary tract. These researchers identified Methylobacterium in the breast tissue of participants unaffected by breast cancer, a finding that will spur further research—and that could have a significant impact on efforts to prevent breast cancer.

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Study Description

The hypothesis for this study grew from evolving evidence of an influence on breast carcinogenesis by the gut microbiome. The possibility that this microbiome reacts to high-fat, low-fiber diets and exposure to antibiotic medications by altering systemic estrogen levels has been a focus of breast cancer research for years. This Cleveland Clinic team developed the study to examine the hypothesis that cancerous breast tissue is associated with a microbiomic profile distinct from that of benign breast tissue, and that microbiomes of more distant sites—specifically the oral cavity and urinary tract—would reflect dysbiosis as well.

Fifty-seven women with invasive breast cancer who were scheduled for mastectomy and 21 healthy women who had scheduled cosmetic breast surgery were enrolled in this study. Of this study population of 78 women, breast tissue could not be obtained at the time of surgery from 13 with breast cancer and one healthy control. From these patients, researchers obtained only urine and oral rinse samples for examination. For two breast cancer patients, urine and oral rinse samples were not obtained and thus only their breast tissue samples were analyzed.

Patients with cancer had a significantly higher mean age than the patients without cancer (55 years vs. 43 years). In addition, mean BMI (27 vs. 35) differed significantly. Forty-seven of the patients with breast cancer were white, nine were black, and one identified her ethnicity as “other.” Eighteen women with breast cancer were premenopausal. Among the women without breast cancer, 11 were white, nine were black, and one identified as “other” ethnicity. Fourteen of the women without breast cancer had not entered menopause. Most women in the study reported their most recent antibiotic use as greater than 6 months prior.

The researchers examined the subjects' breast tissue microbiome, oral rinse microbiome, and urine microbiome. In the breast tissue samples, Methylobacterium was noticeable. The presence of this bacteria was significantly decreased in hormone receptor-positive samples compared to hormone receptor-negative samples and in samples with histopathologic evidence of lymphovascular invasion versus those without. In the oral rinse and urine microbiome samples, the researchers found no significant differences between the patients with breast cancer and the patients without breast cancer.

Important distinguishing factors among the subjects were evident, however. The microbiome of urine from peri- and postmenopausal women was characterized by decreased Lactobacillus and increased appearance of other bacteria, including Varibaculum, Porphyromonas, Prevotella, Bacteroides, and members of the class Clostridia. “Using LEfSe, we identified four genera, five families, two orders, and one class that were significantly increased in cancer relative to noncancer patient urine samples after controlling for menopausal status,” the authors wrote. These findings suggest that urinary microbiomes may play a role in breast cancer.

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Findings & Future Plans

The key takeaways from this study are a notable difference in microbiomes between patients with breast cancer and patients without, and the identification of a potential influence by Methylobacterium in women unaffected by breast cancer.

“Analysis of breast tissue revealed that cancer and noncancer patients had significantly different microbiomes, a difference characterized largely by the decreased abundance of Methylobacterium in patients with cancer,” the authors wrote. “Urine sample analysis showed that, while the biggest microbiomic differences were due to menopausal status, cancer patients harbor urinary microbiomes with increased abundance of gram-positive bacteria associated with skin flora.”

These findings suggest that more similarities than differences exist between the overall breast tissue microbiomes of tumors and adjacent normal tissues, according to researchers. Histologic processing of tissue samples may have influenced some results, and the authors recommend larger studies. “If adjacent benign breast tissue is truly more similar to that of carcinoma tissue than to breast tissue from women without cancer, it may imply a breastwide predisposition to carcinogenesis,” the study authors noted. “Alternatively, these similarities may suggest that the microbial differences observed are secondary to the effect of the tumor rather than a causative agent.”

In an interview with Oncology Times, two of the researchers shared perspective on this study. Stephen R. Grobmyer, MD, a surgical oncologist and Director of the Breast Center at Cleveland Clinic, noted that the research broke new ground.

“A handful of studies have been done [on the influence of the microbiome in breast cancer], but most haven't analyzed breast tissue tumor itself,” Grobmyer said. “The other limitation of most other studies is that tissue wasn't collected for this type of analysis. When you're studying bacteria in this type of tissue, you have to handle tissue meticulously. Ours is the only study to rigorously control the environment in which samples were gathered.”

Charis Eng, MD, PhD, Chair of Cleveland Clinic's Genomic Medicine Institute and Director of the Center for Personalized Genetic Healthcare, added that validation of the findings—using the same meticulous tissue handling practices—is needed.

When research findings are surprising, particularly in a common disease such as breast cancer, two reactions are typical, Eng explained. “When there is something cutting-edge, one group is delighted and the other group says, ‘I don't believe it.’ That's why we need the findings to be validated using the same techniques.”

Further research on the breast cancer microbiome will “inform more precise risk assessment and predictive information to aid in the prevention and management of breast cancer,” Eng said.

In the meantime, Cleveland Clinic is proactively working to help women at risk for breast cancer by analyzing bacteria influences. Grobmyer and Eng described a program in which patients who are at elevated risk for breast cancer by virtue of inherited genetic mutations are enrolled in a high-risk clinic and followed by Cleveland Clinic researchers. “We are prospectively studying bacteria in those patients to see if we can identify in stool, urine, or blood bacteria that might be associated with the development of breast cancer in those patients. Only with longitudinal studies can we examine this,” he said.

Given the rapid advancements in genomic understanding, is it possible that someday a child or adolescent born into a high-risk family could take probiotics to reduce her risk of breast cancer?

“Sure ... that's what research is about,” Eng declared. “The sky's the limit.”

Michelle Perron is a contributing writer.

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