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Researchers have found relationships between the oral microbiome and esophageal cancer; between the vaginal and uterine microbiomes and endometrial cancer; and between the gut microbiome and the efficacy of checkpoint inhibitors.
Jennifer A. Wargo, MD, MMSC
In the early 20th century, research findings about the nature of microbes upended the traditional understanding of science and medicine. The acceptance of germ theory revolutionized medical care, and ultimately led to improved public health and longer life spans. A similar microbe-driven revolution may be afoot in oncology, as researchers uncover and untangle the relationships between the microbiome and cancer.
Between 2005 and 2015, the number of articles published about the microbiome and cancer increased by nearly 2000%.1 Researchers have found relationships between the oral microbiome and esophageal cancer; between the vaginal and uterine microbiomes and endometrial cancer; and between the gut microbiome and the efficacy of checkpoint inhibitors. And, although the research is young, the results so far suggest that the microbiome may, at least in part, help answer 2 of oncology’s most persistent questions: What causes cancer? Why do some people respond favorably to cancer treatment whereas others do not?
The microbiome is broadly defined as the “collective genomes of the microbes, composed of bacteria, bacteriophage, fungi, protozoa, and viruses, that live inside and on the human body.”2 Altogether, these bacteria and microorganisms are characterized as the microbiota, an “ensemble” that inhabits the epithelial barrier surfaces of the human body and influences a range of physiological functions, including metabolism and immunity.3
Researchers from the University of North Carolina at Chapel Hill describe interactions between the microbiota and bodily systems within the context of the “Hallmarks of Cancer” that Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, have elucidated (FIGURE).4 Fulbright and colleagues maintain that these interactions are so complex that the focus should be on the microbial metabolome, the collection of low-molecular-weight molecules in the cell, rather than on individual metabolites.4
Two decades ago, it was nearly impossible to systematically study the human microbiome because most human bacteria cannot grow outside of the human body. Research initiatives such as the Human Microbiome Project, which the National Institutes of Health launched in 2007 as an extension of the Human Genome Project,2 have helped expand knowledge about the microbiota. Advances in genomic sequencing also have brought the microbiome into reach, scientifically speaking. Now, researchers can sequence the DNA of cells and identify the bacterial profile based on DNA formation. As a result, researchers have identified distinct microbiomes of different organs within the body, as well as differences between the microbiomes of individuals.Ninety-nine percent of the microbial mass in the human body is found within the gastrointestinal (GI) tract,5 but the microbiota exerts systemic as well as local effects on physiological functions. In terms of carcinogenesis, the GI microbiota has been linked to cancers in the GI tract and in other organs (TABLE).3 Although GI activity of these microorganisms has been extensively studied, understanding is also growing about the microbiota in other epithelial barriers, such as the mouth and skin.3
Scientists and physicians, for instance, have long been aware of a link between poor oral health and cancer. “We know that periodontal disease mysteriously is related to increased risk of upper gastrointestinal cancer,” said Jiyoung Ahn, PhD, an associate professor of Population Health and Environmental Medicine at NYU School of Medicine, and the associate director of Population Science at NYU Perlmutter Cancer Center in New York City. “But people didn’t have a good explanation why. Some people didn’t believe it at all.”
Research into the microbiome reveals that the same bacteria responsible for poor oral health may also be related to the development of cancer. A 2016 study published in Gut found that the presence and concentration of particular types of oral bacteria may increase or decrease the risk of developing cancers of the upper GI tract.6
The oral pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are associated with an increased risk of pancreatic cancer, while a greater abundance of Fusobacteria and its genus Leptotrichia is associated with decreased risk. Study participants whose oral microbiomes included Porphyromonas gingivalis had a 59% greater risk of developing pancreatic cancer than those whose microbiomes did not contain the bacterium. Participants whose oral microbiomes contained Aggregatibacter actinomycetemcomitans were at least 50% more likely to develop the disease.6
A 2017 study published in Cancer Research provides further evidence of a link between the oral microbiome and GI cancer.7 Researchers analyzed the oral microbes of more than 120,000 people and tracked their health over the next decade, noting which participants developed esophageal cancer and which did not. “We then retrospectively went through their samples to see whether the bacteria profile from when they were healthy carried bacteria related to the subsequent development of cancer,” said Ahn, who was a principal investigator.
The presence of Tannerella forsythia, a pathogen commonly linked to gum disease, was associated with a 21% increased risk of esophageal adenocarcinoma; an abundance of Porphyromonas gingivalis was linked to a higher risk of esophageal squamous cell carcinoma. Streptococcus and Neisseria were associated with a 24% decrease in risk of esophageal cancer.7
Another study by the same team, published in JAMA Oncology online in January 2018, demonstrates a connection between the oral microbiome and head and neck cancers.8 It also shows that “carrying Neisseria abundance is associated with a decrease of head and neck cancer,” said Ahn. Neisseria, known to play a role in carcinogenic metabolism, was found in lower concentrations in heavy smokers, suggesting a biologic explanation for the link between smoking and the eventual development of cancer. “This is the first line of research to show how bacteria is related to the development of preventable cancers,” said Ahn.
Other studies have demonstrated a connection between the microbiome and colorectal cancer (CRC). High levels of Fusobacterium nucleatum, a microbe normally found in the mouth and associated with periodontal disease, are often present in CRC tissue,9 and is related to an increased risk of CRC.10 A 2017 study by researchers at Dana-Farber Cancer Institute suggests that the microbiome plays a role in cancer metastasis as well, because Fusobacterium was found both in CRC tumors and liver metastases.11 “Our findings suggest that the microbiome is a consistent feature of colorectal cancers, regardless of whether it is a primary cancer or a metastasis of that cancer,” said the study’s lead author, Susan Bullman, PhD, in a statement.
The microbiome makeup remained consistent even when researchers transplanted CRC tumor tissue into mouse models. In additon, when researchers treated the mice with antibiotics that target Fusobacterium, tumor cell proliferation and growth declined.11
“The fact that tumor cell growth and proliferation slowed in mice treated with a targeted antibiotic may indicate that the bacteria help drive tumor cell growth, but that is very much an open question,” said Matthew L. Meyerson, MD, PhD, the study’s senior author and director of Cancer Genomics at DanaFarber, in a statement.Several studies now suggest that the composition of patients’ gut microbiomes may explain differences in patients’ response to treatment. Irinotecan is a first-line treatment for patients with metastatic CRC, but can cause severe diarrhea in up to 40% of patients.12 A 2017 study published in npj Biofilms and Microbiomes links the gut microbiome to irinotecan toxicity; patients with “a high turnover microbiota metabotype” had an elevated risk for irinotecan-dependent adverse drug responses.13
Similarly, work by Jennifer A. Wargo, MD, MMSc, an associate professor in the departments of Surgical Oncology and Genomic Medicine at The University of Texas MD Anderson Cancer Center, suggests that differences in individuals’ microbiomes may account for varying responses to immunotherapy. Wargo and her team examined oral, gut, and fecal microbiome samples of 112 patients with melanoma treated with anti—PD-1 immunotherapy through whole-genome sequencing of the microbiome, molecular profiling through whole-exome and RNA sequencing, and immune profiling through immunohistochemistry, flow cytometry, and cytokine analysis.14 They then compared significant differences in the microbiomes of responders versus nonresponders.
“There is a relationship between the gut, the tumor microenvironment, and the bacteria within our intestine that can shape our immune response, and even shape how patients respond to therapy,” Wargo said in an interview with OncologyLive®. “Patients who responded had a much higher diversity of bacteria within their gut and a different composition of the gut bacteria, with more Faecalibacterium, Ruminococcaceae, and Clostridiales. Patients who failed to respond to PD-1 blockade had a low diversity of the gut microbiome and a high abundance of Bacteroides,” Wargo said.
“We also found that both the diversity and the composition [of the microbiome] were associated with a prolonged progression-free survival. And that was an independent prognostic variable.” Additionally, investigators gathered fecal samples from responders to anti—PD-1 therapy and transplanted them into germ-free mice, according to findings presented at the 2017 Society for Immunotherapy of Cancer Annual Meeting by Vancheswaran Gopalakrishnan, PhD, a postdoctoral fellow in Wargo’s laboratory.15 They first evaluated the impact on the mice immune system, and then implanted a melanoma tumor.
The experiment’s results indicated that the mice that received the transplants had delayed tumor growth and a better response to therapy. Notably, the mice had a significantly higher presence of Faecalibacterium in stool samples. Additionally, they had enhanced CD8 immune infiltrates and fewer suppressive myeloid cells.
A phase II clinical trial currently in progress will further assess the link between the microbiome and response to immunotherapy. The open label, single-arm study (NCT02853318) is examining how patients with ovarian, fallopian tube, or peritoneal cancer respond to combination therapy with pembrolizumab (Keytruda) plus bevacizumab (Avastin) and cyclophosphamide.
Researchers also are analyzing blood, stool, vaginal, and skin microbial samples to see whether changes in microbiome composition may be related to response to treatment and patient outcomes. Study participants will be assessed 30 days after treatment, then every 3 months for a year, and every 12 weeks and 6 months thereafter. The hope is that such research will allow physicians to more precisely target treatment. “Should we be profiling the gut microbiome in patients going on immunotherapy? That is something to consider, but my hunch is yes,” said Wargo.Since the microbiota plays such an extensive role in human physiology, it is not surprising that many factors would influence its composition, including an individual’s genetic profile, lifestyle, incidence of disease, and use of antibiotics.3 For example, research findings presented at the 2017 Genitourinary Cancers Symposium raised suspicions about the relationship between gut microbiota and antibiotics and their effect on responses to immune checkpoint blockade agents. Retrospective study results demonstrated that the use of antibiotics up to a month before treatment with a checkpoint inhibitor may decrease the efficacy of the immunotherapy agent.16
In patients with metastatic renal cell carcinoma, those who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate of 2.3 versus 8.1 months for those who had not received antibiotics when treated with checkpoint inhibitor immunotherapy (P <.001). In a group of 62 patients who were treated with nivolumab (Opdivo) monotherapy, patients who had not taken antibiotics showed a higher PFS rate, which also achieved statistical significance (P <.009). Overall survival also was significantly higher in patients who had not recently taken antibiotics (P <.003).16
“Immune-based therapies for cancer may have a complex interplay with the host’s microbiome,” said Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope in Duarte, California, commenting on the findings. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”Information about the microbiome may also eventually be used to assess an individual’s risk of certain cancers, and possibly enable healthcare providers to intervene and interrupt disease progression.
A 2016 study published in Genome Medicine examined the vaginal and uterine microbiomes of women with endometrial cancer, endometrial hyperplasia, and benign uterine conditions.17 Researchers discovered a structural microbiome shift in the cancer and hyperplasia cases; they also found differences in the bacterial composition of the vaginal microbiome in women with and without endometrial cancer. 17
“These findings provide important insights into the etiology or manifestation of the disease with broad implications for biomarker development in the early detection of, and screening for, endometrial cancer,” said Marina R. WaltherAntónio, PhD, assistant professor of surgery at Mayo Clinic in Rochester, Minnesota, and lead author of the study, in a statement. “There’s a possibility that we can do a vaginal swab in a patient and have an indication as to whether or not the patient has cancer.”
Ahn’s research, which demonstrated a link between certain types of oral microbes and pancreatic cancer and head and neck cancer, could point the way toward early detection of cancers that currently claim many lives.
“Right now, there is no way we can detect pancreatic cancer early,” said Ahn, noting that a lack of early detection is one reason that the 5-year survival rate for pancreatic cancer is only 7%.18 “I’m hoping this research will help lead the way to detect this disease earlier in the future,” she said.Ahn’s team plans to study whether the use of probiotic supplements can alter the oral microbiome and decrease the risk of upper GI cancers in humans. “Right now, we have identified specific bacteria related to cancer. The second step is designing a preventive trial for the future,” she said. “With antibiotics or probiotics, we can modify the bacteria. Then, we can do a randomized trial.”
Administration of probiotics has already been shown to slow disease in mouse models. A 2016 study by Finnish and Chinese researchers found that mice that were fed a microbial cocktail containing Lactobacillus rhamnosus GG, Escherichia coli Nissle, and heat-inactivated VSL#3, a pharmaceutical composed of multiple bacterial strains, experienced much less tumor growth than mice that were not fed the cocktail.19 Both groups of mice were injected with liver cancer; the tumors of mice that received the cocktail demonstrated a 40% reduction in tumor weight and size compared with tumors affecting the control group.19
Administering antibiotics that target specific bacteria to mice with cancerous tumors has also been shown to slow disease. After researchers at Dana-Farber implanted CRC tumor tissue into mouse models, they treated the animals with metronidazole, an antibiotic that kills Fusobacterium, a microbe that is now known to be associated with colon cancer. In treated animals, tumor cell proliferation and overall tumor growth declined. These observations, investigators said, “argue for further investigation of antimicrobial interventions as a potential treatment for patients with Fusobacterium-associated colorectal cancer.”20
It is also possible that research into the gut microbiome may reveal bacterial strains that could be developed into immunotherapies. Vedanta Biosciences and NYU Langone Medical Center are currently collaborating on the development of microbiome-derived immunotherapies for patients with cancer being treated with checkpoint inhibitors.21No one is yet sure what accounts for differences in individuals’ microbiomes, or even which changes are clinically significant. Findings from research conducted so far strongly suggest that the microbiome influences the immune system, and that such influence may contribute to the development of disease or the response to treatment. However, much work remains to be done.
“We are now in a discovery phase,” said Ahn. “In the next 5 or 10 years, I really want to know whether we can use this information to actually prevent some cancer.”