Findings from a new NCI study suggest an imbalance of the gastric microbiome may be increasing the incidence of a potentially new type of lower stomach cancer mainly impacting non-Hispanic white Americans under age 50 and among the first generations to be exposed to the widespread use of antibiotics.
The researchers found incidence rates for noncardia gastric cancer fell by 2.6 percent per year in non-Hispanic white Americans over 50, while for those under 50 the rates increased 1.3 percent per year (J Natl Cancer Inst 2018; doi:10.1093/jnci/djx262).
According to the researchers, based at the Division of Cancer Epidemiology and Genetics at the NIH, atrophic gastritis, triggered by either Helicobacter pylori infection or autoimmunity, is the first step in the development of lower stomach cancer, or noncardia gastric tumors.
However, in recent decades, the prevalence rates of these two major causes declined and increased, respectively, with changes in Western lifestyles, including reduced exposure to bacteria with better hygienic practices.
Non-Hispanic White Women at Greater Risk
For the study, researchers assessed gastric cancer incidence trends for race and ethnic groups in the U.S. between 1995 and 2013, using the SEER Database and the North American Association of Central Cancer Tumor Registries in 45 states, which cover roughly 80 percent of the U.S. population.
Among 137,447 individuals and 4.4 billion person-years of observation, the researchers found non-Hispanic whites over age 50 living in counties with less than 20 percent poverty had the highest incidence of noncardia gastric cancers with an age-standardized rate of 2.2 per 100,000 person-years.
The increase in noncardia gastric cancer occurred more often in younger non-Hispanic white women than men, according to the researchers, with incidence among women born in 1983 twofold (95% CI=1.1-fold to 3.6-fold) greater than those born in 1951.
Non-Hispanic white women also had the largest birth cohort split with those under age 50 having an estimated annual percentage change of 2.6 percent (95% CI, 1.7-3.4) per year, compared with -2.2 percent (95% CI, -2.5 to -1.9) per year among women over 50. Among Hispanics, researchers observed slightly rising rates in those under 50 compared with decreasing rates in older individuals. There was no increase observed in young non-Hispanic black women or those from other races.
“The rapid increases in younger women are especially alarming,” noted Martin Blaser, MD, the Muriel and George Singer Professor of Medicine, Professor of Microbiology, and Director of the Human Microbiome Program, and Yu Chen, MD, PhD, Associate Professor for the Department of Population Health, Department of Environmental Medicine, and Department of Medicine, both of the New York University School of Medicine, in an editorial that complemented the study. The pair called for more research to confirm and expand upon their findings, which they believe provide evidence of “a new [type] of gastric cancer among us.”
The “strong sex effect” (increasing incidence of lower stomach cancer in women) is one of three lines of evidence verifying the tumors represent a new type of lower stomach cancer, the researchers contend, along with the “age-specific effect” (increasing incidence among younger generations), and the location of the majority of new tumors located in the gastric corpus and adjacent areas.
Exposure to antibiotics, which began to be used in a widespread basis in the 1950s, may also play a role, noted the study's lead author, M. Constanza Camargo, PhD, of NCI's Division of Cancer Epidemiology and Genetics.
“We are seeing an increasing risk of this cancer in people born after 1950, and that coincides with the introduction of antibiotics,” Camargo said. “The increase in noncardia gastric cancer rates is more pronounced in females than males, and we know that females take more antibiotics than males.” However, she believes antibiotics should continue to be used whenever medically necessary.
Considering the Carcinogenesis
Cardia tumors may start with damage from acid reflux and/or metabolic syndrome, similar to esophageal adenocarcinoma. While non-atrophic gastritis and a sequence of increasingly severe mucosal lesions typically precede noncardia tumors , said Asha Nayak, MD, Co-Leader of the Gastrointestinal Cancer Program and Associate Professor of Medicine (Hematology/Oncology), Georgia Cancer Center at Augusta University.
“Chronic H. pylori infection is a well-known cause of this pathologic cascade, variably progressing to atrophic gastritis, intestinal metaplasia, and dysplasia. However, autoimmune gastritis is increasingly recognized as a contributing etiology, with or without the presence of H. pylori,” Nayak told Oncology Times.
Chronic infection with H. pylori and autoimmune gastritis, in which the immune system attacks cells in the lining of the stomach, can overlap and, as a result, some patients with noncardia gastric cancer may have both, Nayak explained. As Western lifestyles have changed in recent decades, H. pylori prevalence has decreased while autoimmune disorders have increased, she said. H. pylori infection mostly occurs in childhood via person-to-person transmission and, without antibiotic treatment, remains throughout a person's life, she added.
“Presumably due to improvements in sanitation, as well as widespread use of antibiotics, H. pylori infection has been progressively disappearing, particularly in industrialized nations. Thus, the proportion of H. pylori-infected individuals is lower with each succeeding generation,” she explained. “On the other hand, the proportion of people developing allergic and/or autoimmune disorders has been increasing with each generation.”
Though unproven, the connection between antibiotics and the increase in noncardia cancer is plausible, said Anton Bilchik, MD, PhD, Professor of Surgery and Chief of Gastrointestinal Research at John Wayne Cancer Institute and Chief of General Surgery at Providence Saint John's Health Center in Santa Monica, Calif. “This is a very important population-based study with unexpected, provocative findings. It makes it clear that gastric cancer is increasing in younger people despite declining overall.”
The increase in people under 50 getting noncardia stomach cancer despite overall declining rates, and the fact the increase is more significant for women than men, is similar to colon cancer, Bilchik told Oncology Times. In both cases, “the increase does not appear to be related to known carcinogenic factors, such as obesity, but rather an autoimmune gastritis. This may be caused by disruption of the bodies of microbiome by taking antibiotics or other yet unknown factors,” he explained.
Clinical implications from the findings of the NCI study, Bilchik said, would appear to be that “gastric cancer can potentially be prevented through a healthy lifestyle, nutrition, and the avoidance of unnecessary medication, such as antibiotics, which may disrupt the bacteria in the stomach that protect against cancer.”
Predicting the Future
Earlier studies have shown a similar increase in incidence among young people, but the researchers were not able to distinguish between Hispanic white and non-Hispanic white individuals due to lack of specificity in census data.
By contrast, the data that included the Camargo-led study not only showed decreasing rates of noncardia cancer in people over 50 while incidence went up in later generations, but also allowed the researchers to predict two major reversals in gastric noncardia cancer in the U.S., noted Nayak, from the Georgia Cancer Center.
First, they project incidences will be higher in women than men by 2025, reversing the current trend. Second, by 2030, overall incidence of noncardia cancer will no longer be decreasing. As a result, “in coming decades, the medical community may need to re-envision the ‘typical’ noncardia gastric cancer patient,” said Nayak.
Additionally, the researchers question one of the leading explanations for changing noncardia cancer incidence in young people: an increase in H. pylori bacterial infections due to immigration from countries with higher infection rates, said Nayak. Instead, they suggest a decrease in bacterial exposure due to modern living conditions and the beginning of the widespread use of antibiotics in the 1950s may explain the increase of noncardia cancer in younger Americans.
But while autoimmune gastritis may be similarly increasing, “there are no firm data on prevalence or incidence,” Nayak said. “Why these increases are occurring is still uncertain, but a leading hypothesis is that insufficient exposure to microbes during childhood could interfere with maturation of the immune system.”
The NCI researchers further explain that the upswing in noncardia cancers in women is consistent with them using more antibiotics during their lifetimes. They point to increasing rates of autoimmune conditions and speculate that antibiotics may increase the risk of autoimmune gastritis, she said. “No matter what the underlying cause of the trends, however, antibiotics remain a lifesaving tool and should be used when medically necessary,” Nayak emphasized.
While the NCI study “is descriptive in nature and not designed to evaluate causality,” additional epidemiologic studies, as well as laboratory and animal studies, are needed to investigate possible mechanisms that may explain the observations made by the researchers, Nayak said.
“I strongly feel that research is needed on antibiotic medications that can disrupt the native microbiome of the stomach and may lead to autoimmune gastritis as a cause of noncardia stomach cancer. Also, studies should be designed to evaluate whether the prevalence of autoimmune gastritis is increasing over time in the U.S. and other populations,” she said.
Chuck Holt is a contributing writer.
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