These findings by Rebecca Rudolph, M.D., M.P.H., and colleagues at Fred Hutchinson Cancer Research Center will appear in the May 21 issue of the Journal of the National Cancer Institute.
Researchers at the University of Washington School of Medicine also collaborated on the study, which was funded by the National Cancer Institute.
Rudolph and colleagues studied the relationship between levels of selenium in the blood and changes in the lining of the esophagus that represent advancement toward cancer.
"Our research suggests that low blood levels of selenium are a risk factor for progression of Barrett's esophagus. We found that Barrett's patients with low selenium levels had a two- to three-fold greater risk of advanced precancerous changes than patients with selenium levels in the middle or high end of the normal range," said Rudolph, an epidemiologist and clinical researcher in Fred Hutchinson's Public Health Sciences Division and lead author of the study.
Although the investigators do not currently recommend selenium supplements for people with Barrett's esophagus, they caution that anyone who decides to take these supplements should take only low doses.
"When it comes to selenium and Barrett's, there appears to be a law of diminishing return. More selenium is not necessarily better," Rudolph said. "In fact, laboratory studies indicate that high doses of selenium can be toxic and could even promote cancer, so 'megadosing' with selenium supplements is a bad idea," Rudolph said. Symptoms of selenium toxicity can range from hair and nail loss to gastrointestinal disturbances and nerve damage.
The U.S. recommended dietary allowance for selenium is 55 micrograms (mcg) for adults. Most individual supplements contain 50 mcg or more, while the average multivitamin has up to 20 mcg. Fish, meat and bread are common dietary sources of dietary selenium in the United States. Brazil nuts and walnuts are also good sources.
"If there's a lot of selenium in the soil, there will be high amounts in the food in which it is grown. But since food is shipped from all over the place, it's the luck of the draw how much you'll really be getting from food sources," Rudolph said.
Previous randomized clinical trials in humans have shown that selenium significantly reduces risk and mortality for multiple cancers, including prostate and colorectal. Laboratory studies suggest selenium may be a powerful cancer fighter because it inhibits the changes that cause cells to spin out of control and become cancerous. For example, selenium has been found to slow abnormal cell growth, prevent DNA damage and facilitate the normal process of cell death, or apoptosis. It's also known to act as an antioxidant, so it may interfere with the cell-damaging effects of free radicals produced during normal cell metabolism.
Although the researchers' results suggest that adequate selenium consumption may inhibit the progression of Barrett's esophagus, currently there is no proven, recommended medical therapy for lowering cancer risk in people with this condition; care is limited to frequent endoscopic surveillance, which involves inserting a tube-like instrument down the throat to examine the esophageal lining and to take tissue samples that are examined for signs of cancer or precancerous changes.
While only 5 percent to 10 percent of Barrett's patients develop cancer of the esophagus, the outlook is grim if it is not diagnosed early. More than 90 percent of patients with invasive esophageal cancer die within five years of diagnosis.
"Most Barrett's patients will never get esophageal cancer, but since it is such a rapidly fatal cancer once you get it, it's really important to figure out ways to prevent it," Rudolph said. "This research gives us hope that we will be able to develop medical means by which to lower Barrett's-related cancer risk and perhaps even reverse the risk among people who already show signs of progression toward esophageal cancer."
For the study, Rudolph and colleagues analyzed data from 399 people with Barrett's esophagus and found that those with higher concentrations of selenium in their blood were less likely to have as many biological markers of progression toward cancer as compared to those with less circulating selenium.
Precancerous changes that were less prevalent among those with higher levels of selenium included:
- dysplasia - abnormalities in cellular size, shape or growth pattern;
- loss of heterozygosity at 17p - partial loss of chromosome 17, which can inactivate the tumor-suppressor gene p53, a gene that is critical for controlling cell growth;
- aneuploidy - the accumulation of cells with grossly abnormal amounts of DNA, which indicates substantial genetic damage and is a sign of advanced progression toward cancer; and
- increased 4N fraction - an excessive number of cells with twice the normal amount of chromosomes, which may indicate a problem with cell division.
Most significantly, the researchers found that higher blood levels of selenium were associated with a three-fold decreased risk of aneuploidy and a two-fold decreased risk of cellular dysplasia and loss of the p53 gene.
Selenium appeared to have the greatest effect on markers associated with advanced progression of Barrett's, which suggests that the nutrient might be most beneficial for people with later-stage disease.
"While blood levels of selenium weren't associated with one of the earliest markers of Barrett's progression, people with selenium levels in the middle or upper range of normal were less likely to have advanced precancerous changes than those with lower selenium levels," Rudolph said.
Rudolph and colleagues noted that selenium might reduce Barrett's-related cancer risk by preventing the inactivation of the p53 tumor-suppressor or preventing further progression toward cancer after the gene has been shut off.
While the results are promising, more research is needed, Rudolph said. A limitation of the study is its cross-sectional design; the analysis was based on data collected from Barrett's patients at a single point in time, representing an isolated snapshot of biological activity.
"Following these same people over time eventually will give us a stronger understanding of how selenium and other dietary factors affect precancerous progression," Rudolph said. "If the results of our study are confirmed in longitudinal studies and randomized controlled trials, the public-health impact could be substantial," she said.
Study participants were selected from a group of more than 450 Barrett's patients whose disease progression is being carefully monitored through the Seattle Barrett's Esophagus Program, a multidisciplinary research effort established in 1983 at UW. The goals of the program, now based at Fred Hutchinson and conducted in collaboration with researchers at UW, are to understand the biological mechanisms by which esophageal cancer develops, to identify lifestyle and other factors that promote or inhibit progression toward cancer, and to identify genetic markers of increased risk so the disease can be prevented or detected early, while it is still curable.
The Barrett's research team has shown that a systematic, multidisciplinary approach to early cancer detection can improve the five-year survival rate for Barrett's-related esophageal cancer by a factor greater than 20.
Other promising research findings from the Seattle team - all of which require additional research - suggest that taking non-steroidal anti-inflammatory drugs such as aspirin and keeping one's weight below the obese range also may prevent progression of Barrett's.
Barrett's-related esophageal cancer strikes more than 8,000 Americans a year. For unknown reasons, the incidence is rising faster than that of any other cancer in the United States.
Barrett's-related cancers tripled from 1976 and 1990 and more than doubled in the past decade. While the condition is most prevalent in middle-aged white men, the incidence is rising among women and African Americans.
Senior authors on the paper included Fred Hutchinson researchers Brian J. Reid, M.D., Ph.D., director of the Seattle Barrett's Esophagus Program; and Thomas L. Vaughan, M.D., head of the center's Epidemiology Program. For more information about the Seattle Barrett's Esophagus Program, visit http://www.fhcrc.org/phs/barretts/index.htm.
For more information about Barrett's esophagus, visit http://www.barrettsinfo.com, a peer-reviewed Web site developed by researchers at Fred Hutchinson and UW that is supported by AstraZeneca LP through an unrestricted educational-research grant from the Ryan Hill Research Foundation, Seattle.
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 39 nationwide. For more information, visit the center's Web site at http://www.fhcrc.org.
Advancing Knowledge, Saving Lives
MANAGING THE SYMPTOMS OF CHRONIC ACID REFLUX, A RISK FACTOR FOR BARRETT'S ESOPHAGUS
More than 20 million Americans experience chronic heartburn, or gastroesophageal-reflux disease. Of these, between 1 million and 2 million develop Barrett's esophagus, a premalignant condition of the esophagus, the tube that carries food from the throat to the stomach. "We know that Barrett's is caused by long-term, chronic acid reflux. What we don't know is whether reflux influences progression of the condition toward esophageal cancer," said Rebecca Rudolph, M.D., M.P.H., an epidemiologist and clinical researcher in the Public Health Sciences Division of Fred Hutchinson Cancer Research Center in Seattle. Rudolph and colleagues offer the following suggestions to reduce the symptoms of acid reflux, a major risk factor for Barrett's esophagus:
- Don't smoke.
- Keep your weight down.
- Refrain from eating four hours before bedtime.
- If you're having heartburn, sleep with the head of your bed elevated (talk to your doctor about how to do this).
- Avoid foods and beverages that promote heartburn, including alcohol, chocolate, peppermint, onions and foods that are high in fat, all of which can relax the muscle that prevents stomach acid from washing up into the esophagus.
- Take antacids as needed for occasional heartburn. Talk to your doctor if you have frequent heartburn or if over-the-counter medications don't relieve your symptoms.
JNCI Journal of the National Cancer Institute