Thwarting cancer's call

Most cancers arrive like an unwanted houseguest: without warning and with plans to stay awhile. This complicates the job of researchers trying to tease out all the steps that occur before a tumor develops. So when cancer calls ahead and tells you it may be coming soon, it creates a unique opportunity to examine closely the steps from a pre-cancerous state to malignancy.

It also allows patients who are at risk of developing cancer to be given the best possible clinical care to keep them cancer-free. This unique nexus of cutting-edge research and world-class clinical care within a single group of patients is the hallmark of the Seattle Barrett's Esophagus Program.

Finding Barrett's

Barrett's esophagus is a pre-cancerous condition of the lower esophagus — the muscular tube that carries food from the mouth to the stomach — in which elongated columnar cells that resemble cells of the intestine replace the flat, squamous cells that normally line the tube. Barrett's develops in 10 percent to 15 percent of people with chronic gastroesophageal-reflux disease, a condition in which the contents of the stomach move up into the esophagus through a leaky sphincter muscle, causing chronic heartburn. People with Barrett's esophagus develop a type of cancer called esophageal adenocarcinoma at a rate 30 to 45 times greater than in the normal population.

In the mid 1970s, Yakima native Dr. Brian Reid had just completed a doctorate in genetics under Dr. Lee Hartwell and wanted to find a model he could use to study how mutations in the cell-cycle-control genes might lead to human cancers. "I found Barrett's esophagus," Reid said. He reasoned that studying patients with this early harbinger of esophageal cancer might allow him to observe the genetic changes that precede human-cancer development.

When Reid, along with Drs. Douglas Levine and Cyrus Rubin, started the Seattle Barrett's Esophagus Program at the University of Washington in 1983, esophageal adenocarcinoma was thought to be relatively rare. By the time he moved the program to the Hutchinson Center in 1996, it was clear esophageal adenocarcinoma was the most rapidly increasing cancer in the United States, rising 600 percent in the last 30 years. "We really stepped into an epidemic that no one knew was happening," said Reid, principal investigator in the Human Biology Division and head of the Barrett's esophagus program.

The program is unique because it is both a research study and a clinic offering the highest quality patient care. Every patient entering the study is assessed on a wide variety of epidemiological, clinical and biological attributes, so prospective studies can determine which of these factors is associated with progression to adenocarcinoma. The cancer surveillance offered in the program substantially increases the likelihood that cancer will be found when it is small and curable, greatly improving the five-year cure rate for these patients.

Interdisciplinary team

This approach to studying cancer takes a truly interdisciplinary team. "One of the main reasons the program has been as successful as it has is because there's input from all different kinds of scientists: clinical, basic and public health," said Dr. Thomas Vaughan, head of the Epidemiology Program in the PHS Division and lead epidemiologist for the Barrett's program.

The Barrett's research group is made up of around 350 Barrett's patients. "Patients are generally referred by their private gastroenterologist, although increasingly, patients are finding us by searching on the Internet," said Christine Karlsen, clinical assistant, who fields calls from worried patients recently diagnosed with Barrett's.

When a patient first comes to the Center, they are counseled by Dr. Patricia Blount, director of the Barrett's clinical-research core, on their risk of developing cancer, which is estimated to be 0.5 percent to 1 percent each year. If he or she decides to participate in the program, an appointment is scheduled for an upper endoscopy at the Seattle Cancer Care Alliance. This involves placing a flexible video endoscope down the esophagus and removing small samples of Barrett's tissue for biopsy. The tissue is easily differentiated because it appears pink while the surrounding normal tissue is white.

In the early years of the program, there was little precedent for how to conduct these biopsies. Some of the first contributions of the project were a standardized way to sample the Barrett's region and a five-stage grading scheme for proximity to cancer. "Both our systematic biopsy protocol and dysplasia classification for cancer risk are now recommended by practice guidelines and routinely practiced around the country," Reid said.

Predicting cancer progression

Reid's lab has spent the last 10 years using a technique called flow cytometry to examine these biopsies for biomarkers, genetic abnormalities that consistently develop in Barrett's tissue before cancer does. "After characterizing the patients at baseline on these abnormalities, we followed them prospectively for a 10-year period," Reid said. "We're at the end of this 10-year study and now we're publishing the results."

According to Reid, four biomarkers predict the progression to cancer very well. Two of these are cell-cycle genes known as tumor suppressors (called p16 and p53) and two are DNA content abnormalities that indicate problems in cell division: aneuploidy, which is an abnormal number of chromosomes, and tetraploidy, which is the presence of twice the normal amount of genetic material. "If you don't have any of them, you have an extremely low chance of getting cancer over the next eight years or so," Reid said. "If you have all them, you've got a very high chance of progressing to cancer."

Another part of Reid's research is the role of genetic diversity among cells of the Barrett's segment in the development of adenocarcinoma. A paper published in Nature Genetics in April of this year reported that biopsies containing a wide range of genetic differences among cells are a strong predictor of progression to cancer. Reid believes this is a clear example of evolution at work within the human body — genetic diversity helps tumor cells evade cell-cycle controls and immune surveillance in the body. This information may someday be used clinically to predict a patient's likelihood of progression to cancer or to determine how each patient is likely to respond to cancer treatment.

Vaughan, who joined the program in 1995, looks for common environmental and genetically determined "host" factors among those in the Barrett's research group who eventually develop cancer. "What we have learned so far is that reflux, obesity and smoking are the big factors in progression to adenocarcinoma," Vaughan said. "Each one of these has a story and now we're trying to tease out the specifics."

Reflux is combated in Barrett's patients by medications called proton-pump inhibitors (PPIs) such as Nexium, which reduce stomach-acid production and relieve the heartburn symptoms. Though PPIs help the discomfort, these widely used medications are not a magic bullet. "There is no evidence at all that taking PPIs reduces your cancer risk," Vaughan said.

In a study soon to be submitted for publication, Vaughan and colleagues measured the Barrett's patients when they entered the program on all types of body parameters including body-mass index (BMI), a measure of obesity. "It turned out that BMI was not a predictor at all. Instead waist circumference was one of the most important factors in progression to adenocarcinoma," Vaughan said.

One of the long-term goals of the program is to find interventions that help reduce the risk of progression to adenocarcinoma. Two of the best things to do are quitting smoking and losing weight. Last year, Vaughan, Reid, Blount and colleagues provided the first evidence that something very simple may be very effective in preventing cancer. A study published in The Lancet Oncology showed that patients in the Barrett's research group who reported taking non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen at least once a week were about half as likely to develop adenocarcinoma as those who did not take NSAIDs.

Effectiveness of NSAIDs

More recently, Vaughan and the team found that NSAIDs were not only protective for the early stage Barrett's patients, but for those with biomarkers of advanced disease as well. "The gist of the study is NSAIDs appear to be effective at all stages in Barrett's progression to esophageal adenocarcinoma," Vaughan said. Reid points out that this soon-to-be-published study demonstrates the strength of the interdisciplinary approach since it relied upon work from all three of the program's research areas: clinical, basic and epidemiological.

Ten years ago, the dysplasia-grading system developed by the team was the best available information on which to base the surveillance interval between endoscopies. The higher your biopsy grade was, the more often you came in for regular surveillance. Now, the tissue is sent for analysis by flow cytometry and interpreted by Dr. Peter Rabinovitch, an investigator with a joint appointment in the PHS division and the UW. The results can greatly impact the clinical outlook for the patient. "I think that using flow cytometry for our patients has been one of our biggest accomplishments," Blount said. "We know that when patients come into our study with DNA-content abnormalities, aneuploidy and tetraploidy in their Barrett's tissue, they are at increased risk for developing cancer." The cancer rate for these patients is about a 28 percent cumulative five-year risk compared to almost zero for those without the abnormalities.

While flow cytometry for DNA content abnormalities is now used in clinical practice, the more recent biomarker studies with the tumor suppressors are not yet ready for the clinic. "We're to the point that we're on the verge of translation to the clinic," Blount said. Reid looks forward to the day when that translation is complete. "One of the great benefits of our biomarker study – if we can implement it all in clinical practice — is we can pretty well say that if you don't have any of these genetic abnormalities, you're pretty safe for five to 10 years," Reid said.

The success of the Seattle Barrett's Esophagus Program over the last 23 years gives hope not only to patients with Barrett's esophagus, but also to scientists studying all types of cancers. "I think there's much to be learned. But we have learned a lot and we are on the cutting edge of research in this disease." Blount said. With the hard work and the continued success of interdisciplinary programs that successfully bridge the research-clinic divide, we may soon be able to bid the unwanted houseguest cancer goodbye before it even gets to the door.

The Seattle Barrett's Esophagus Program team

Current members of the Seattle Barrett's Esophagus Program include Drs. Alan Kristal, Xiaohong Li, Carlo Maley and Tom Paulson, and Patricia Galipeau, Carissa Sanchez and David Cowan. To learn more about the Seattle Barrett's Esophagus Program see www.fhcrc.org/science/barretts. For more information on Barrett's esophagus see www.barrettsinfo.com.