Early test offers a chance to head off pancreatic cancer

After losing her mother and brother to pancreatic cancer, Sheri Mayer faced the difficult choice of having her pancreas removed or trying to beat the odds.

When Sheri Mayer flew to her parents’ South Dakota home in 1992, it was a bittersweet homecoming. The occasion was Mother’s Day, and it was going to be the last one for her mom, who was losing her battle with pancreatic cancer.

What Mayer didn’t realize was that in less than a decade, she would watch her older brother die from the same disease—and then face a life-or-death choice herself.

Mayer’s family seemed to be under a biological curse. Pancreatic cancer cut her mother’s life short at age 54. Seven years later, her brother started suffering severe stomach pains. In April 1999 he was treated for an ulcer, but recurring pains sent him back to his doctor. That September, a CT scan revealed a three-inch mass on the tail of his pancreas. Three months later, at the age of 44, he was dead.

It was Mayer’s second encounter with a vicious killer. Pancreatic cancer is a virtual death sentence—of the 29,000 Americans diagnosed this year, 28,900 will die within 12 months. While lung cancer kills the most Americans, pancreatic cancer ranks fourth in U.S. deaths due to cancer. Early symptoms include, but are not limited to, stomach pain, jaundice and weight loss. Extremely lethal, it is resistant to both chemotherapy and radiation, and usually invades other vital organs by the time it is discovered.

My children are 23 and 20, and I want to be a grandmother someday.

Sheri Mayer

“Before he died, I was able to sit down with my brother and his wife, and I made them a promise to have my own pancreas checked out,” Mayer remembers. But the medical information she was receiving was confusing. “At the time, all we were hearing from doctors was that it was not a genetic disease like breast cancer or colon cancer.”

Living in Wenatchee, Mayer, now 42, was well connected to the local medical community, since she was a lab technician at the Wenatchee Valley Clinic. Early in 2000, just weeks after her brother died, a Wenatchee oncologist uncovered an article about a hereditary form of pancreatic cancer, and showed it to Mayer.

The author, UW Gastroenterologist Teri Brentnall, was not only researching the genetics of pancreatic cancer, she was also part of a new surveillance program for patients at high risk. Thanks to breakthroughs in molecular biology, researchers at the UW and other schools were developing early diagnostic tests for pancreatic cancer.

The UW’s Surveillance Program started in 1994, the first of its kind in the world. In addition to Brentnall, the team includes Medicine Professor Michael Kimmey, head of GI endoscopy at the UW Medical Center; Pathology Professor Mary Bronner; and Surgery Professor David Byrd. The group has one important goal: identify affected patients before they develop invasive cancer but after “dysplasia” or pre-cancer has developed.

But the results of these tests can leave patients with an almost impossible choice: Continue living normally and hope the pre-cancer will not develop into the ravaging form of the disease, or let doctors remove the pancreas, becoming a full-fledged diabetic, forever dependent on insulin. While it is possible that the precancerous cells will not turn into cancer, it is a serious risk. Doctors can’t be sure because there is no natural history data on cancer development in the pancreas.

Two months after her brother’s death, Mayer, who was showing no symptoms and in seemingly perfect health, traveled to the UW for an appointment with Brentnall. There she underwent an endoscopic ultrasound, where a tube-like probe is inserted through the patient’s mouth and into the stomach. A microchip television camera embedded in the tip of the probe allows the physician to see inside the body without surgery.

UW Gastroenterologist Teri Brentnall is part of the world’s first pancreatic cancer surveillance program. Photo by Kathy Sauber.

“The pancreas is deep in the body and extremely hard to locate,” says Brentnall. “It sits behind the stomach, almost against the spine.” Larger than the gallbladder and smaller than the liver, it plays a key role in the digestive system, secreting enzymes that join bile from the liver and gallbladder to drain into the small intestine. The pancreas also produces valuable insulin and hormones that control the body’s ability to use sugar.

But this vital organ can be a time bomb for some families. Brentnall says pancreatic cancer is clearly hereditary in at least 10 percent of cases, a risk that triples if one first-degree relative is affected and increases to as much as 50 percent if multiple members are affected.

“There are certain risk factors to cancer of the pancreas—chief among them smoking,” says Brentnall. “But people with a family history likely have family genes that increase their risk. Losing her mother and brother made Sheri a certain candidate.”

Just last year the disease struck three legendary UW leaders. Two former presidents of the Board of Regents, Andrew Smith and Samuel Stroum, died from pancreatic cancer in February and March respectively. Then it hit retired Communications School Director Alex Edelstein, who died that May.

Other well-known victims include comedian Jack Benny; actors Steve McQueen, Rex Harrison, Michael Landon, Donna Reed, Fred Gwynne and Fernando Lamas; musicians Dizzy Gillespie and Henry Mancini; former Dallas Cowboy Harvey Martin; and game show host Art Fleming.

Those with a hereditary risk may be able to hold off the cancer by avoiding tobacco. Smoking increases the risk seven times in men and three times in women with a family history of the disease. It also quickens the onset of the disease by a decade. Exposure to environmental chemicals, such as benzines, hydrocarbons and dry cleaning solutions, can also be harmful.

No one is sure what causes pancreatic cancer, but a team of geneticists that includes Brentnall and scientists at the Fred Hutchinson Cancer Research Center and the University of Pittsburgh have mapped the location of a gene associated with inherited pancreatic cancer. It is the first genetic defect linked directly to this form of cancer.

While genetic research may benefit Mayer’s children and grandchildren, her own fate depended on the UW surveillance program. The first test, in 2000, found no signs of cancer. “Everything came back normal,” Mayer remembers, “and they told me to come back in another year.”

She went back to her business, her family and Wenatchee, feeling as good as ever. In February 2001 she returned to Seattle for what she thought would be another normal procedure. This time the first tests indicated abnormalities: critical tumor marker chemicals in her blood had risen from 11 (normal) to 53.

These abnormalities meant Mayer would have to undergo more tests—a spiral CT scan and an endoscopic examination of the pancreatic duct. When Mayer awoke from anesthesia, Brentnall was at her side. “She just said, ‘I’m sorry to tell you but we found dysplasia (pre-cancer) on your pancreas, and you’ll need surgery,’ “ Mayer says.

The operation didn’t necessarily mean Mayer would lose her entire pancreas. Before removing the whole organ, surgeons use a laparascope to confirm that precancerous changes are present. In addition, pathologists look at pancreatic tissue while the patient is still under anesthesia in what is called frozen section analysis. If dysplasia is present, doctors perform a total removal during the same operation.

Mayer scheduled the surgery for March. Byrd, her surgeon, told her he was planning a partial pancreatectomy, removing only a section of the tail of the pancreas. The frozen section analysis on the rest of the pancreas was negative, and Byrd removed six inches of the tail. Seven days later, Mayer returned to Wenatchee to recover.

“I went back to work and I was feeling great. Everything seemed fine,” Mayer says. But the final pathology report was still pending. “Near the end of June, I received word that they found dysplasia in the rest of my pancreas,” she recalls.

Though the news seemed devastating, Mayer took comfort in the knowledge she had gained from her own medical background, and in the support from her family and doctors. At a conference with Brentnall and Byrd, they told her that she had three options. She could only make one choice—and had less than six months to make it.

“Dr. Byrd told me I could either do nothing, I could continue surveillance and see how it progresses, or I could have the entire pancreas removed,” Mayer says.

A total pancreatectomy removes the pancreas, part of the small intestine, often part of the stomach, the bile duct, the gallbladder, spleen and most of the lymph nodes in the area. Because Mayer’s pancreas was still precancerous, doctors felt that the rest of her abdominal organs could be saved. But she would live the rest of her life as a diabetic.

It really was no question of if I would have my pancreas taken out, but when.

Sheri Mayer

While doctors couldn’t be certain the precancerous cells would turn into cancer, once they did become malignant, it would be too late to save Mayer.

“My children are 23 and 20, and I want to be a grandmother someday,” Mayer says. “It really was no question of if I would have my pancreas taken out, but when. I didn’t want to mess with it, so we made the appointment.”

Last November Mayer underwent a six-hour pancreatectomy, instantly turning her from a patient with a high pancreatic cancer risk into an insulin-dependent diabetic. Having seen what the former can do, she’s glad to take the latter.

“The last time I saw my mom, she had lost all of her hair, and she was essentially a skeleton with skin on it,” Mayer remembers. “The last time I saw my brother was two months before he died. Knowing how my mom looked, I wanted to remember him as he was, before he deteriorated so much.

“As for me, I’m not a brittle diabetic. My blood sugars are not much different than they were. I have an insulin pump. It’s basically an artificial pancreas that gives me the amount of insulin I need day and night,” she says. But Mayer knows the long-term risks of diabetes: heart disease, stroke, blindness, kidney failure, amputations and nerve damage.

With her children (and hoped-for grandchildren) in mind, she also donated blood and pancreatic juices to research, knowing that information might one day save their lives—or at least keep them from having to endure the shock and uncertainty of many pre-cancer tests.

Mayer’s case is typical of the 35 patients from 13 families in the UW surveillance program. Each has at least two relatives who had pancreatic cancer, or else a first-degree relative who developed the disease younger than the age of 50.

Sheri Mayer. Photo by Dathan (Dave) Devnich.

“The patients in the surveillance program are doing very well,” Brentnall says. “They are all alive without any development of pancreatic cancer. Everybody whose pancreas has been removed had pre-cancer present in the organ but had not yet developed cancer. We hope to make surveillance programs even better in the future. Ideally it would be best if we could identify patients who are on the brink of developing cancer by using a blood test or by taking a sample of fluid from the pancreas. Currently a tissue biopsy is required.”

Mayer was back to work full-time in the first week of 2002, overseeing 21 employees at the clinic. She says she’s having less trouble with the diabetes than she is with her stomach, which has had trouble emptying completely. She can never eat fatty or spicy foods again, and she must consume antacids every day to control a constant heartburn.

“Dr. Byrd has a great deal of experience taking care of familial pancreatic cancer patients,” Brentnall says. “Sheri’s surgery left no complications other than the expected loss of pancreatic function and the need to use insulin and digestive enzymes.”

“I check my blood sugars four to six times a day, and the endocrinologist thinks I’m doing wonderfully,” Mayer says. “I’ll continue to build up my stamina. Nothing is really messing up my routine.”

But the family curse may not be over. Her only living brother—still in South Dakota and two years her junior—is not taking his own fate seriously.

“If I had not promised my older brother that I’d get myself checked, I could have been dead, too,” Mayer says. “I feel like my younger brother is living in denial. He’s always been the ‘it-will-never-happen-to-me’ type. He says his doctor told him it wasn’t necessary to check for the cancer. But I send him literature all the time.”

While her brother avoids any decision, Mayer has already made another life choice. “We’ve been in Wenatchee for a long, long time. We really love the small town atmosphere, but we decided we needed to make a better life for ourselves,” she says.

This April she and her husband left Wenatchee to live in a log cabin near Helena, Mont. They are building it themselves. “I tend to tire out quicker and need more rest,” she says, “but that’s really a small price to pay.”

Breaking the genetic curse

Because of the threat of pancreatic cancer, Sheri Mayer must live the rest of her life as a diabetic.

Worse, she says, is that because of her family history, the lives of her children and future generations are at risk. But Mayer takes comfort in knowing that her doctor, Teri Brentnall, is also a groundbreaking researcher in the fight to find a cure for the deadly disease.

Earlier this year, Brentnall and a team of researchers from the University of Washington, Fred Hutchinson Cancer Research Center, and the University of Pittsburgh, announced a breakthrough in mapping the location of a gene associated with inherited pancreatic cancer. It is the first genetic defect linked directly to the disease.

“At least 10 percent of pancreatic cancer is hereditary, and by understanding that form of the disease we can also learn a lot about the non-hereditary form, which is far more common,” says Brentnall. “There are about 100 genes in the region we’ve been searching, and we know we’re getting close.”

Brentnall says the genetic investigation is like looking for one house somewhere in the world. “You narrow it to somewhere in the Northwest,” she says. “Then it’s somewhere in the city. You keep narrowing it down, and then you have to find it.”

In addition to Brentnall (a UW associate professor of medicine and pathology), the research team includes Leonid Kruglyak and Michael Eberle of Fred Hutchinson; and David C. Whitcomb and Rolan Pfutzer from Pitt.

With the assistance of an anonymous and wide-ranging Pacific Northwest family—dubbed “Family X”—Brentnall continues to gather data on the largest pancreatic cancer family ever researched. Twenty members of the family have been scrutinized, 18 of them with pancreatic cancer or pre-cancer, and two with pancreatic insufficiency.

“Five out of the six brothers in this family have died. Nine people in all,” says Brentnall, who has followed “Family X” for seven years. “The cancer really hit this family early, most in their middle 40s, and it gets younger with each generation.”

Brentnall says it is most common for people with a family history to be diagnosed in their 50s and 60s on the West Coast, and as late as their 70s in the East.

Using DNA samples that Brentnall’s group collected from Family X, Pitt researchers genotyped hundreds of areas of the genome. This helped Kruglyak’s team to show which genetic variations affect family members with pancreatic cancer or dysplasia (pre-cancer).

A specific genetic marker was found on nearly every member of Family X, all on the chromosome 4 arm, where the single-gene mutation responsible for pancreatic cancer is often found.

As a result, future generations of Family X will be more easily screened for the disease, perhaps a simple blood test being enough to determine if they have inherited the gene.

“We are hoping that the future may help us understand the genes that cause pancreatic cancer,” says Brentnall, “and help us develop the drugs or vaccines that prevent its development.”