A Team Approach

With her husband stationed overseas in Korea and an active 1-year-old son and 7-year-old daughter in tow, Erin Allmon decided she was way too busy to have any further complications in life. So when she went to be tested for a familial gene mutation that might cause pancreatic cancer, she was determined that there was no way she had it.

Erin’s sister felt the opposite. Kristine Gregoire-Cope says she was certain she had the same genetic mutation she believed caused their mother’s rapid decline and death from pancreatic cancer in 1995.

“I look more like my mom than my sister, and I already have type 2 diabetes. My mother died at 45, and I was turning 39. For me, I felt like it was not so much fated, but my biggest fear was to wake up and have stage IV cancer and repeat history,” Kristine said.

Both women were tested at Vanderbilt’s genetic counseling office in early 2012. Both results were positive.

Erin’s husband was in the room via online connection when Vanderbilt genetic nurse practitioner, Kate McReynolds, MSc, MSN, ANP-BC, delivered the news. Erin called it “flooring.”
Her first thought: “What does this mean for our children?” Then: “What now?”

Hope for early detection, prevention

There is a sense of urgency where familial pancreatic cancer research is concerned. Pancreatic is the fourth leading cause of cancer death in both men and women in the United States, yet it is so rare, the average person only has a 1 percent chance of getting it in his or her lifetime. But once someone does have a diagnosis, the prognosis is the worst of any major tumor type. Only 6 percent of patients live past five years.

With such poor response to treatment and no known prevention, hope focuses on early detection of pancreatic cancers so they can be removed or treated before they can become deadly. But it would be much better to predict who is at greatest risk for pancreatic cancer before it occurs. This offers the greatest possibility of early detection, and makes prevention at least a hope, even for those at greatest risk.

Those at greatest risk for pancreatic cancers include people with a strong family history of the disease. When two closely related people in one family get the same cancer, epidemiologists consider it a “cluster,” with an increased probability that there is genetic basis, especially if it is a rare cancer like pancreatic. Currently, 17 familial pancreatic cancer registries in the U.S. are tracking patients and their families, searching for genetic mutations that may be involved.

Pre-cancer risk prediction is what Kristine says she hopes for. It’s what she focused on when her uncle was the first of her family members to receive a positive result for a little-known mutation in a tumor-suppressor gene called PALB2. She says the news offered a sense of hope that deaths like her mother’s, and illnesses like her uncle’s, might one day be preventable.

What she didn’t know at the time was how critical her own participation would be in efforts to develop a model to predict the risk of PALB2 familial pancreatic cancers.

Finding the PALB2 link

In 2009, Kristine’s uncle, Mark Gregoire, a Trumansberg, N.Y., native, was among the first 96 pancreatic cancer patients to participate in a sentinel study with researchers at the Johns Hopkins Medical Institutions to test for mutations related to pancreatic cancers. He was one of only three confirmed to have a non-functional version of the PALB2 tumor suppressor gene. Despite the tiny numbers, Johns Hopkins experts told him their research showed that the broken PALB2 gene was likely involved in the development of his cancer. They advised him to tell his close relatives so they could also be tested for the mutation.

Both Kristine and Erin say they remember the flurry of family emails between their uncle and his five surviving siblings. Their mother – Mark Gregoire’s older sister, Veronica Gregoire Cope – had died from pancreatic cancer before being tested. But one by one, the surviving siblings received good news: they didn’t have the PALB2 mutation.

Kristin and Erin recalled the sense of relief felt by their extended family. That is, until 2011, when their cousin – just months before her father Mark Gregoire passed away from pancreatic cancer – got tested. She had the PALB2 mutation.

“And that’s when we thought, ‘whoa, this is our generation,’ We hadn’t really thought about getting tested ourselves up until then,” Erin said.

Kristine was interested in getting tested right away. But she says none of her own physicians seemed encouraging of genetic testing. None had heard of PALB2, and after all, pancreatic cancers generally occur after age 50. But when Kristine approached S. Sadia Zaidi, M.D., assistant professor of Endocrinology, at the clinic where she is seen for type 2 diabetes, the response was different.

“I walked in and said ‘I may or may not have a PALB2 mutation, but to be on the safe side I wanted to let you know.’ Dr. Zaidi told me she was not familiar with the PALB2 pancreatic cancer link, but right then and there she pulled up the information on the Internet… about four sentences worth,” Kristine said.

“It is more associated with breast cancer and anemia. But because of my personal experience, I told her she shouldn’t just let it go,” Zaidi recalled. “My own father died after a painful course with metastatic pancreatic cancer. Other than my father, I don’t have a strong history of family cancer, but if there had been, I would have been the first to get myself tested for genetic risk.”

What is PALB2?

In 2007 researchers found the PALB2 protein to be a partner and localizer of the BRCA2 protein. The more famous BRCA1 and BRCA2 genes, known for their strong link with familial breast and ovarian cancers, are tumor suppressor genes, working within the body’s cells to isolate genetic mutations, and repair them so they don’t have a chance to produce disease within the body.

The name “PAL”B2 might aptly describe this adjunct gene’s function. It is a friendly helper of BRCA2. It both recruits BRCA2 to sites of DNA breakage and acts as molecular scaffolding to hold it in place as repairs are made. If someone is missing a functional PALB2 gene, tumor suppressor BRAC2 is unable to do its work.

Zaidi suggested Kristine and her sister should contact The Clinical and Translational Hereditary Cancer Program at Vanderbilt-Ingram Cancer Center to talk with a cancer genetic counselor. Kristine quickly made an appointment to visit Kate McReynolds and Erin agreed to go too.

“I tested the sisters for the known family mutation in PALB2, called single site testing. This cost just $200 since we knew what we were looking for,” McReynolds recalled.

But once the positive results were known, McReynolds’ path to guide the sisters became much less clear.

“One of the interesting issues with these new genetic discoveries is that the studies have not been done yet to establish penetrance of the gene. Unlike others, like the BRCA genes, we cannot give people a lifetime risk, even though we know risk is increased,” McReynolds explained.

Waiting for the math

Penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. After the better-known BRCA1 and BRCA2 mutations were linked with breast and ovarian cancers, it took about 10 years and scores of breast and ovarian cancer patients, as well as those with the mutations, but without disease, to allow scientists to generally agree on penetrance. Once penetrance is determined, counselors like McReynolds are able to tell a patient how greatly their lifetime risk is increased by a gene defect. That’s about as specific as information can get about lifetime risk for cancer.

Patients who do not test positive for a known genetic defect are not out of the woods. In some common cancers, like breast cancer, there is enough data today to use family and personal medical history to calculate increases in risk even without a known gene link.

“High risk is anyone with a 20 percent risk or greater, with average risk for a woman being 12.5 percent for breast cancer. When risk is greater than 20 percent, we start talking about management options of three types: surveillance, chemoprevention or risk-reducing surgery,” said Ingrid Meszoely, M.D., a surgical oncologist and clinical director of the Vanderbilt Breast Center.

Because the penetrance of BRCA1 and BRCA2 genes are fairly well known, doctors have been able to develop a prescribed course of action for each patient. The course of action may vary significantly, depending on the type of gene, the degree of risk and a patient’s wishes.

“Our ability to know more about what these mutations mean has grown vastly. The BRCA genes only came to our awareness in the 1990s. The only prevention option early on was mastectomy. Now there are other choices with good data to back them up including MRI surveillance and chemopreventive drugs,” Meszoely said.

But breast cancers—both familial and sporadic—are far more common than pancreatic cancers. Penetrance, and the lifetime risk of pancreatic cancer for those with PALB2 gene defects, is simply not known. PALB2 mutations occur only in 1 percent to 3 percent of the familial forms of pancreatic cancers, and the volume of cases needed to determine penetrance is quite large. That’s where families like the Gregoires come in.

Alison Klein, Ph.D., M.H.S., lead author of the 2009 paper describing the PALB2 link to pancreatic cancer, directs one of the larger pancreatic tumor registries in the U.S.: the National Familial Pancreas Tumor Registry at Johns Hopkins. She says registries will help uncover the answers, but families will have to be both patient and involved.

“It’s not the technology that’s limiting us, it’s the number of families, and identifying more of them. I am cautious about this, but I am optimistic that what we have learned about PALB2 will ultimately help. First the registries help inform who should be screened and who shouldn’t, and then will quantify what the genes mean in families. Our understanding will improve in the coming years and will inform screening trials and therapies,” Klein said.

Vanderbilt-Ingram is currently in the process of developing a hereditary cancer registry as well. According to the new director of the Clinical and Translational Hereditary Cancer Program, Georgia Wiesner, M.D., registries will help families like the extended Gregoire family in many ways.

“Rare cancer susceptibility syndromes, such as those caused by PALB2 mutations, require coordination as well as a multi-site approach in order to begin to understand both the health and the emotional impact on patients and families.  Registries keep in contact with these families, keeping them informed, helping them to understand more about their risk, while their participation helps to expand our body of knowledge,” Wiesner said.

The Team Approach

Kristine says having stumbled into the opening pages of this cancer story has its benefits. Her family now has access to a cross-country team of top clinicians. She and one of her two brothers have spoken directly with the Johns Hopkins group, and McReynolds has worked with Johns Hopkins to learn about their screening program and implement it with the family here.

Erin and Kristine’s first clinical stop within the Cancer Center, was to Meszoely’s high-risk breast cancer clinic. Meszoely says Kristine and Erin are her first PALB2 patients. Erin’s mammogram showed a suspicious area and so she underwent a biopsy. The biopsy was thankfully negative. That was followed by visits to gastrointestinal specialists where the first round of tests so far, including endoscopies and MRIs, have all been normal.

The sisters will return for annual surveillance for breast and pancreatic cancers. It’s a lot of medical testing to add to the lives of young, healthy and busy women. And even their health care team admits the benefits are unknown.

“Our younger brother hasn’t decided to be tested yet, and that’s fine for him. But if I didn’t have this information, I wouldn’t have this plan. At 36 years old, I had no intention of going for a mammogram for several years, but I am glad I did,” Erin said.

Kristine and Erin say they are glad to be full partners, working with the team writing a new prescription for care of those with PALB2 familial cancers. They have joined a cancer registry. They call themselves “pre-vivors:” free from the rigors of cancer treatment, they can focus on prevention. Kristine and her family remind others that pancreatic cancer is the “most under-funded, under-recognized and least studied of all major cancer killers.” Family and friends recently joined Kristine in a 5K fun run called the PurpleStride to raise awareness about pancreatic cancer. She said that as she looked around at the people at the event – participants who were either patients with pancreatic cancer or their loved ones – it was a poignant reminder of how little is known about PALB2, and how little survival rates have improved for pancreatic cancers as a whole.

“All of those people touched by pancreatic cancer, who knows if some of them might be affected by the PALB2 gene. I would like to be part of this, to keep the momentum up,” Kristine said. “My mom died in four months, for my uncle it was five years. We don’t know if that’s because he participated in PALB2 registry and research trials, but we would like to hope, at least on a personal level, that represents advancement.”