Interview with an Expert: Familial Pancreatic Cancer

Our Familial Pancreatic Cancer Expert: Ralph Hruban, M.D., is Professor of Pathology and Oncology, and Director of the Sol Goldman Pancreatic Cancer Research Center at the Johns Hopkins University School of Medicine in Baltimore, MD. Dr. Hruban founded the National Familial Pancreas Tumor Registry (NFPTR) and helped define the clustering of pancreatic cancer in families as well as discover new familial pancreatic cancer genes (PALB2 and ATM). These discoveries now guide genetic counseling.

Q: Is the chance of getting pancreatic cancer increased if someone has a family member with pancreatic cancer?

The risk of developing pancreatic cancer does increase when someone has a family member with the disease. In fact, approximately 10 percent of pancreatic cancer cases are attributed to genetic causes. The risk increases with the number of first-degree relatives (i.e., a sibling, parent, or child) that someone has who have been diagnosed with pancreatic cancer.

Q: How much does the chance of getting pancreatic cancer change from having one first-degree relative with the disease, to two first-degree relatives, etc.?

One first-degree relative confers a two-fold to four-fold risk, two relatives increases the risk by six-fold or seven-fold, and three first-degree relatives, which is highly unusual, results in a 32-fold risk. A family member who had a young age of onset of pancreatic cancer (younger than 50) confers an added risk of pancreatic cancer.
It is important to realize that despite these increased risks when pancreatic cancer runs in families, the disease strikes only nine people per 100,000 each year. Even in the older population, comprised of people over 55 years old, the risk is still only 68 people per 100,000 in the United States.

Q: The genomes of over 600 people with familial pancreatic cancer were recently sequenced. What was learned from this study? Do you believe there are still other unidentified genetic mutations responsible for pancreatic cancer that we have yet to discover?

This study is a wonderful example of how pancreatic cancer researchers pull together and collaborate to advance our knowledge of this devastating disease. The study included investigators from Johns Hopkins University, Mayo Clinic, Baylor University, Dana-Farber Cancer Institute, University of Pittsburgh, Memorial Sloan Kettering Cancer Center, University of Pennsylvania, Wayne State University, University of Michigan, and McGill University and Mount Sinai Hospital in Canada. The study involved the sequencing of DNA in the blood of 600 people who themselves had pancreatic cancer or had a very strong family history of pancreatic cancer. The study furthered what is known about familial pancreatic cancer by producing four key findings:

1. The findings confirmed many of the genes that were known before the study such as BRCA2, CDKN2A (the p16 gene), ATM (which plays a role in the processes that repair DNA double-strand breaks), and other genes that are linked to familial pancreatic cancer.
2. The research helped identify some novel candidates that could also be additional familial pancreatic cancer genes, such as BUB1B, which is involved in cell division.
3. The study revealed that familial pancreatic cancer is not one disease. There appear to be several different genes that explain familial pancreatic cancer, rather than just one gene. The 600 study participants didn’t have one genetic mutation that explained all 600 families.

Instead, the research demonstrated that one family had one mutation, another family had a different gene targeted, and the third family had yet another different gene targeted.

4. Some people who develop familial pancreatic cancer have two genetic defects. They inherited two different genes that predispose them to developing pancreatic cancer.

This research, led by principal investigator Dr. Nick Roberts and made available to other scientists, demonstrates how exciting advances can be made in the study of pancreatic cancer when researchers from across institutions join together and are united by their common purpose of fighting this disease.

Q: What are the specific genes responsible for familial pancreatic cancer, and are these genes different from the genes responsible for sporadic (noninherited) pancreatic cancer?

There are several genes that have been identified that when inherited in an abnormal form, increase the risk of developing pancreatic cancer, including the breast cancer genes BRCA1, BRCA2, and PALB2. An abnormal copy of the BRCA2 gene confers a three-fold to 10-fold increased risk, resulting in a lifetime risk of pancreatic cancer in carriers of this mutation as high as 10 percent. The PALB2 gene’s official name is “partner and localizer of BRCA2,” and this gene works with the BRCA2 gene to repair damaged DNA. It is now known that approximately three percent of patients with familial pancreatic cancer have inherited mutations in this gene, and mutations in this gene have also been associated with an increased risk of breast cancer.

When the CDKN2A/p16 gene is inherited in an abnormal form, it can cause familial pancreatic cancer and melanoma, and the increased lifetime risk of pancreatic cancer is 15-35 percent. Mutations in this gene are rare and are believed to account for three percent of familial pancreatic cancer cases.

There is another gene called the Peutz-Jeghers gene or STK11, and individuals who inherit an abnormal copy of this gene have a 130-fold increased risk of developing pancreatic cancer, amounting to approximately 35 percent by age 60. However, mutations in this gene are rare and account for less than one percent of familial pancreatic cancer cases. There is also a class of genes called the mismatch repair genes that cause a type of hereditary colorectal cancer, and individuals with those genes have an eight-fold increased risk of getting pancreatic cancer, amounting to a four percent lifetime risk. Additionally, the PRSS1 gene, which is the familial pancreatitis gene, confers a 50-fold to 80-fold increased risk of developing pancreatic cancer, amounting to a 25-40 percent lifetime risk.

What is so critical about these genes is that when we know the gene that causes pancreatic cancer to run in a family, we can calculate the risk that the carriers of that genetic defect have for developing pancreatic cancer. Moreover, almost all these inherited genes, except for the pancreatitis gene, raise the risk of additional cancers outside of the pancreas, and these cancers can also be screened for, potentially saving lives.

For many of these genes, there are targeted therapy options available. For instance, when someone with a BRCA2 mutation develops pancreatic cancer, the doctor can prescribe a specific targeted cancer therapy such as a PARP inhibitor.

Understanding the genes that cause familial pancreatic cancer is critically important. It helps us quantify the risk of pancreatic cancer and the risk of cancers outside of the pancreas, and we can save lives by monitoring and detecting these cancers when they are at a very early, potentially curable state.

Q: Besides the genes you’ve just identified, are there environmental factors or health risks that could cause pancreatic cancer?

Cigarette smoking is the leading preventable cause of pancreatic cancer, and if we could get people to quit smoking, we could save lives by reducing pancreatic cancer as well as other cancers. Obesity has been associated with an increased risk of pancreatic cancer, so I urge people to eat a well-balanced diet, maintain a healthy body weight, and get regular exercise. There are also several studies that diets high in red meats, particularly barbecued red meats and smoked red meats, increase the risk of cancers including pancreatic cancer.

Q: If someone thought he or she might be at risk for developing pancreatic cancer because of a family history or a specific risk factor, what advice would you give?

There are proactive measures people can take to reduce their risk, including maintaining a healthy body weight and not smoking. Additionally, if there is a significant family history of breast cancer in the family, as well as pancreatic cancer, there is genetic testing available for the breast cancer genes BRCA1, BRCA2, and PALB2. If there is a strong family history of melanoma in addition to pancreatic cancer, there is genetic testing available for the p16 or CDKN2A gene. If this strong family history exists, one immediate next step is to speak to a cancer genetic counselor who can advise patients on the benefits and risks of genetic testing. The genetic counselor will go over the family history, ascertain if there appears to be a hereditary component, and try to determine a person’s lifetime risk for pancreatic cancer. Moreover, some people may choose to participate in familial pancreatic cancer research registries at leading institutions across the United States.

Q: Some people without any known risk factors for developing pancreatic cancer develop the disease, while other people with risk factors such as a strong family history of pancreatic cancer never develop pancreatic cancer. Please explain how this could be possible.

There are three reasons that people develop cancer. The first is that they inherit a genetic defect that predisposes them to develop the disease, such as breast cancer genes increasing the risk of pancreatic cancer. The second is that people can damage their DNA due to environmental factors. For example, if someone is smoking cigarettes, the carcinogens they inhale can enter the bloodstream and damage a cell in the pancreas, potentially causing pancreatic cancer. The third reason that people develop pancreatic cancer is due to chance. We have trillions of cells in our bodies, and the cells are constantly dividing. Every time a cell divides, it must copy all six billion base pairs of DNA in the cell. Mistakes get made during this process. If a mistake is made in copying DNA in a pancreas cell and it affects a cancer gene, someone may develop pancreatic cancer.

Inheritance accounts for approximately 10 percent of pancreatic cancer cases; environmental factors such as smoking and obesity are estimated to cause between 20-30 percent of pancreatic cancer cases; and the remaining 60-70 percent of cases are due to chance.

Q: Is there a universal clinically validated screening process? How can patients determine where they should go to receive screening that is best for them?

There currently isn’t a clinically validated screening process, although significant strides are being made in this area. Most cases of pancreatic cancer are unfortunately not detected until the disease has reached an advanced stage, where patients are no longer candidates for surgery and other potentially curable approaches. In fact, pancreatic cancer is often labeled a silent disease because many times the signs and symptoms can go unnoticed until the cancer is in the advanced stage.

If we can detect the disease earlier, then we can save more lives. There are multiple studies ongoing using techniques such as endoscopic ultrasound, including the Cancer of the Pancreas Screening (CAPS) study being conducted by my colleague Dr. Marcia Canto at Johns Hopkins University. As part of the CAPS study, at-risk family members are screened using endoscopic ultrasound for precancerous lesions and early cancers in their pancreas. In addition to Johns Hopkins, the CAPS study is taking place at Case Comprehensive Cancer Center; Columbia University Medical Center; Dana-Farber Cancer Institute; University of Michigan; University of Pennsylvania; University of Pittsburgh; and Yale University.

My colleague Dr. Bert Vogelstein, also at Johns Hopkins, is working on a blood test called CancerSEEK that can detect the early presence of pancreatic cancer as part of a panel of eight common cancers and identify where the cancer originated in the body. The FDA recently granted “Fast Track” status for the pancreatic and ovarian cancer portions of CancerSEEK, accelerating the approval process of this important blood test.  Dr. Vogelstein and his team continue to improve the sensitivity of this test so that it can become the first blood test used routinely, like the PSA test for prostate cancer. The Lustgarten Foundation is supporting this research.

Dr. Vogelstein and his team also developed a Comprehensive Cyst (CompCyst) test, which combines clinical, radiological, genetic and protein marker information to distinguish if pancreatic cysts, which can be common amongst the general population, can develop into pancreatic cancer or remain as benign cysts. They are working to further develop the CompCyst test into a clinically approved test for many people harboring pancreatic cysts. This research to determine which cysts require surgery and which require surveillance only is critical so that difficult surgery could be avoided in patients with benign cysts, while patients with potentially malignant cysts (approximately 20 percent) could benefit from early surgical intervention.

Additionally, my research has shown that small precursor lesions in the pancreas can give rise to pancreatic cancer. I believe that just as there is a colonoscopy available to test for early curable colon cancer, we need an early detection test for pancreatic cancer.

Q: What is the National Familial Pancreas Tumor Registry (NFPTR)?

We founded the NFPTR in 1994 at Johns Hopkins University. It is the first familial pancreas tumor registry in the country and is the longest standing and one of the largest familial pancreatic cancer registries in the world, attracting international participants as well. There have been more than 7,200 families enrolled in this registry, and the participants have been part of several different studies that have helped identify and quantify the risk of pancreatic cancer in relatives. We’ve helped identify pancreatic cancer genes, the other tumor types that are associated with pancreatic cancer, and the pathology changes in the pancreas that occur in people with a strong family history of the disease. The research that has emerged through this registry has helped to significantly advance our understanding of familial pancreatic cancer. In fact, using the registry, we’ve produced more than 50 peer-reviewed publications, and we work with a team of clinicians and scientists with backgrounds and training in areas such as epidemiology, pathology, gastroenterology, genetics, radiology, and oncology.

Q: What do you do with the information you collect from the family registry?

When individuals join the registry, they answer a detailed personal family history and personal exposure history questionnaire, including questions such as whether the person who developed pancreatic cancer was a smoker and if this person has a family history of other types of cancers such as melanoma or breast cancer. We then use this information to determine patterns of inheritance and calculate risk, using a sophisticated computer model called PancPRO developed by Dr. Alison Klein, Director of the NFPTR at Johns Hopkins University. The PancPRO model is now available to genetic counselors across the country so that they can help family members calculate their risk of getting pancreatic cancer. Using the registry, we’ve been able to show that in women, having a family member with pancreatic cancer increases the risk of developing breast cancer and ovarian cancer. We can also compare the importance of gene-environment interactions. For example, smokers who have relatives with pancreatic cancer are at an increased risk due to both heredity and cigarette use.

Q: At what age would you recommend screening and/or participation in a familial pancreatic cancer registry?

Any adult 18 years or older can participate in a familial pancreatic cancer registry. While there isn’t currently a clinically validated screening test, participating in research studies like the National Familial Pancreas Tumor Registry can help advance the field.

Q: Are there any costs incurred to an individual who wants to become part of a registry?

No, individuals who join a registry do not incur costs. The costs are usually taken care of by the registry, from mailing costs to blood-drawing and blood-shipping costs. Individuals can sign up for the registries online.

Q: Who would you encourage to participate in the registry? For example, if someone has only one family member who currently has or previously had pancreatic cancer, would you encourage him or her to join the registry?

I would encourage anyone with even one family member with pancreatic cancer, and anyone who is a pancreatic cancer patient, to join the registry. With each person who joins the registry, there is new information that could help us with potential new discoveries.

Q: How could a family register, and what are the next steps once a family registers?

People interested in joining the registry can email us at [email protected], or register online through our website, http://pathology.jhu.edu/pc/.

Q: What other groups do you collaborate with? What is PACGENE’s role in working with people who have a family history of pancreatic cancer?

As I mentioned earlier, we partnered with several other major familial pancreatic cancer research centers to study the DNA of 600 people with familial pancreatic cancer. Johns Hopkins University is also very involved in a consortium called PACGENE (Pancreatic Cancer Genetic Epidemiology), founded by Gloria M. Petersen, Ph.D., at the Mayo Clinic, and originally funded by the National Cancer Institute, to collaborate in the search for familial pancreatic cancer genes. This group worked together on a paper in which samples from multiple centers were pooled and analyzed to determine which of the known genes cause familial pancreatic cancer. Research demonstrated that the BRAC2 and p16 genes are the most common causes of familial pancreatic cancer.

Q: Are there any new studies or advances regarding screening tests and early detection tests?

Screening and early detection are two very promising research areas. As new genes are identified that predispose people to pancreatic cancer, we can quantify the risk, and we can offer these individuals options including endoscopic ultrasound (EUS), which is a minimally invasive procedure using high-frequency sound waves to create detailed images of the lining and walls of the digestive tract and organs such as the pancreas and liver, and lymph nodes.

There are also many novel DNA-based techniques. They range from analyzing circulating tumor DNA, which gives researchers and physicians insights about cancer mutations and how they react to treatment, to sequencing pancreatic secretions/pancreatic juices at the time of endoscopy. We also know what the pre-cancerous lesions and pancreatic cysts look like. Just as we know a colon polyp can lead to colon cancer, we know that there is a window of opportunity to detect precancerous lesions in the pancreas before they become cancerous, as well as early stage pancreatic tumors, so they can be treated before they lead to metastatic pancreatic cancer. Through monitoring of family members who have loved ones with pancreatic cancer, I am confident that our research will significantly change the future of pancreatic cancer.

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