Genomic Risk Factors of Pancreatic Cancer

Kristie L. Kahl: How does family history play a role in the risk for pancreatic cancer?

Diane Simeone: Obtaining a family history is actually critically important in evaluation of patients with pancreatic cancer. What we have determined over time, is that when a thorough family history is obtained, we clearly identify patients who are at heritable risk for pancreatic cancer. We’ve advocated for a thorough family history for patients with pancreatic cancer, and in fact a thorough family history for all patients that are seen by their physician so that if there were any clues that someone might be at risk for a heritable cause of cancer, and pancreatic cancer, that it's picked up.

Kristie L. Kahl: What would this family history consist of?

Diane Simeone: You’d be surprised at how many people out there have family members that have a history of pancreatic cancer. The definition of a familial pancreatic cancer is a family that has two or more members with pancreatic cancer, with at least one of those members being a first-degree member. By that, I mean a parent, a child or sibling. But what we also find is there are many people that are living in the gray zone where they may have multiple members in their family of pancreatic cancer and that it might not necessarily be a first-degree relative. We're still in the learning phase of determining who's really at elevated risk for pancreatic cancer.

Importantly, we want to try to make sure we record that information. As we learn going forward, that will help us ascertain who are the appropriate people to get screened. It's also important to know that there are other cancers that can be tied to pancreatic cancer. It's important not just to ask if family members have had pancreatic cancer, but if they have associated cancers like breast cancer, colon cancer and melanoma, for mutations in genes that are called BRCA genes or the PALB2 gene. There can be an association between colon cancer, Lynch syndrome and pancreatic cancer. And there's a tumor suppressor gene called the p16 gene that can cause familial melanoma and pancreatic cancer. So really having a comprehensive family history helps a clinician start to sort that out whether someone might be at elevated risk.

Kristie L. Kahl: Can you discuss some of those genetic mutations that are associated with pancreatic cancer?

Diane Simeone: As we delve into this area a little bit more, we're actually uncovering that more patients with pancreatic cancer had a heritable risk. We talked about family history and that getting a thorough family history is important, but we actually embarked on a large study a number of years ago to do genetic testing, or what we call germline testing, of all of our pancreatic cancer patients. This was a large study we started at thee University of Michigan and carried out at NYU. What we found is 15% of all pancreatic cancer patients actually carried a known mutation that put them at risk for pancreatic cancer. Now, in some of those patients, there was a family history that went along with that. But we've also found in patients who didn't have a family history that would suggest they had a heritable cause, we also found germline mutations.

With that, we've now pushed forward to establish guidelines that all patients with pancreatic cancer should get germline testing. What I mean by germline testing, that's getting a sample of blood, and from that blood, their white blood cells in the blood, you can isolate the DNA and look for mutations in a set of genes that are associated with an increased risk pancreatic cancer.

The most common ones people have heard about are the BRCA genes, which are also linked to breast and ovarian cancer. There are other genes out there, about 15 in total, that have been identified so far that are associated with increased risk of pancreatic cancer. ATM is one of those genes. There is also Lynch syndrome where you can have mutations in mismatch repair genes, and then there's a number of less frequent germline mutations. It's also important to know that this is still an area of active investigation. Even in families that we know that they have a number of members with pancreatic cancer, when we test for the known mutations associated with risk, that assessment might come back negative and I think it's because we still are in the discovery phase of identifying all the genes that are associated with pancreatic cancer.

Kristie L. Kahl: Why is it important for families to also be having these discussions?

Diane Simeone: There's been a tradition of those at pancreatic cancer risk and screening, where people think “Even if I am at elevated risk, there's nothing that can be done about it.” That is, in fact, not true. There are now a couple studies, each with 200 to 300 patients that show for patients who are at elevated risk, if they're in a screening program, our ability to pick up an early pancreatic cancer, should it develop in that person, and resect it surgically, approaches 90% as opposed to the typical patient with pancreatic cancer who comes in to our clinic. We're only at about 15% of patients who are candidates for resection and removal of the tumor, because the tumors are more advanced. So, we have a growing body of data that shows that screening finds earlier cancers with a much higher likelihood of cure. And as a surgeon, I can tell you that our ability to move towards long-term survival is going to be much higher if we shift our whole thinking about really identifying who's at risk out there and make sure appropriate at-risk patients are put in to screening programs.

Kristie L. Kahl: Why is genetic testing important and who should be getting tested?

Diane Simeone: Genetic testing is really something that needs to be done with higher frequency. We're finding that, especially since the cost has come down pretty dramatically over the last few years, you can get a high quality genetic test for $200 or $300, as opposed to the old days where it was a $4,000 or $5,000 test. So. with a relative low cost, and insurance often covering that cost, we can liberalize who gets testing.

We even offer testing to people that have a single first-degree or second-degree family member with pancreas cancer because the cost is low. And the yield, which is about 7% to 8%, can be very impactful for that patient. We have definitely found patients who have germline mutations even with a single family member with pancreas cancer. I think highlighting that increasingly deploying this kind of test is going to better help us understand who out there is at risk for pancreatic cancer and should be screened.

Kristie L. Kahl: How can a family history of diabetes or pancreatitis also increase risk for pancreatic cancer?

Diane Simeone: First let's discuss diabetes. Diabetes is definitely linked to an increased risk of pancreatic cancer. There's a two-fold relationship between diabetes and pancreatic cancer. The first is if someone has long standing type 2 diabetes that increases their risk of pancreatic cancer about two-fold. We’re talking about somebody who's got type 2 diabetes that has the disease for eight to 10 years. That’s one category. Sometimes pancreatic cancer presents with new onset diabetes, especially if it's associated with weight loss instead of weight gain, and in people over the age of 50. That should be a little bit of a red flag if you have new onset, difficult-to-control diabetes associated with weight loss, that that can be a sign of pancreatic cancer. Importantly, research has shown that that may happen six to nine months before someone develops any other signs or symptoms of pancreatic cancer. So that's a really important thing for patients to know about and also for primary care doctors and internist and gastroenterologist to be aware of that association.

Now, let's talk a little bit about pancreatitis. Pancreatitis is inflammation of the pancreas. It comes in two forms. You can have acute pancreatitis, which is often brought on by either gall stones or heavy alcohol use. We have an episode of pancreatitis and it resolves. We don't know if there's a relationship between an episode of acute pancreatitis and pancreatic cancer risk. Alternatively, folks can have what's called chronic pancreatitis where they have chronic fibrosis and inflammation of the pancreas. There are different causes of chronic pancreatitis. Sometimes it's genetic. Sometimes it's due to heavy, longstanding alcohol use. Sometimes we don't know what the cause is. But in those patients, they can also have about a two-fold increased risk of pancreatic cancer. Another point to bring out is sometimes pancreatic cancer will present as a bout of pancreatitis. Anytime a patient has pancreatitis, it's important to get a thorough evaluation by their physician. Certainly if it's a little bit of an older patient with unexplained pancreatitis, sometimes it's due to a tumor that's blocking the pancreatic duct that causes pancreatitis.

Kristie L. Kahl: If an individual does have any any of these genomic risk factors, what should they do?

Diane Simeone: It's important that you see a physician that has expertise in this area. Importantly, the National Pancreas Foundation has identified pancreatic Centers of Excellence around the country, so that if you're in any part of the country, you should be within striking distance of a center that has expertise in pancreatic diseases. So that's really important to make sure you see a knowledgeable physician.