Non-Genomic Risk Factors of Pancreatic Cancer


Kristie L. Kahl: What is a risk factor and a protective factor in pancreatic disease?

David Whitcomb: So, these are things that doctors think about and patients should begin to think about as well, because they really help us understand if we're likely to get a disease or not. A risk factor is if you take a group of people that have a certain feature, and another group that does not have the feature. Do they get a disease at the same rate? And if the patients you're concerned about have a factor, and other ones don't, and that makes a difference, then we know that's a risk factor. So smoking, and lung cancer is a good example. If you take people who smoke and people who don't smoke, the people who smoke in that population are more likely to get lung cancer. Now, there's some people that smoke like a chimney and they never get cancer. And there's people who don't smoke and they do get cancer. So, there's other things that are involved as well, but it's really weighing out the balance.

Now there's other people who may have factors such as they have a healthy lifestyle. They eat good fruits and vegetables and maintain a healthy weight and they can be protected so that the chance of them getting a disease is lower. That's a protective factor. When these factors are identified, it doesn't prove something's going to happen. It means in a group of people, a lot more of them that have a risk factor are going to get it. People who have a protective factor are less likely, but on a case-by-case basis, we just don't know 100%. But it helps us balance our lifestyle. If we have some bad things, you have to balance it with some good things.

Kristie L. Kahl: With pancreatic cancer, what are the most common risk factors and protective factors?

David Whitcomb: The worst thing you can do is smoke cigarettes, because that is a high risk factor, and is responsible for a large part of pancreatic cancer. Fortunately, the smoking rate in the United States is dropping, which is a very good thing and that's probably one of the most important public health initiatives is to address smoking.

Other things that are important are having am infection of the stomach with H. pylori that causes ulcers. The reason for that is unclear, but that's been recognized as something that is important.

Having acute pancreatitis even once or chronic pancreatitis. Those types of inflammation increase the risk for getting cancer.

Family history is very important. Those things interact with the environmental factors, and the combination is much worse than either alone. Now it's hard to change your family, but we can change other risk factors. For example, a person being overweight is a risk factor. Being diabetic is a risk factor, especially if the diabetes is mixed with inflammation of the pancreas or pancreatitis. And so those types of things are all negative.

Eating a healthy diet with fruits and vegetables, like broccoli and green vegetables, are protective. And so those are things that are good: a healthy lifestyle, exercise, less red meat, more vitamins and minerals and antioxidants are protective.

Kristie L. Kahl: How does inflammation play a role in the development of pancreatic cancer?

David Whitcomb: This is a fascinating story, because there's a lot of work that has been done on trying to understand the genetics of pancreatic cancer because it seems to come out of the blue. But when you do the genetics and start looking at the family trees, it turns out that the genes for pancreatic cancer are also the genes for breast cancer, colon cancer, ovarian cancer, prostate cancer and other types of cancer.

When you look at the risk of those genes in a big populations like they did in the Scandinavian countries, we see that if one person in your family had breast cancer, or if an identical twin has a breast cancer, the other twin is likely to get a breast cancer. However, if one twin, an identical twin gets pancreatic cancer, it's more likely that they're identical twin gets a different type of cancer. Those genetics are important, but they can't focus on the pancreas.

In some cases, what we’re learning is that you have to have something happen to the pancreas to cause DNA damage, cell turnover, and that's the kind of mix you need to have it started. Chronic pancreatitis is the most common risk factor that releases all kinds of things that are designed to damage bacteria and can actually damage the cells of your own body. The cells die and they turn over and the new ones in the process of making new cells means that genetic mutations can get incorporated into the daughter cells.

There are genes that can actually correct broken DNA that was copied wrong. Unless you inherited a gene that fails to correct DNA, then you start getting the mutations. So the combination of smoking, which causes direct, toxic damage to the pancreas, pancreatic inflammation, which causes cells to turn over and damage, and a process of not being able to correct the broken DNA, that is a formula for a disaster. We think it's this process. That's important and inflammation is a major part of it.

Kristie L. Kahl: How are smoking, inflammation and genetics all connected through this?

David Whitcomb: It’s probably sequential. It takes a number of years. Many cancers begin developing in patients when they're in their 40’s and 50’s. Pancreatic cancer occurs a little bit later in life, usually in the late 60’s or 70’s. Because It takes a long time for all these events to accumulate, and to start building up, we think about how smoking is causing damage. The inflammation is causing cell turnover. And then there's a couple key mutations that randomly occur. One of them is called KRAS. And that starts auto driving this process. It just keeps going in a bad direction.

If you look at the pathology, how the cells start accumulating more mutations, because they have to have mutations that prevent them from being shut off when they're replicating too fast, that caused them to start pushing into other areas they don't belong, causing them to be resistant to the immune system, which is trying to kill them. And so each of these is a different type of mutation. And so you have to kill dozens of mutations in a single cell. And that takes time. That's why people usually don't develop pancreatic cancer until older in life.

The good thing is the damage caused by smoking and inflammation, your body has some defenses for it. And those defenses can actually shut down the inflammation and protect the body from toxins. That's what vitamins do and antioxidants, and many of them have been shown to markedly reduce the risk of cancer. Remember our two populations, the ones that eat vegetables and antioxidants and vitamins have a lower rate than those that don't, because they help protect the body from the effects of toxins and inflammation.

Kristie L. Kahl: Can demographics like age, race or gender also play a role and if so, how?

David Whitcomb: In the United States, the highest risk of pancreatic cancer is in African American men. However, if you go to look at people in Africa, their ancestry, the rates of pancreatic cancer are low. So, what is it about coming to the United States that increases the risk for cancer? That’s an interesting demographic question. What we've learned from studying the colon and the mix of things inside the colon, the biome, is that African American malese from the United States have one of the highest risks of colon cancer, whereas it's very low in South Africa. But if you switch their diets, then within two weeks, the whole thing reverses.

That tells us that there are people at risk, but we don't know if it's nurture or nature. We see the same types of things in India where there are some genetic causes for inflammation that's widespread. Yet cancer doesn't seem to develop as rapidly, even though there's a lot of pancreatitis. But in the United States, African American men are at very high risk. Men in general are at increased risk. And as I mentioned earlier, age is very important. Diabetes is important as well. And we're beginning to learn that it's not just diabetes in general, which means the blood sugar is too high. It's why do you have diabetes? And there's some reasons for having diabetes that are very bad. And there's some reasons for having diabetes that just don't matter when it comes to pancreatic cancer.

Ongoing research is beginning to sort this out and help us understand exactly what's doing it, because we'd like to just zero in on where the problem is and eliminate it and help prevent a disease that's almost impossible to treat if it's past the earliest stages.

Kristie L. Kahl: If there's an individual who has just received a diagnosis of new onset diabetes, but they don't have a family history and their disease isn't associated with obesity, how does that affect a person's risk for pancreatic cancer?

David Whitcomb: This is actually a very interesting observation that a doctor from Mayo Clinic made and he noted there was a very high rate of people developing diabetes within two years of the diagnosis of pancreatic cancer. Usually what we see is that if you're young and get diabetes, it's because it's an autoimmune disease to attack the cells of the pancreas that's called type 1. Type 2, you get it when you get older when you're out of shape, if you're overweight, especially if you're a man. As you start getting older and heavier, that blood sugar becomes harder and harder to control. However, what Dr. Cherry recognized is that the people that are getting cancer weren't gaining weight, they were losing weight. And the family history and some of the other factors weren't so important.

What they found out was that the diabetes was a different type than either type 1 or type 2. It's part of a type 3 diabetes. What they found is that the pancreatic cancer, when it's small and hard to even see, is releasing substances that actually goes to the cells that make insulin and shut them off. And that's why they get diabetes. It also affects a certain type of fat. So, you begin losing weight, because the fat starts melting away. The same process seems to be able to affect those two things. Interestingly, if you look for pancreatic cancer, and you detect it and find where the cancer is, and remove it, the diabetes goes away. So usually we think of a surgery of the pancreas to remove those cells that make insulin, making diabetes worse. In this case, it makes it better. And so an individual who is losing weight and has unexpected diabetes really should be in one of the research projects where there is a focus expert panel that tries to zero in on what the cause is, and whether or not they have a hidden cancer that can be identified with new techniques. Now we have early detection, the early diagnosis, early treatment, and long-term cure.

Kristie L. Kahl: What should an individual do to either hopefully have early detection for a potential diagnosis or assist in having an early day diagnosis?

David Whitcomb: Part of the problem is that the many physicians that were trained with me and in the years afterwards were taught that pancreatic cancer is a hopeless disease, and the recommendation is for the patient to get their house in order, because they're going to die. However, major progress has been made. There are doctors who have the capacity to make the diagnosis and to provide treatment, but they have to be connected quickly. That's why places like the National Pancreas Foundation, which is a patient advocacy group, and others are working to make sure they answer the patients’ and their families’ questions. They get involved in either a research project or to a center that understands the promise of early detection and treatment, and hopefully a long-term cure. It's not always possible, but that's an option that has to be looked at.

We do have a chance to really make a big difference. There's new things that are happening. There are studies that are going on. My own group is working to develop ways of sorting out whether or not new onset diabetes with weight loss is due to cancer or due to regular diabetes. These types of things are a real help for the future for a disease that for a long time has been a very poor prognosis.

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