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Pancreatic Cancer Foundation

"If I had not had kidney stones," says Linda B., "I probably wouldn't be alive today."

While certainly no one is usually grateful for kidney stones, Linda is now because the painful problem led to the discovery of a much more life-threatening condition. In 1998 during a CT scan prior to treatment for kidney stones, radiologists noted a suspicious growth located on the head of her pancreas. Her doctor dismissed the incidental finding, assuring Linda that it was nothing to worry about, perhaps a birth defect.

"He told me to go home and enjoy life," she recalls. "But as the days went by, I just didn't feel comfortable with his diagnosis."

The young Delaware mother had good reason to be alarmed.

"Although I was not having any symptoms of the disease, my mother died from pancreatic cancer about a month before that," she told the Post. "And she had two siblings--a brother and sister--as well as an uncle and nephew die from the disease. In all, seven members of my family; including myself, have had pancreatic cancer--six of them are dead. And my brother and uncle were recently diagnosed with pancreatitis, another risk factor for the disease."

She sought a second opinion at Johns Hopkins, one of the country's leading centers of pancreatic treatment and research. There, gastroenterologist Dr. Marcia Canto performed a procedure frequently used to aid in the diagnosis of pancreatic cancer called an ERCP, which revealed a tumor on the head of her pancreas.

"If I had went by the Delaware doctor's diagnosis," she now says, "I would be dead."

Fortunately, the disease was detected at an early and operable stage, and in 1998, Linda underwent a Whipple procedure, followed by chemotherapy and radiation. Today, she is alive and healthy--one of the fortunate few to survive the deadly disease.

Grateful for her survival, Linda's battle against the disease took a new turn. To help her children and future generations, Linda and her family volunteered to join hundreds of other families participating in the Johns Hopkins National Familial Pancreas Tumor Registry.

"My main goal in participating in this genetic research project is to help my children and my children's children, as well as everyone else," she says. "That is why I was so persistent with my family to participate in this study. The quicker they can focus on pancreatic cancer, the sooner they can come up with a treatment that will help everyone."

Although relatively rare--with about 29,000 individuals diagnosed each year and about the same number dying annually of the disease--pancreatic cancer is one of the most deadly forms of cancer. Researchers hope that by studying families like Linda's and former President Jimmy Carter's (which lost four members to the disease), a common thread may emerge to help explain the cause and molecular biology of cancer. Families with genetic predisposition to diseases such as pancreatic cancer provide invaluable clues for researchers because they share the same genes, as well as similar environments, diets, and lifestyles. By locating the genetics at work in high-risk families, scientists can better understand the cause and biology of pancreatic cancer in the general population.

"Certain families just give you incredible, incredible clues," says Nancy Wexler, president of the Hereditary Disease Foundation. "They give you a way of looking at everyone else in the population. Sometimes all it takes is some exceptional patient, or family, to crack an entire disease."

Through family studies, scientists have been able to pinpoint where in the genetic makeup--sometimes down to the specific gene and its location on a specific chromosome--the inherited problem originates. And that is exactly what researchers at Johns Hopkins and the University of Nebraska hope their ongoing studies of families with the genetic form of pancreatic cancer will reveal.

Over 200 Post readers have completed and returned the "Pancreatic Cancer Survey" (page 38), sharing both personal stories and a willingness to participate in the ongoing genetic studies taking place at two of the leading familial pancreatic tumor cancer research centers in the United States. The centers will receive the Post surveys, but both encourage continued participation by filling out the Post survey and enrolling in the registries.

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The Post spoke with Dr. Ralph H. Hruban, professor of pathology and oncology at the Johns Hopkins University School of Medicine and director of the National Familial Pancreas Tumor Registry, and Dr. Randall Brand, associate professor of medicine at the University of Nebraska and director of the Pancreas Cancer Family Registry, to learn more about the genetic advances researchers have made and how families can participate in finding a cure for the disease.

Dr. Ralph Hruban

Q: How can studying families help researchers determine the cause(s) of pancreatic cancer?

A: It turns out that the genes that cause "sporadic" cancers in the general population are often the same genes that cause the familial clustering of a cancer. The cancer-causing changes in these genes in sporadic cancers are acquired after birth, while in familial forms of the cancer, the changes are inherited. Just as we can inherit our eye and hair color from our parents, so, too, can one inherit a gene change that increases cancer risk.

Q: Are certain ethnic groups at higher risk of getting pancreas cancer?

A: Yes. In the United States, pancreatic cancer is more common in African-Americans than it is in whites. In addition, several studies have suggested that pancreatic cancer occurs more frequently in Ashkenazi Jews than in non-Jews. The high rate in Ashkenazi Jews is probably caused by the higher frequency of inherited breast cancer gene mutations in that population.

Q: Do environmental exposures to pesticides, for example, possibly raise one's risk?

A: DDT exposure has been suggested as a possible risk factor for pancreatic cancer.

Q: How long have you been a pathologist at Johns Hopkins?

A: I came to Johns Hopkins as a medical student in 1981. I graduated in 1985, completed my residency training at Hopkins in 1989, and soon thereafter I began studying pancreatic cancer.

Q: By virtue of the volume of procedures performed at the hospital over the past two decades, does Johns Hopkins have more clinical pathological specimens relating to pancreatic cancer than any other institution?

A: Yes. Dr. John Cameron and the other surgeons here at Hopkins are extraordinarily gifted. Twenty or 30 years ago, surgery on the pancreas was associated with a 20 percent mortality rate. That means if you went in to have your pancreas removed, you had a one in five chance of dying from the surgery. Dr. Cameron has dedicated his career to improving surgery on the pancreas. Today, patients treated at Johns Hopkins have a very low mortality rate of 1 or 2 percent. As a result, many patients come to Johns Hopkins for treatment. Remarkably, so many patients now come to Hopkins for surgery that we have actually decreased statewide operative mortality for the procedure. Getting to know these patients has had an impact on my work. On the one hand, these patients are living proof of the devastation caused by the disease. Their suffering gives our research a sense of urgency. On the other hand, they also provide an enormous opportunity for us to study the disease. Simply put, here at Johns Hopkins, we have more pancreatic cancer samples than any other institution.

Q: Could you tell us about the National Familial Pancreas Tumor Registry at Johns Hopkins?

A: One of my big areas of interest is familial pancreatic cancer. We now have the world's largest research registry of familial pancreas cancer and continue to try to encourage more families to register. Our registry is called the National Familial Pancreas Tumor Registry, and we study why pancreatic cancer seems to run in some families. For example, it's been reported that former President Jimmy Carter lost two sisters, a brother, and a father to pancreatic cancer.

The aggregation of pancreatic cancer in an individual family could be related to chance or shared environmental exposure. Or it could be that there is a gene inherited in the family that causes the aggregation of pancreatic cancer. We are taking a multiprong epidemiological-genetic approach to study these families.

One of the first things that we did was to follow our families forward in time. We felt that if the disease occurred simply by chance, then nothing should happen to other healthy family members that we followed. They should have the same risk of pancreas cancer as you or me. Unfortunately, new pancreatic cancers have already developed in 11 of these families.

If you can imagine, these people had already lost two or three family members to pancreatic cancer only to have another family member diagnosed with the disease. Even worse, 10 of the 11 people who developed pancreatic cancer in our study presented with disease that was no longer treatable. It had already spread to their liver. They knew the symptoms and about the disease, but they still presented late. Because of this experience, we are also focusing our research efforts on the early detection of pancreatic cancer. Just as there is a PSA test for prostate cancer, so, too, do we want to develop a blood test for early pancreatic cancer.

Q: How many families participate in your registry?

A: To date, 660 families have registered with us. Of those, 266 have at least a pair of first-degree relatives--a brother, sister, parent, or child. The breakdown is: 394 families with one family member, 174 with two family members, 62 with three family members, 19 with four family members, 8 with five family members, 2 with six family members, and one with seven family members with pancreas cancers.

Q: When you say seven family members, how many generations are we talking about?

A: The most we have are three generations affected by pancreatic cancer. An important aspect of our registry is that we confirm the cases registered. We try to get the pathology material or x-rays and confirm all diagnoses. This greatly improves the quality of our studies.

Q: In families with this family history, is it too early to tell if they will also inherit the disease?

A: A very important aspect of our research is to try and understand why certain families are developing pancreatic cancer faster than expected. Clearly, some families are at increased risk--it is not just by chance. We are now trying to determine which genes are involved. Already there have been five genetic syndromes identified that increase one's risk of pancreas cancer. These syndromes are caused when a patient inherits an altered ("mutant") copy of a cancer-associated gene from one of their parents. Each of the five known pancreatic cancer syndromes has a well-defined risk of developing pancreatic cancer. Therefore, if we can determine the syndrome, we can quantify a person's risk. For example, individuals who inherit a defective copy of the second breast cancer gene (called BRCA2) have about a tenfold increase of getting pancreas cancer. Similarly, we now know that patients who inherit a defective copy of the p 16 gene have about a 20-fold increased risk of pancreatic cancer. In addition, patients with Peutz-Jeghers syndrome--in which patients develop spots on the lips and inside of the mouth--have an astronomically high (100-fold increased) risk of pancreas cancer. Patients with familial chronic pancreatitis also have an increased risk of pancreas cancer. Finally, people with the HNPCC (hereditary non-polyposis colorectal cancer) syndrome also appear to have an increased risk of developing pancreatic cancer. Based on the quantification of risk, we are starting to screen some at-risk patients using endoscopic ultrasound. Dr. Marcia Canto at Johns Hopkins is conducting an NIH-funded study in which at-risk relatives of patients enrolled in our family registry are screened for early asymptomatic pancreatic cancer. She performs an endoscopic ultrasound (EUS) and a CT scan. During the ultrasound, she can obtain a sample of the pancreatic juice, and we are analyzing these samples in the research lab to determine if we can identify new markers of early pancreatic cancer.

Obviously, this screening is done in consultation with the patient. She explains to them what she found, what she thinks it is, and what we know, or think we know, about the risks of the finding eventually becoming a cancer. We don't present anything as a medical certainty, nor do we tell them what to do. We have trained genetic counselors at Johns Hopkins. If we find someone who has a genetic abnormality, a genetic counselor will work with that patient. Some people don't want to know, and that's fine. Others want to know, but you have to make sure that they know what knowing their genetic information means to them, as far as insurance and similar matters.

Q: In your research, do you cue into the genome databanks?

A: The information provided by the human genome project has been wonderful. It has just been like being a kid in a candy store. For example, I mentioned that we are interested in developing new genetic markers for early pancreatic cancer. You can think of the genes that we are studying as looking at the roots of a tree to figure out why the tree is having problems. We are also looking at the fruits of the tree--the proteins and RNA produced by cancer cells.

We use modern gene and protein "chips" to determine the RNA and protein levels in tumors with the idea that if you find excess RNA or protein of a specific type in a tumor, it may be a good marker for that cancer. The federal government has established a Web site on which they have put a lot of this data from close to a hundred different samples online and free to the public. We went to this free online database. We clicked "pancreatic cancer" and we clicked "normal pancreas." A program on the database allowed us to find which RNAs are up-regulated in the cancers compared to normal. In so doing, we have found some wonderful new markers of pancreas cancer.

Q: That must save years of research work.

A: We did in ten minutes what would have taken ten years a decade ago.

Q: How critical is the pathologist in pancreas cancer?

A: The pathologist plays a critical role, and more pathologists are being aided by the revolution in our understanding of cancer genetics. As we find new markers of pancreatic cancer, we can use them to help us interpret difficult biopsies. For instance, Dr. Scott Kern here at Johns Hopkins discovered a gene, called "DPC4," that is deleted in 55 percent of pancreatic cancers. We now have a stain for DPC4, so if we have a difficult biopsy, we can stain the tissue. If the cells in question have lost DPC4, it is a pretty good indicator that this is probably cancer. Other markers that we are finding are up-regulated in pancreatic cancer. Even with these molecular tools, the expertise of the pathologist certainly is important. Expertise of the pathologist is particularly important when it comes to pancreatic cancer, because so few pathologists have much experience diagnosing pancreatic cancer. As I mentioned before, surgery is rarely performed at smaller hospitals. As a result, most pathologists don't have much exposure to pancreas cancer. Unlike for the prostate, where every hospital does a lot of prostate biopsies, only certain hospitals do significant numbers of operations on the pancreas. Pathological expertise is at centers such as Hopkins.

Q: What role does cytology play in differentiating between malignant versus benign cells in adenocarcinoma of the pancreas?

A: Cytology can be very useful, providing the lesion is adequately sampled. For example, cytology can be used to distinguish between an adenocarcinoma and a benign islet cell tumor (neuroendocrine tumor) of the pancreas. This distinction can help guide the surgeon as to how aggressive the lesions are. Because cytology only samples a very small portion of the tissue, a negative cytology, however, does not mean that there isn't a cancer there that just wasn't sampled. In addition, some cases are "atypical" but not diagnostic of cancer on cytology. As discussed earlier, we are working on developing new markers that will help make this distinction easier.

Q: In your research, besides smoking, what other factors emerge that might put people at higher risk of pancreatic cancer?

A: Besides smoking cigarettes, the other known or suspected risk factors include: diabetes mellitus, chronic pancreatitis, remote (20 years) history of gastric resection, and family history of pancreatic cancer. We like to emphasize smoking, because that is something one can control; the others, one has no choice about.

Dr. Randall Brand

Q: What is your principal area of interest and research?

A: Actually, I am interested in several areas of pancreatic research, including early diagnosis. My mentor, Dr. Henry T. Lynch at Creighton University's Hereditary Cancer Institute, is considered the grandfather of familial cancer syndromes. He was one of the first individuals to recognize and associate an inheritance pattern in cancer-prone families for a variety of tumors. More recently, he has had a major interest in pancreatic cancer. I work very closely in studying families with a high incidence of pancreatic cancer.

Q: In recent years, have there been any promising developments in the use of genetic or other market's in the early, detection of pancreatic cancer?

A: That is a great question and another one of my fields of interest. Right now the gold-standard marker, which is still not very good for early detection, is the level of CA19-9.

Let me give you a little background. The ideal situation is to find pancreatic cancer when it is very small. Dr. Ralph Hruban is an expert at characterizing these precancerous lesions. If you can find tumors at these early stages of pancreatic cancer, you can cure the patient. Pancreatic cancer is one of those cancers that if it is detected after the patient develops symptoms or the tumor can be seen on an imaging study, it is too late in the vast majority of patients. This is in contrast to breast cancer, where one can use mammography to detect a small curable tumor. Our current imaging technology for pancreatic cancer has not matched this success. To date, cure for pancreatic cancer can only be achieved with the use of surgery. We have improved our surgical techniques, but this has only had a minor impact upon survival.

Q: How can we improve the prognosis for patients facing pancreatic cancer?

A: One approach is to try to find tumor markers in the blood. One of the promising markers that we are looking at right now is a novel protein called MUC4. One of my colleagues at the University of Nebraska Medical Center, Dr. Surinder Batra, has found the presence of MUC4 in the blood to be very specific

for pancreatic cancer.

There are other markers being tested by a variety of people, but to date no one has found a marker with adequate specificity. By specificity, I mean just being abnormal in pancreatic cancer but not other conditions. Unless the marker is specific, you can work up thousands and thousands of patients, but you will be doing many workups and subjecting a lot of patients to risk who do not have the disease. Specificity is very important, and we don't have good markers now with good specificity.

In colon cancer, screening and surveillance have been able to prove that if you remove a polyp, you decrease the patient's risk of developing cancer. Or if you detect a cancer at an early stage of development, you improve the patient's chance of cancer-free survival. And it's also easier and safer to examine the colon. The pancreas, however, is in an awkward spot. In pancreatic cancer, we haven't been able to prove that if you pick up a cancer that is small, like a centimeter or two (size of a dime), you have changed the natural history of the disease. So unlike in colon cancer, applying screening to the general population is probably not the way to go.

This then ties into my study of pancreatic families. We investigate high-risk individuals from families who are prone to the development of pancreatic cancer and thus are at a higher risk than the average person to develop pancreatic cancer. Our current study protocol involves the collection of blood, stool, and pancreatic juice from these individuals and examining them for different potential tumor markers.

Q: Are you recruiting patients for this study or trial?

A: We are only trying to recruit members of pancreatic cancer-prone families.

Q: Is your familial pancreatic cancer database different from that of Dr. Hruban's at Johns Hopkins?

A: Yes and no. We both collect information on these families. However, we are in the process of trying to standardize the collection of data, so that an investigator could come and say, "I have a project where we are researching a particular gene, and I am trying to find patients who have so many relatives with pancreatic cancer." They could come to one central clearinghouse and identify that a certain center has this many patients, another has this many patients, and so on. Everyone then has collected data and specimens in a common way so that we can make some meaningful conclusions and share some of our data or specimens.

Q: Is CA19-9 a marker for acute pancreatitis as well?

A: Yes, in a sense. You can see elevated levels of CA19-9 in this condition. Again, specificity is important. CA19-9 level is abnormal in other conditions besides pancreatic cancer, such as acute pancreatitis and cirrhosis, cholangiocarcinoma, and other tumor types--bile duct tumors, for example.

Q: How important are the pathologist, radiologist, and cytologist--as well as centers with the current state-of-the art technology--in getting an accurate diagnosis? It appears to be such a difficult disease to diagnose.

A: It depends. I practice at a tertiary care hospital that has all this expertise. But I have to be honest with you; it probably isn't the case for the majority of the tumors, since they present at an advanced stage. These patients are usually diagnosed appropriately. We tend to only hear about the cases that aren't. Those cases are the more atypical and difficult. Unfortunately, most cases are diagnosed late, because the symptoms are so vague. There aren't classic presenting symptoms for pancreatic cancer. If there are concerns about pancreatic cancer and it has not been diagnosed, it can be very useful for the patient to get a second opinion at a more experienced pancreatic center. Again for the majority of patients, it is a straightforward diagnosis--regrettably it's just a late diagnosis.

Q: Which is a key factor.

A: Yes. But again, if you find it sooner, I am not sure that it is going to make a difference with our current technology. That's the point. We have to learn how to find it at these earlier stages.

Q: Is pancreatic cancer singular or different in a way from other forms of cancer? It seems like we are having great progress with other forms of cancers and in getting genetic markers for these forms, but pancreatic cancer seems to be so elusive and difficult to diagnose early.

A: Pancreatic cancer has several unique problems. First, its location is probably the biggest problem because it is in a spot that is inaccessible. Second, it is a tumor that spreads or metastasizes when it is very small. Third, we have learned from animal models that pancreatic cancer is composed of a mixture of cells. You may find a drug that can kill some of the cells, but not all of them. Not every cell is sensitive to it.

You may not find an agent that prevents pancreatic cancer, but you would make an impact on this tumor if you could find an agent that prevented it from spreading. That is another option.

Q: Does a history of breast or colon cancer put you at higher risk for pancreatic cancer?

A: Any family history of cancer puts an individual at a higher risk for developing pancreatic cancer.

Q: Have you identified any specific genes in the families that you have been studying?

A: In the majority of families, no gene has been identified.

Q: Any comorbidity or other factors that may indicate why they are at high risk?

A: That is something that we are trying to study. We have recently found that smoking appears to increase your risk in one of these pancreatic cancer-prone families. We know that smoking is a risk factor anyway, but it is an even worse risk factor if you are in a pancreatic cancer family. This emphasizes the importance of gathering data from multiple academic sites to see if we can identify other factors.

Q: President Carter's family is a perfect example. Four family members died, and all of them were smokers, I believe.

A: Exactly. What we don't know is whether President Carter carries the gene.

Q: Do you screen other family members in high-risk families?

A: Our present strategy is screening with endoscopic ultrasound and the collection of pancreatic juice, along with stool and blood specimens. We are in the process of establishing a national group to standardize surveillance in these high-risk families, so we can find out what method is most effective. For example, we would collect patient data, stool, blood, and pancreatic juice, as well as report their imaging studies in a common way.

Q: You mentioned stool specimens. Obviously, those are the least invasive ways of screening. What are you picking up there?

A: We are looking for DNA mutations in the stool. The pancreas makes digestive enzymes and secretions (juice) that help digest your food in your intestines. This juice can have pancreatic cancer cells in them, which in theory could be detected in the stool.

Q: But again, when we mentioned these to some other researchers, they seemed to downplay their role.

A: Oh, yes. Again, it comes back to specificity.

Q: Again, it comes back to the point that we have no specific marker at this point in time.

A: That is why it will become a panel of markers. It may be that you have mutations in the k-ras and p53 genes that give you an almost 100 percent chance of pancreatic cancer.

Q: Has the situation improved at all for patients diagnosed with this disease?

Q: We have really not made a significant impact on survival. However, we have accomplished a great deal in our ability to palliate many of the symptoms from pancreatic cancer in a less invasive manner. Gemcitabine has helped improve the quality of life. For a modest percentage of patients, we can offer them a little longer life, but for the majority, probably not.

Q: How soon do you think that we will have a vaccine?

Q: I hope within the next five to ten years. The use of vaccines would be wonderful if they work. Vaccines could play a role in treatment or prevention, but they are still in their infancy.

Q: Is there anything else that you think your readers should know about pancreatic cancer and its treatment and detection?

A: It's a disease where people, if possible, should try to participate in clinical trials, and the only way that we are going to successfully fight this disease is to study it in a systematic manner. The readers should be aware that there are pancreatic cancer centers where family members can be counseled about their cancer risk and informed about current surveillance approaches.

Risk Factors for Pancreatic Cancer

Age: The incidence of pancreatic cancer is relatively low in individuals up to age 50, after which it increases significantly. The age group 65-79 has the highest incidence of cancer of the pancreas.

Smoking: Smokers develop pancreatic cancer more than twice as often as nonsmokers do.

Diet: Frequency of pancreatic cancer may be associated with high intakes of meat and fat.

Medical factors: Pancreatic cancer is more common among individuals with histories of the following conditions: cirrhosis (a chronic liver disease), chronic pancreatitis, diabetes, and a history of surgery to the upper digestive tract.

Environmental factors: Longterm exposure to certain chemicals, such as gasoline and related compounds, as well as certain insecticides may increase the risk of developing cancer of the pancreas.

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