Epidemiology Research in Pancreatic Cancer

Dr. Harvey Risch, Epidemiology Research in Pancreatic
Cancer
June 27, 2010Welcome to Yale Cancer Center Answers with Dr. Ed Chu and
Dr. Francine Foss, I am Bruce Barber.  Dr. Chu is Deputy
Director and Chief of Medical Oncology at Yale Cancer Center and
Dr. Foss is a Professor of Medical Oncology and Dermatology
specializing in the treatment of lymphomas.  If you would like
to join the conversation, you can contact the doctors
directly.  The address is canceranswers@yale.edu and
the phone number is 1888-234-4YCC.  This evening Ed and
Francine welcome Dr. Harvey Risch, Dr. Risch is a Professor in the
Division of Chronic Disease Epidemiology at Yale School of Public
Health and he joins us to talk about pancreatic cancer.  Here
is Ed Chu.Chu
Why don't we start off by defining for our listeners out there what
pancreatic cancer is? Risch
Pancreatic cancer is a cancer that occurs in the pancreas,
obviously. The pancreas is an organ that is just underneath the
stomach and makes enzymes to digest food and fluid to help with
neutralization of stomach acid.Chu
How common is pancreatic cancer as a public health problem?Risch
It's not a major problem, but it is a significant one. 
Probably about 1% of the population will get pancreatic cancer over
their lifetime, and that translates to about 42, 000 cases in the
US per year, and about 35,000 deaths from pancreatic cancer per
year.Foss
Harvey, what are the ages and gender of patients with pancreatic
cancer?Risch
It mostly occurs in individuals over age 50, especially over 60 and
in their 70s, and it used to be that it was more a disease of males
than females, but in the last few years women are now getting
pancreatic cancer at the same rate as men.Chu
What do we know about the underlying risk factors for pancreatic
cancer?Risch
The classical risk factors have been identified as tobacco smoking,
mostly cigarette smoking, which perhaps accounts for 20% of
cases.  There are some rare genetic mutations, and also
chronic pancreatitis, which is inflammation of the pancreas, and
together those may account for perhaps 10% of the disease, so
overall we know about 30% of what causes pancreatic cancer and the
remaining 70% is unknown.  Recently, there has been some work
showing evidence for ABO blood group, AB and AB blood groups,
compared to group O as being associated with risk and that's just a
developing story.2:43 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3Foss
There was a paper in the New England Journal a number of
years ago about coffee and the risk of pancreatic cancer, has that
ever been proven?Risch
No, and like many findings we have in epidemiology, we tend to
believe our own findings until the next paper comes out that
refutes it, so when one puts together the whole literature, there
is no other evidence really to show that.Chu
And is there any linkage say between other diseases of the pancreas
such as diabetes and the development of pancreas cancer?Risch
Diabetes is an interesting story because there is an increased risk
that one measures in studies, but on the other hand, within about
three years before the diagnosis of pancreatic cancer, there is
also an increased incidence of diabetes that we believe is the
result of the cancer itself developing, so it's unclear which
direction the cause goes, whether diabetes causes pancreatic cancer
or vice versa, and we do not really know yet.Foss
Harvey, you mentioned smoking is a risk factor.  I do not
think many people in the audience connect smoking with pancreatic
cancer.Risch
Smoking causes a number of different kinds of cancers, not just
lung cancer, there's a whole class of smoking related cancers and
pancreas is one of them.  The carcinogens for pancreatic
cancer reach the pancreas from the lungs to the blood stream rather
than being deposited in the lungs directly, but it's still an
important source of carcinogenic material that's in the tobacco
smoke that causes the cancer.Foss
Likewise with passive exposure to smoke, is that also a risk?Risch
I think that's harder to prove.  There may be, in theory there
could be, but we do not really know that.Chu
What's remarkable is that, as you say, pancreatic cancer may effect
about 40-45 thousand patients in the United States each year, but
yet just within the last few years there is so much publicity about
sports stars and Hollywood personalities that have developed
pancreatic cancer and so you get the sense that it really is a
pretty significant issue.Risch
It's hard to know, once you turn 40 you know people who had some of
the more rare kinds of cancer, either among your friends,
acquaintances, or relatives.  And in general I think that
these are noteworthy kinds of occurrences, and so we pick up on
that.  It's hard to know whether it was just not talked about
as much in past generations, or that the risks have been5:07 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3increasing, but they certainly have not been increasing
dramatically.Foss
Do you think that many pancreatic cancers are not picked up on
early enough? This is always a question we have about screening and
detecting cancers early so that we can actually impact the
survival.Risch
That is true.  The cancers that occur deep in the abdomen, are
in general, unless they have some root at the outside, not
diagnosed early so it's mostly late stage disease, which has poor
survivalFoss
And is it also true that many patients do not have symptoms until
they are very advanced?Risch
That's correct.Chu
For our listeners out there, for breast cancer we have screen
mammography, for colorectal cancer, we have screening colonoscopy.
 For pancreatic cancer, as of yet there is no screening or
early detection method that has been developed.Risch
That's largely correct; one would have to have an index of
suspicion, a reason to look for pancreatic cancer, and in any
cancer like the pancreas, ovarian and others where the rates are
sufficiently low, like 1-2 percent of a lifetime risk, there is no
reason that you would screen because the number of people who would
be falsely diagnosed after you do more invasive tests would be too
large to compare to the number you would actually find as truly
having pancreatic cancer, so it's not effective.Foss
Can you tell us if there is an association with other cancers, say
patients who may have colon cancer or breast cancer, are they going
to be at an increased risk for pancreatic cancer?Risch
Not that I know of, unless they carry a BRCA2 mutation, which would
put them at increased risk for breast cancer, pancreatic cancer,
ovarian cancer and a few others, but that's relatively rare.Foss
You study the epidemiology of pancreatic cancer.  Can you talk
a little bit about what epidemiology is for our audience?Risch
Epidemiology is the study of human diseases or conditions by using
representative samples of people from the population; both people
with the disease and people for control purposes who are selected
randomly from the7:18 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3general population to be a comparison to the cases. It's the
representativeness that characterizes epidemiology because
everything else that we do could be done in any kind of medical
research study.  We could study genetic factors, behavioral
factors, exercise or hormonal factors, diet, occupation,
environmental factors, and we can measure all sorts of things such
as chemicals in the blood and bacterial colonization and so on, so
what we actually measure is the same as other kind of research
studies, but it's the representativeness and the large sample size
to get enough statistical power to make conclusions that
characterizes epidemiology.Chu
Harvey, what made you develop this interest in trying to understand
the epidemiology of pancreatic cancer?Risch
This is really a very interesting story.  I am an editor of
the Journal of the National Cancer Institute and I
received a manuscript to consider for publication looking at the
risk of pancreatic cancer and colonization by the bacterium
Helicobacter pylori, and I wondered why in the world should there
been an association between Helicobacter and pancreatic cancer? I
asked a few experts about whether Helicobacter colonizes the
pancreas, whether it gets into the pancreas, and everybody
uniformly said no, and to me that meant that there had to be some
physiological reason why what the bacterium was doing in the
stomach was somehow related to digestion and therefore causing the
pancreas to do what it was doing, and I spent about six months
reviewing the literature and trying to figure out why this process
was going on until I had a clear hypothesis about it and published
that and that started the studies that I have been doing.Chu
It's interesting because Helicobacter pylori has been associated
with other kinds of cancers that typically arise within the
stomach.Risch
That's correct, with gastric cancer predominantly, stomach cancer,
and we believe that's a direct effect of the bacterium on the
lining cells of the stomach, along with carcinogenic
substances that are taken in mainly from diet.Foss
Most patients don't actually know they have Helicobacter, is that
correct?Risch
Most of it is asymptomatic, that is it's only a very small fraction
that causes heart burn or reflux that gets to be diagnosed. Most
people don't know they have it.9:49 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3Chu
How does one develop that infection?Risch
Helicobacter is typically acquired in childhood or adolescence and
in the United States perhaps a third of individuals are colonized,
which is relatively low. In Europe and in Asia it's perhaps 60% or
even higher, as high as 80-85% of individuals that carry
Helicobacter.Foss
In the United States, if a person knows that they have
Helicobacter, how worried should they be about developing
pancreatic cancer?Risch
It is still not a huge risk.  The major risk from Helicobacter
is more stomach cancer then pancreatic cancer because it causes
both.  It also is associated with cancer of the esophagus and
it's a complicated organism behavior because it may reduce risk of
asthma and have other health related risks and benefits, and so we
don't think of it as an infection, we think of it as a colonization
because so many people carry it and because most of its course is
silent and it does not do that much, but it does raise the risk of
stomach cancer and may increase the risk of pancreatic cancer.Chu
People have been talking about this association between
Helicobacter and stomach cancer. I think there is also an
association between this organism and lymphoma, a special type of
lymphoma which is Dr. Foss's domain, but I guess it kind of
highlights this association that people have been increasingly
aware of relating to inflammation, and then the development of
cancer down the road.Risch
It's very interesting how we think the Helicobacter works for
pancreatic cancer.  Helicobacter comes in lots of different
varieties which we refer to as strains.  Some of the strains
are more virulent and some are less virulent.  The more
virulent strains of Helicobacter shut off stomach acid production,
and over time lead to an inflammation of the lining of the stomach
and increased risk of stomach cancer, but the milder strains do not
do that and they tend to increase the production of stomach acid
and in response the pancreas increases its production of fluid and
bicarbonate which is a chemical that neutralizes the stomach
acid.  When the pancreas does this it becomes more sensitive
to the effects of carcinogens, which are these chemicals,
for  pancreatic cancer they are of a class called
nitrosamines, which arise in tobacco smoking and also in smoked and
processed meats like bacon, salami, baloney, and so on.  And
these chemicals get to the pancreas through the blood stream and
the pancreas is sensitized to the effects of the chemicals more so
because it's been turned up because of the Helicobacter effect, and
so that's the total picture that we think is why the12:53 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3Helicobacter is involved in pancreatic cancer.Foss
So the Helicobacter does not itself actually infect the
pancreas?Risch
No it does not.Foss
That's interesting because the pancreas is actually connected to
the whole stomach system through ducts.Risch
That's right, but there are other species of Helicobacter that do
colonize the pancreas, but not Helicobacter pylori, not the one
that does with stomach cancer.Foss
You talked about nitrosamines and certainly nitrosamines are in a
lot of the food that we eat, particularly the hot dogs at baseball
games.  Can you talk a little bit about the risk, and how much
nitrosamine will put a patient at risk?Risch
Like most human behaviors, it's things that you do regularly that
matter.  If you have hot dogs once or twice year, it's not a
big deal, but multiple times per month is what matters.Foss
And you specifically also mentioned bacon.Risch
Any of those together multiple times per month is where the risk
increases.Foss
This was really useful to hear this information about pancreatic
cancer and we would like to continue our discussion after a short
break.  Please stay tuned to learn more information about
pancreatic cancer with our guest Dr. Harvey Risch.14:55 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3chemotherapy to reduce side effects of treatment and help
cancer drugs work more effectively.  This has been a medical
minute and more information is available at
yalecancercenter.org.  You are listening to the WNPR Health
Forum on the Connecticut Public Broadcasting Network.Foss
Welcome back to Yale Cancer Center Answers.  This is Dr.
Francine Foss and I am here with my co-host Dr. Ed Chu.  Today
our guest is Dr. Harvey Risch who joins us to discuss pancreatic
cancer. Right before the break Harvey, we were talking about
nitrosamines as a risk for pancreatic cancer.  Are
nitrosamines also a risk for other kinds of cancer?Risch
Nitrosamines are mainly a risk for pancreatic cancer and gastric
cancer.  It is possible that they may be involved in other
cancers, but the evidence is strongest for stomach cancer and
pancreatic cancer.Foss
Is there any kind of racial or genetic predilection to sensitivity
to nitrosamines? Do certain people need to watch out for this?Risch
I would say no we do not know that to be a factor in the risk for
nitrosamines.  There are some racial ethnic differences and
risks for pancreatic cancer.  It is seen a little more
frequently in whites and African-Americans and a little less
frequent in Asians.Chu
Harvey, maybe we can go back to the basics of pancreatic cancer for
those who may have missed the first part of the show. Based on your
research have you observed any changes in the incidence of
pancreatic cancer over the recent years?Risch
Pancreatic cancer has been slowly increasing in frequency over the
last say two decades.  It's more or less leveled off for men,
but it has been increasing more for women who have caught up with
men. Probably the reason for this increase is cigarette smoking
among women.Foss
In terms of looking at smoking, does it make any difference how
young a person starts to smoke, or is it total pack years of
smoking that impacts the incidence?Risch
The most interesting thing about smoking is it matters what you
have done in the last few years and therefore, for pancreatic
cancer, quitting is important because the risk goes down to almost
that of a nonsmoker in 5-10 years after quitting.  And it goes
down the fastest, the sooner you quit.  As soon as you quit,
it start to drop and after 10 years it is almost all the way17:30 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3down and after 15 years it's distinguishable from a lifelong
nonsmoker.  So quitting really matters for this disease.Chu
Again, like the patients that you studied in your research, did you
notice that the incidence of pancreatic cancer increased in those
who smoked and who also had this underlying Helicobacter
infection?Risch
Yes, definitely.  Each one of them contributes to the risk and
the combined picture of risk between smoking and Helicobacter
colonization and blood groups, as I mentioned, that we can perhaps
talk about more, can get to 5 to 10 fold increased risk if one has
the whole combination of risk factors.Foss
Can you talk about the blood group data?Risch
This is another interesting story.  It's been known for almost
fifty years that ABO blood group is involved in certain diseases,
they are involved in ulcers of the stomach and duodenum and gastric
cancer and now we have some recent evidence that they are involved
in the risk of pancreatic cancer as well.  It also is curious
that Helicobacter pylori colonization is involved in the risk of
stomach cancer and stomach ulcers, gastric ulcers and duodenal
ulcers, and we believe also in the risk of pancreatic cancer. 
So the four conditions seem to be related to both ABO blood group
and to Helicobacter pylori colonization.  Now why in the world
should ABO blood group be related to something that occurs in the
stomach or the pancreas?  The answer to this is that the
molecules that define the blood groups do not just sit on the
surface of red blood cells but they also sit on the surface of the
cells that line the stomach, and it turns out that these little
molecules that are on the stomach lining cells are immediately next
to the parts of the cells that bind to the Helicobacter pylori, to
the bacterium that sits in the stomach, and so it matters which of
these blood group molecules is present because they interact
physically, or they may interact physically, with the bacterium
that they are adjacent to and because of that they have an effect
on risk and that is how we believe the ABO effect occurs through
the bacterium.Foss
For our listeners, can you tell us if there is a specific blood
type that is at highest risk?Risch
We believe that the non O blood groups are at the most increased
risk.  We are talking about A, B, and AB, it's not a dramatic
risk, perhaps 40 % increased risk for individuals who carry those
blood groups, but on the other hand there is the interaction with
Helicobacter pylori and we have to sort that out and that's a very
hot topic for research.20:20 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3Chu
Have you or others found that perhaps there is a linkage between
the blood type and the development, or presence of Helicobacter
infections?Risch
It does not appear that ABO blood group is related to the
likelihood of developing infection and colonization with the
bacterium, but when the blood group is present it changes a little
bit how the bacterium operates and we think that is how it is
working.Foss
On the flip side, if you have type O, is your risk lower?Risch
Yes, it would be a little bit lower.Foss
Does that make any difference in terms of how clinicians approach
patients with Helicobacter pylori? Because as you have said, a lot
of patients are colonized with this, so should physicians be
thinking about a matrix in terms of how to approach patients who
are positive?Risch
In my opinion if somebody is known to be positive for carrying
Helicobacter pylori they should be treated.  The treatment is
a course of three antibiotics over a short, two or three week
period, and it cures about two thirds of individuals on the first
pass and perhaps if you need a second pass at it, it would get to
95%.  One interesting study that took a cohort of about 13000
individuals who were carrying this bacterium and treated them,
showed that of the two thirds that were successfully eradicated,
they had a 40 percent lower risk of subsequent pancreatic cancer,
so that's almost like a human experiment showing the
association.Chu
Harvey, how is Helicobacter infection colonization initially
diagnosed and how is it followed for treatment?Risch
Well, for an adult who has never been colonized, if they get it in
adulthood they will have an episode of gastritis, that is acute
inflammation of the stomach.  It could be painful and they
will wonder what happened to them and they may seek medical
attention.  For individuals who get it in childhood and
adolescence, they would never know they had it and it might be
totally asymptomatic, they would never know. They might have had a
slight bout of gastritis, but in childhood there are any number of
childhood illnesses that would appear the same and so it would not
be remarkable.Chu
Is there a blood test to detect the infection or does a procedure
have to be done to actually gather the bacterial organism?Risch
Actually, it is quite easy.  There are blood tests, but even
easier, one can22:52 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3take in a small amount of chemical that will add bacteria, if
they are present
 it will convert to hydrogen gas and that can be measured in breath
and so there is a breath test that can be done.Chu
That's interesting.Foss
Let's get back to the question about nitrosamines again and talk
about other potential carcinogens.  We have heard, and
continue to hear on the radio, about the risk of pesticide exposure
from fruits and vegetables and I am wondering, are there other
chemicals that are specifically associated with pancreatic
cancer?Risch
The major animal models that have looked at pancreatic cancer for
at least 30 years have used nitrosamines.  They work in the
animal models and they were thought to characterize human exposures
from smoking and that's probably why they were originally
developed.  To my knowledge, pesticides, and for example
overcooked food and burned food are another class of chemicals that
are also thought to be a carcinogen although they may not be as
important as nitrosamines, have been looked at, but there is very
little convincing evidence of their associations.Chu
Harvey, what do we know about the role of alcohol and pancreatic
cancer? Clearly there is an association between alcohol and some
chronic pancreatic diseases.Risch
Yes, there is an association but it appears only at the very
highest levels of alcohol intake, people who have six or more
drinks per day on the average.  Less than that, there is no
significant evidence of an association.Foss
So the average social drinker, for instance, should not really have
to worry as much about this.Risch
Not unless they smoke.Foss
You mentioned that chronic pancreatitis is associated, so if you do
not have chronic pancreatitis, and you drink for instance, what is
your risk, is that a marker?  The chronic pancreatitis, is
that a marker?Risch
Chronic pancreatitis is a serious disease, but it's
infrequent.  Less then 2% of people in the general population
will have had chronic pancreatitis at some time.25:03 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3Chu 
            
 You focus on the epidemiology of pancreatic cancer. What's your
sense about where things have evolved with respect to our
understanding of the biology and treatment advances that have been
made in pancreatic cancer?Risch
Treatment is very difficult primarily for the reason that most
cases are diagnosed after the disease has spread from the pancreas,
and the pancreatic enzymes are very caustic chemicals that will
digest parts of the body if they get out of the pancreas. This
makes it a very serious disease in the later stages, so it's very
important to get it at an early stage when there is some hope for
surgical cure; today that characterizes perhaps 20 or 25 percent of
cases that are diagnosed. That means the majority are too late to
save that way and our chemotherapy and radiation treatments help a
little bit, they prolong life, but in general they do not cure the
patients, so prevention is really the big item for pancreatic
cancer.Chu
Are there specific genetic tests that could be done to predict risk
for pancreatic cancer?Risch
Only for the rare individuals who carry BRCA1 or BRCA2 mutations
and even for them the risks for breast and ovarian cancer are much
higher compared to pancreatic cancer.Chu
You just mentioned the potential role of prevention, so what are
the types of chemo preventive strategies that people are taking or
thinking about to prevent pancreatic cancer from developing?Risch
For pancreatic cancer the best thing to do is to try to minimize
the consumption of smoked and processed meats, it is not something
to obsess about, but just in general to be prudent try to have them
relatively infrequently. Also stop smoking if one smokes, or do not
start in adolescence and if one has heartburn at least be tested
for Helicobacter coverage and treat it if it is present.Foss
Are there clinical trials, epidemiologic trials going on at the
national level looking at pancreatic cancer?Chu
 I am in the process of organizing a large study, consortial study,
of case control and large epidemiologic studies to try to put
together a picture of how the ABO blood group, Helicobacter
colonization, nitrosamines in the diet, smoking and so on are
involved in the cause. We do this by collaborating with scientists
all over the world who have done
 individual studies and we know have a collection of studies that
involve27:41 into mp3 file 
http://yalecancercenter.org/podcast/jun2710-cancer-answers-risch.mp3
 approximately seven thousand cases and seven thousand controls. We
are seeking grant funding from the NIH to be able to do a combined
analysis.Foss
And all of these patients have had extensive questionnaires about
lifestyle and diet and all other factors that might be
important?Risch
Yes, that's correct.Foss
Just for the audience to understand, these epidemiologic studies do
require huge numbers of patients.Risch
We certainly value when patients participate in our studies. 
In general we try to identify everyone that we can find with the
disease in a defined area from the state of Connecticut, but we
identify for comparison purposes normal people in the population
and we do this by calling people on the telephone or mailing them
letters and so on.  And this is not something that people are
used to and we have to convince them that we are not doing market
research and we are not selling things, we are doing medical
research, and it's important that they participate and in general
we have been very successful with that.Chu
Harvey, it has been great having you on the show to share with us
your really interesting research on the epidemiology of pancreatic
cancer and hopefully we will have you back on a future show and you
can tell us where you are in your large clinical trial, and how
that study is doing.Risch
Thank you very much.Chu
Until next week, this is Dr. Ed Chu from Yale Cancer Center wishing
you a safe and healthy week.If you have questions or would like to share your comments,
visit yalecancercenter.org, where you can also subscribe to our
podcast and find written transcripts of past programs.  I am
Bruce Barber and you are listening to the WNPR Health Forum on the
Connecticut Public Broadcasting Network.