Pancreatic Cancer Research

Transcript

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00:13 --> 00:14Welcome to Yale Cancer
00:14 --> 00:16Answers with your host
00:16 --> 00:18Doctor Anees Chagpar.
00:18 --> 00:19Yale Cancer Answers features the
00:19 --> 00:22latest information on cancer care by
00:22 --> 00:23welcoming oncologists and specialists
00:23 --> 00:26who are on the forefront of the
00:26 --> 00:28battle to fight cancer. This week
00:28 --> 00:29it's a conversation about pancreatic
00:29 --> 00:31cancer with Doctor Mandar
00:31 --> 00:32Deepak Muzumdar. Doctor Muzumdar
00:32 --> 00:34is an assistant professor of
00:34 --> 00:36genetics and medical oncology
00:36 --> 00:37at the Yale School of Medicine
00:37 --> 00:40where Doctor Chagpar is a
00:40 --> 00:41professor of surgical oncology.
00:42 --> 00:43Maybe you can
00:43 --> 00:45start by telling us a little
00:45 --> 00:47bit about pancreatic cancer.
00:47 --> 00:49It's certainly not one of the Big 5.
00:49 --> 00:51We talk about breast
00:51 --> 00:53cancer and lung cancer and colon
00:53 --> 00:54cancer and prostate cancer.
00:54 --> 00:57Pancreatic cancer is a little bit rarer. Is
00:57 --> 00:58that right?
00:58 --> 01:00Yes, pancreatic cancer is
01:00 --> 01:01somewhere between the 10th and 11th,
01:01 --> 01:03most common cause of
01:03 --> 01:05cancer in the United States.
01:05 --> 01:06But it's rapidly contributing to
01:06 --> 01:08cancer deaths in the United States.
01:08 --> 01:10It's now the third leading
01:10 --> 01:11cause of cancer death in the
01:11 --> 01:13United States and is soon expected
01:13 --> 01:15to be the second leading cause
01:15 --> 01:17within the next few years.
01:17 --> 01:19So I think it's becoming a very
01:19 --> 01:21important cause of cancer that
01:21 --> 01:23we really have to deal with.
01:23 --> 01:25Yeah, and that's I guess
01:25 --> 01:26because pancreatic cancer,
01:26 --> 01:28although it may be rare,
01:28 --> 01:30is often pretty fatal. Is that
01:30 --> 01:31right?
01:31 --> 01:33Most patients with pancreatic cancer
01:33 --> 01:35are diagnosed at advanced stages.
01:35 --> 01:37Either it's beyond surgical resection,
01:37 --> 01:38which is our mainstay of
01:38 --> 01:40therapy for cure or it is
01:40 --> 01:42already spread to other organs,
01:42 --> 01:43making it exceedingly
01:43 --> 01:45challenging to treat at that
01:45 --> 01:48point. And so the idea is
01:48 --> 01:50to either find it early
01:50 --> 01:51or prevent it altogether.
01:51 --> 01:54So let's take each of those in turn.
01:54 --> 01:55I know that your lab is
01:55 --> 01:57really looking at prevention,
01:57 --> 01:59but maybe you can talk a little
01:59 --> 02:01bit before we get into that
02:01 --> 02:03as the bulk of our discussion today,
02:03 --> 02:05what are the signs and
02:05 --> 02:07symptoms that people should be aware
02:07 --> 02:10of so that they could try to catch it
02:10 --> 02:11a little bit earlier?
02:11 --> 02:12So pancreatic cancer unfortunately
02:12 --> 02:14is challenging to actually diagnose
02:14 --> 02:16early because many of the symptoms
02:16 --> 02:18that are associated with it are quite
02:18 --> 02:19nonspecific or associated with other
02:19 --> 02:21different more common conditions.
02:21 --> 02:22So some common symptoms include
02:22 --> 02:24abdominal pain or discomfort,
02:24 --> 02:24nausea, weight-loss.
02:24 --> 02:27Many of these things can be caused by
02:27 --> 02:29other factors that are more common,
02:29 --> 02:31such as reflux for example.
02:31 --> 02:33So that's one of the challenges
02:33 --> 02:34with diagnosing,
02:34 --> 02:36but I think that one of the things
02:36 --> 02:39that we do know is that there are a
02:39 --> 02:41number of risk factors associated
02:41 --> 02:42with pancreatic cancer,
02:42 --> 02:44in particular by 10% of all
02:44 --> 02:45pancreatic cancers,
02:45 --> 02:46are associated with some sort
02:46 --> 02:48of genetic
02:48 --> 02:48familial cause,
02:48 --> 02:50and so certainly in patients
02:50 --> 02:53who have first degree relatives with
02:53 --> 02:55a prior history of pancreatic cancer,
02:55 --> 02:55multiple family
02:55 --> 02:57members had pancreatic cancer
02:57 --> 02:59that should alert more complete
02:59 --> 03:00evaluation and discussion,
03:00 --> 03:02at least with their physicians.
03:02 --> 03:02But again,
03:02 --> 03:04it doesn't have very common
03:04 --> 03:05symptoms that are unique,
03:05 --> 03:07making it very challenging
03:07 --> 03:08to diagnose early.
03:08 --> 03:11A number of studies are being done now
03:11 --> 03:13to try to identify factors that
03:13 --> 03:14are involved in early detection.
03:14 --> 03:16Hopefully some of those will
03:16 --> 03:18lead to some blood based,
03:18 --> 03:19tests that we can actually do
03:19 --> 03:21to try to identify some markers
03:21 --> 03:24that might give us an inkling that
03:24 --> 03:26pancreatic cancer may be there.
03:26 --> 03:28That would allow us to do
03:28 --> 03:29some follow-up testing,
03:29 --> 03:31but we're still in the research
03:31 --> 03:32phases of that.
03:32 --> 03:32We're getting
03:32 --> 03:34there, but we're not quite there yet.
03:34 --> 03:37And so because the symptoms are so
03:37 --> 03:38non specific people I would presume
03:38 --> 03:40people don't pay attention to that.
03:40 --> 03:43And by the time things have
03:43 --> 03:45festered on for quite awhile.
03:45 --> 03:47They then present and have are found to
03:47 --> 03:50have disease that's gone and spread to other
03:50 --> 03:52organs making it more difficult to treat.
03:52 --> 03:54You talked a little bit about genetics and
03:54 --> 03:57you said that about 10% of all pancreatic
03:57 --> 03:59cancer patients have a family history.
03:59 --> 04:04That also means that 90% of people don't.
04:04 --> 04:07And so, even if you don't have a
04:07 --> 04:10family history of pancreatic cancer,
04:10 --> 04:12should you be paying attention
04:12 --> 04:14even to those non specific symptoms?
04:14 --> 04:16And if they don't go away,
04:16 --> 04:19or if they don't have a reason behind them,
04:19 --> 04:21maybe get checked out?
04:21 --> 04:22That's exactly right.
04:22 --> 04:24So if their symptoms that are
04:24 --> 04:26persistent or you don't have a great
04:26 --> 04:28explanation for, a discussion with
04:28 --> 04:30your doctor is always necessary.
04:30 --> 04:32It's always possible that it is pancreatic cancer.
04:32 --> 04:33But it's more likely
04:33 --> 04:35that something else is going on.
04:35 --> 04:37But it's better to be evaluated and
04:37 --> 04:39check to make sure that pancreatic
04:39 --> 04:41cancer wouldn't be a cause
04:41 --> 04:42of the symptoms.
04:42 --> 04:44Tell us a little bit more about
04:44 --> 04:46the genetics of pancreatic cancer.
04:46 --> 04:49I mean, when we talk about a
04:49 --> 04:50family history, is it something
04:50 --> 04:52that is age specific?
04:52 --> 04:54Should it run on one side
04:54 --> 04:57of the family or the other?
04:57 --> 04:58Are there multiple family members
04:58 --> 05:01who may be involved or should be
05:01 --> 05:03involved in order for you to
05:03 --> 05:06be a little bit more cautious?
05:06 --> 05:06Does it affect
05:06 --> 05:08other cancers? Tell us a little
05:08 --> 05:11bit more about that whole space of
05:11 --> 05:12the genetics of pancreatic cancer.
05:12 --> 05:14About 10%, like we discussed,
05:14 --> 05:16about 10% of all pancreatic cancers
05:16 --> 05:18are associated with some sort of family history.
05:18 --> 05:21And the things to be aware of,
05:21 --> 05:23are multiple first degree relatives,
05:23 --> 05:24so that is siblings, parents,
05:24 --> 05:26children with pancreatic cancer,
05:26 --> 05:28particularly first degree relatives
05:28 --> 05:29who are diagnosed prior to the age
05:29 --> 05:31of 50
05:31 --> 05:33found in your family.
05:33 --> 05:35There's a greater risk of
05:35 --> 05:36developing pancreatic cancer,
05:36 --> 05:38and there's a number of known gene
05:38 --> 05:40mutations that have been identified in
05:40 --> 05:42pancreatic cancer that are also seen
05:42 --> 05:44in other cancer types such as
05:44 --> 05:45colorectal cancer, breast cancer,
05:45 --> 05:46ovarian cancer.
05:46 --> 05:47So certainly,
05:47 --> 05:49if any of those have been
05:49 --> 05:50found in family members,
05:50 --> 05:53one should at least discuss with the
05:53 --> 05:54geneticists getting tested for
05:54 --> 05:57those types of mutations which might
05:57 --> 05:59alter how to actually screen or to try
05:59 --> 06:01and diagnose pancreatic cancer early.
06:01 --> 06:03And so some of those mutations I
06:03 --> 06:06know as a breast cancer surgeon,
06:06 --> 06:07things like BRCA,
06:07 --> 06:10we think of BRCA.
06:10 --> 06:11We think breast and ovarian
06:11 --> 06:13cancer but be RCA also increases
06:13 --> 06:16your risk of pancreatic cancer.
06:16 --> 06:16Prostate cancer.
06:16 --> 06:18So if you have a family history
06:18 --> 06:21of breast cancer and let's say one
06:21 --> 06:23of your family members has been
06:23 --> 06:25diagnosed with a BRC mutation,
06:25 --> 06:27you're at increased risk of
06:27 --> 06:28carrying that same mutation.
06:28 --> 06:30You go to a geneticists or genetic
06:30 --> 06:32counselor and you test because
06:32 --> 06:34testing now is pretty ubiquitous
06:34 --> 06:35and actually fairly cheap.
06:35 --> 06:38And if you carry that genetic mutation,
06:38 --> 06:40most people think about all of the
06:40 --> 06:42things that they can do to prevent
06:42 --> 06:44breast cancer or ovarian cancer,
06:44 --> 06:45and certainly prophylactic
06:45 --> 06:47surgery is in the cards.
06:47 --> 06:49But what about pancreatic cancer?
06:49 --> 06:50How do you prevent that?
06:50 --> 06:52You can't really remove your
06:52 --> 06:53pancreas.
06:53 --> 06:55There's no surgical removal of
06:55 --> 06:56the pancreas that would be used.
06:56 --> 06:59The prevention, though there are
06:59 --> 07:00certain screening programs that
07:00 --> 07:03one can get, a part of that would
07:03 --> 07:05help you to find it earlier.
07:05 --> 07:08That would include things like image Ng and
07:08 --> 07:10other things that can be done to find it.
07:10 --> 07:12There's also a number of non genetic
07:12 --> 07:14risk factors that we know can contribute
07:14 --> 07:15to pancreatic cancer and they likely
07:15 --> 07:17will cooperate with gene mutations,
07:17 --> 07:19and those are some of the lifestyle
07:19 --> 07:21things that can be done to try and
07:21 --> 07:23decrease your risk of pancreatic cancer.
07:23 --> 07:23For example,
07:23 --> 07:25we know for quite some time now that
07:25 --> 07:27smoking is associated with pancreatic cancer,
07:27 --> 07:29two and a half fold increased
07:29 --> 07:31risk of developing the disease
07:31 --> 07:32over the general population,
07:32 --> 07:33so quitting smoking might be
07:33 --> 07:35one thing to do.
07:35 --> 07:36We know there's several other
07:36 --> 07:38modifiable risk factors
07:38 --> 07:38including obesity,
07:38 --> 07:40which is soon
07:40 --> 07:42to surpass smoking as the leading
07:42 --> 07:44modifiable risk factor for pancreatic
07:44 --> 07:46cancer and its associated with
07:46 --> 07:48somewhere between 2 and a
07:48 --> 07:502 1/2 fold increased risk
07:50 --> 07:51again over the general population,
07:51 --> 07:53and so losing weight may be
07:53 --> 07:55helpful in terms of reducing risk.
07:55 --> 07:57There are a number of dietary
07:57 --> 07:59things that have been associated,
07:59 --> 08:01but none of them are convincing,
08:01 --> 08:03but there are lifestyle modifications in
08:03 --> 08:05terms of tobacco cessation, stopping smoking.
08:05 --> 08:07Or altering diets or losing
08:07 --> 08:09weight that might be helpful.
08:09 --> 08:10What about alcohol?
08:10 --> 08:12So there are some studies that
08:12 --> 08:14do see an association of alcohol
08:14 --> 08:15with pancreatic cancer.
08:15 --> 08:17Development of the studies
08:17 --> 08:18are not conclusive.
08:18 --> 08:19There's also an association
08:19 --> 08:21with excessive alcohol use.
08:21 --> 08:23An inflammation of the pancreas,
08:23 --> 08:24also known as pancreatitis
08:24 --> 08:26and certainly chronic pancreatitis.
08:26 --> 08:28That is inflammation that's recurrent,
08:28 --> 08:30can be a risk factor.
08:32 --> 08:35But in terms of limited exposures of alcohol,
08:35 --> 08:37there is some association,
08:37 --> 08:39though it's not necessarily as
08:39 --> 08:40strong as tobacco and or
08:40 --> 08:41obesity so
08:41 --> 08:44you make a good point.
08:46 --> 08:48We often talk about obesity and
08:48 --> 08:50sitting is becoming the new
08:50 --> 08:52smoking and the number of cancers
08:52 --> 08:54that are increased with obesity.
08:54 --> 08:56Your lab has been looking
08:56 --> 08:57at that in particular,
08:57 --> 08:59with pancreatic cancer. Tell
08:59 --> 09:01us a little bit more about the
09:01 --> 09:03research that you do.
09:03 --> 09:05We've become interested in
09:05 --> 09:07looking at non genetic factors
09:07 --> 09:09that might be contributed to
09:09 --> 09:11cancer development and this is
09:11 --> 09:13in part due to the fact that we
09:13 --> 09:15can study the cancer associated gene
09:15 --> 09:17mutations in animal systems or model
09:17 --> 09:19system such as the mouse and what
09:19 --> 09:21we found is when we engineer the
09:21 --> 09:23cancer associated mutations into mice
09:23 --> 09:25while they do get the human cancers,
09:25 --> 09:27we can engineer them in a large
09:27 --> 09:28fraction of the pancreas.
09:28 --> 09:30But we get very little tumor
09:30 --> 09:32that develops and even the tumors
09:32 --> 09:34that develop, most of them don't
09:34 --> 09:35progress to the advanced stages.
09:35 --> 09:37So this suggested to us perhaps
09:37 --> 09:39non mutational factors,
09:39 --> 09:40non genetic factors may
09:40 --> 09:41be driving it or
09:41 --> 09:43the environment or some other factors
09:43 --> 09:46within the person might be contributing.
09:48 --> 09:49And so we actually turned to
09:49 --> 09:51epidemiological studies that had actually
09:51 --> 09:53shown risk of increased pancreatic
09:53 --> 09:55cancer development in obese individuals,
09:55 --> 09:57and this has been known
09:57 --> 09:59now for nearly two decades,
09:59 --> 10:00in fact.
10:00 --> 10:01Obesity is associated with 13
10:01 --> 10:02different cancer types,
10:02 --> 10:04including many of the cancers in
10:04 --> 10:05the gastrointestinal tract,
10:05 --> 10:07including pancreatic cancer,
10:07 --> 10:09and our research is really focused
10:09 --> 10:11on trying to understand how
10:11 --> 10:12obesity might contribute to cancer
10:12 --> 10:14development in hopes of maybe
10:14 --> 10:16identifying new ways of preventing
10:16 --> 10:17and or treating the disease.
10:17 --> 10:20And what we've found actually in
10:20 --> 10:22studying obesity in mice in which
10:22 --> 10:25we can engineer the mice to be
10:25 --> 10:27obese or give them a high fat diet,
10:27 --> 10:29for example, to make them dietarily,
10:29 --> 10:30obese,
10:30 --> 10:32that the obesity
10:32 --> 10:33itself can actually cooperate
10:33 --> 10:35with gene mutations to promote
10:35 --> 10:37the development and progression
10:37 --> 10:38of pancreatic cancer.
10:38 --> 10:40And we can actually do studies in
10:40 --> 10:42mice to make them lose weight using
10:42 --> 10:45either genetic or again dietary tricks,
10:45 --> 10:46and we've found that if you do
10:46 --> 10:49that at an early stage prior to
10:49 --> 10:51the development of advanced tumors,
10:51 --> 10:53you can actually use that as a
10:53 --> 10:54preventative strategy
10:54 --> 10:56to actually prevent the
10:56 --> 10:58emergence of advanced pancreatic
10:58 --> 11:00cancer.
11:00 --> 11:01So what you're basically telling us
11:01 --> 11:03is that obesity kind of is
11:03 --> 11:04synergistic with genetic mutations
11:04 --> 11:06in pancreatic cancer in their
11:06 --> 11:08progression and in their development.
11:08 --> 11:10And so if you have a BRC mutation,
11:10 --> 11:13one of the things you can do before you
11:13 --> 11:15ever get pancreatic cancer as soon as
11:15 --> 11:18you know about that genetic mutation,
11:18 --> 11:20or even when you just have a
11:20 --> 11:22family history is to lose weight
11:22 --> 11:24because you will reduce your risk
11:24 --> 11:26of getting pancreatic cancer,
11:26 --> 11:29or at least having the pancreatic cancer
11:29 --> 11:31be as aggressive as it otherwise could be.
11:32 --> 11:33That's right, that's what
11:33 --> 11:34our studies are suggesting,
11:34 --> 11:36both in humans from the epidemiology
11:36 --> 11:38and also in our mouse models
11:38 --> 11:40that actually weight loss might
11:40 --> 11:42be helpful in reducing the
11:42 --> 11:43risk of pancreatic cancer.
11:46 --> 11:49And so does the
11:49 --> 11:51same thing apply to quitting smoking?
11:51 --> 11:53That is less well studied in
11:53 --> 11:55the realm of pancreatic cancer.
11:55 --> 11:57We do know, for example,
11:57 --> 11:59in heart disease that quitting smoking
11:59 --> 12:01can have a dramatic improvement in
12:01 --> 12:03reducing the risk of heart disease.
12:03 --> 12:05And losing weight or reducing obesity
12:05 --> 12:06also has cardiovascular benefits.
12:06 --> 12:08So in terms of heart disease
12:08 --> 12:10as well as cancer,
12:14 --> 12:16and as challenging
12:16 --> 12:19as it may be to reduce or stop
12:19 --> 12:20smoking and to lose some weight
12:20 --> 12:23it might be very helpful in terms of
12:23 --> 12:25not only improving general health,
12:25 --> 12:26including cardiovascular disease,
12:26 --> 12:27but also might play a role
12:27 --> 12:29in cancer prevention.
12:29 --> 12:30Yeah, it sounds like
12:30 --> 12:32those two things
12:32 --> 12:35if you want to live longer and better
12:35 --> 12:38are two things that should be at the
12:38 --> 12:41top of the ticket. You talked about
12:41 --> 12:43genetically or doing
12:43 --> 12:46dietary tricks to get mice to lose weight
12:46 --> 12:49and so we can make mice lose weight,
12:49 --> 12:51it's harder to get people to lose weight.
12:51 --> 12:54Do you have any tricks or tips on
12:54 --> 12:56studies that have been done that may
12:56 --> 12:58have helped people to lose weight?
12:58 --> 13:00So this is a big
13:00 --> 13:02problem. And how do we get
13:02 --> 13:03people to lose weight?
13:03 --> 13:07And a lot of it is genetics?
13:07 --> 13:09Some of it can be genetic,
13:09 --> 13:11some of it is trying to maintain the weight
13:11 --> 13:14when people have already lost weight.
13:14 --> 13:16I can't speak to any specific tricks
13:16 --> 13:19or tips that would be very helpful.
13:19 --> 13:20There are clinics now,
13:20 --> 13:22including here at Yale,
13:22 --> 13:23obesity clinics that do use
13:23 --> 13:25adjunctive medications that can be
13:25 --> 13:27very helpful in reducing weight
13:27 --> 13:29and keeping the weight off.
13:29 --> 13:31and I would suggest that for those
13:31 --> 13:33individuals that are having a hard time
13:33 --> 13:35through just altering their diet or
13:35 --> 13:37exercising to lose weight that trying to
13:37 --> 13:39take advantage of some of
13:39 --> 13:39these opportunities,
13:39 --> 13:41including potentially going to some of
13:41 --> 13:42these clinics might be very helpful.
13:45 --> 13:47There's a lot of focus from a public
13:47 --> 13:48health standpoint in reducing obesity.
13:48 --> 13:50I don't think anyone has a
13:50 --> 13:51Magic Bullet,
13:51 --> 13:53but I do think that there are dietary,
13:53 --> 13:55exercise as well as medications that might
13:55 --> 13:57be helpful for large fraction of people.
13:57 --> 13:58And as I've discussed already,
13:58 --> 14:00I think that is really important,
14:00 --> 14:02not only for a general health outcomes,
14:02 --> 14:04but I think it actually plays an
14:04 --> 14:05important role for cancer prevention.
14:05 --> 14:07For again, a large fractions of cancers.
14:07 --> 14:08Well thank you
14:08 --> 14:10so much for that. We are going to
14:10 --> 14:12take a quick break for a medical
14:12 --> 14:15minute please stay tuned to learn
14:15 --> 14:17more about pancreatic cancer,
14:17 --> 14:21the role of genetics and the environment with
14:21 --> 14:24my guest doctor, Mandar Deepak Muzumdar.
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14:35 --> 14:38This is a medical minute about lung cancer.
14:38 --> 14:40More than 85% of lung cancer diagnosis
14:40 --> 14:43are related to smoking and quitting even
14:43 --> 14:46after decades of use can significantly
14:46 --> 14:48reduce your risk of developing lung
14:48 --> 14:50cancer. For lung cancer patients,
14:50 --> 14:52clinical trials are currently under
14:52 --> 14:55way to test innovative new treatments.
14:55 --> 14:58Advances are being made by utilizing
14:58 --> 15:00targeted therapies and immunotherapies.
15:00 --> 15:02The battle 2 trial aims to learn if
15:02 --> 15:05a drug or combination of drugs based
15:05 --> 15:07on personal biomarkers can help to
15:07 --> 15:10control non small cell lung cancer.
15:10 --> 15:13More information is available at
15:13 --> 15:14yalecancercenter.org.
15:14 --> 15:18You're listening to Connecticut public radio.
15:18 --> 15:18Welcome
15:18 --> 15:20back to Yale Cancer Answers.
15:20 --> 15:22This is doctor Anees Chagpar and
15:22 --> 15:25I'm joined tonight by my guest doctor
15:25 --> 15:26Mandar Deepak Muzumdar.
15:26 --> 15:27We're discussing pancreatic
15:27 --> 15:29cancer and the role of genetics
15:29 --> 15:31and the environment in cancer,
15:31 --> 15:33and one of the things that we talked
15:33 --> 15:36about right before the break is that
15:36 --> 15:38while pancreatic cancer is pretty rare,
15:38 --> 15:3910th or 11th,
15:39 --> 15:41most common cancer in the United States,
15:41 --> 15:44it is rapidly becoming one of the most
15:44 --> 15:46common causes of cancer related death.
15:46 --> 15:48Getting up there into the second
15:48 --> 15:50or third leading cause of
15:50 --> 15:51cancer related deaths.
15:51 --> 15:53So something really to think
15:53 --> 15:55about and what you had mentioned
15:55 --> 15:58was that there are a number
15:58 --> 16:00of things that increase our risk.
16:00 --> 16:02Some things we can't control.
16:02 --> 16:04Our genetics, our family history.
16:04 --> 16:06Some things we can control,
16:06 --> 16:07quitting smoking,
16:07 --> 16:09losing weight
16:09 --> 16:12to reduce your risk
16:12 --> 16:13of developing pancreatic cancer
16:13 --> 16:15and reducing the stage at which
16:15 --> 16:17it's likely going to present at.
16:17 --> 16:20But I wanted to go back and
16:20 --> 16:21talk about genetics.
16:21 --> 16:23We had talked about
16:23 --> 16:25the fact that people
16:25 --> 16:27have a family history.
16:27 --> 16:29They may have a genetic mutation.
16:29 --> 16:31Tell us a little bit more about
16:31 --> 16:33the work that you've been doing
16:33 --> 16:34looking at genetics and pancreatic
16:34 --> 16:36cancer and and how that
16:36 --> 16:37might actually affect people.
16:37 --> 16:39So a number of mutations have
16:39 --> 16:40been identified in pancreatic
16:40 --> 16:42cancer and specific cancer genes
16:42 --> 16:44and that's given us a great
16:44 --> 16:45understanding in terms of how
16:45 --> 16:47pancreatic cancers develop.
16:47 --> 16:48One of the hallmark genes
16:48 --> 16:50in the disease is really
16:50 --> 16:52the gene KRAS which
16:52 --> 16:55is mutated in more than 90% of
16:55 --> 16:56all human pancreatic cancers.
16:56 --> 16:58And it's clear that it's important in
16:58 --> 17:00the development of pancreatic cancer
17:00 --> 17:02when we engineer mice with KRAS,
17:02 --> 17:04mutations in the pancreas,
17:04 --> 17:06they get pancreatic cancers that look
17:06 --> 17:08and behave just like the human disease.
17:08 --> 17:10We also know that KRAS mutations
17:10 --> 17:12can promote the growth and development
17:12 --> 17:14of tumors in many other organs,
17:14 --> 17:16including the lungs and the colon.
17:16 --> 17:17In fact,
17:19 --> 17:2130% of lung cancers and in about 50%
17:21 --> 17:23of colon and rectal cancers.
17:23 --> 17:25And we know from cell studies
17:25 --> 17:26that KRAS really promotes
17:26 --> 17:27cell proliferation,
17:27 --> 17:29their ability to duplicate themselves is
17:29 --> 17:31a hallmark of cancer development.
17:31 --> 17:32Now
17:32 --> 17:32importantly,
17:32 --> 17:34KRAS has
17:36 --> 17:39been known for nearly four decades now,
17:39 --> 17:41and we know from other tumor types in
17:41 --> 17:43which we've identified the hallmark
17:43 --> 17:46genetic mutations that we can often target
17:46 --> 17:47those mutations with therapies
17:47 --> 17:49that can be quite effective.
17:49 --> 17:50Unfortunately,
17:50 --> 17:51for KRAS
17:51 --> 17:53it's actually been very hard to develop
17:53 --> 17:55drugs that can block its function,
17:55 --> 17:59and so one of the things that is actually
17:59 --> 18:02emerged recently is new developments in
18:02 --> 18:04drugs and one of those is a specific
18:04 --> 18:06drug that targets a specific
18:06 --> 18:08flavor or mutation of KRAS
18:08 --> 18:10which we call the G12C Mutation,
18:10 --> 18:12which is found in about 14%
18:12 --> 18:13of all lung cancers,
18:13 --> 18:16but only about 2 to 3% of pancreatic cancers.
18:16 --> 18:18Nonetheless, this
18:18 --> 18:21class of drugs is now being tested
18:21 --> 18:23in clinical trials and in lung cancer
18:23 --> 18:25at least the data are quite
18:25 --> 18:28promising that they can lead to
18:28 --> 18:29shrinkage of the tumors in
18:29 --> 18:32a large fraction of patients.
18:32 --> 18:34Now it remains to be seen whether the
18:34 --> 18:36effect will be true in pancreatic cancer,
18:36 --> 18:38but we're excited that now for
18:38 --> 18:39the first time,
18:39 --> 18:41we actually have a drug that
18:41 --> 18:43can target at least a specific
18:43 --> 18:44mutation in pancreatic
18:44 --> 18:46cancer, so I just wanted to clarify
18:46 --> 18:48for our listeners out there,
18:48 --> 18:50there's a difference in terms of
18:50 --> 18:51genetics that are germline genetics
18:51 --> 18:53and cancer genetics. Can you
18:53 --> 18:55clarify that a little bit?
18:55 --> 18:57Because I think when we've
18:57 --> 18:58talked about genetics,
18:58 --> 18:59we've talked about, you know,
18:59 --> 19:02going and if you have a family history,
19:02 --> 19:04seeing a geneticists and seeing if you
19:04 --> 19:07carry a genetic mutation like BRC and so on,
19:07 --> 19:10and then we kind of transitioned and we
19:10 --> 19:12talked about looking at cancer genetics,
19:12 --> 19:14the genetic mutations of a cancer cell.
19:14 --> 19:16Can you talk about and clarify
19:16 --> 19:18that difference just so that
19:18 --> 19:20I make sure that everybody out
19:20 --> 19:21there understands that difference?
19:21 --> 19:23Absolutely so germline genetics is really
19:23 --> 19:26based on mutations that are rise from
19:26 --> 19:28the very beginning that you inherit or
19:28 --> 19:30have been there from the very start.
19:30 --> 19:32So those are mutations that are
19:32 --> 19:34found in all of your cells.
19:34 --> 19:37And we think some of them predispose
19:37 --> 19:38to cancer development because they
19:38 --> 19:40affect the ability of your body to
19:40 --> 19:42maintain fidelity or to maintain the
19:42 --> 19:44DNA without creating new mutations.
19:44 --> 19:47So these are what we call DNA repair genes
19:47 --> 19:49they get when they get mutated.
19:49 --> 19:51Now when the cells duplicate themselves
19:51 --> 19:52during development, they make errors.
19:52 --> 19:54And new mutations can occur.
19:54 --> 19:56So that includes genes such as BRCA1
19:56 --> 19:58and 2 has been discussed,
19:58 --> 20:00as well as other genes
20:00 --> 20:02that are involved in DNA repair pathways
20:02 --> 20:04and we've gotten to actually be able
20:04 --> 20:06to take advantage of these mutations.
20:06 --> 20:08from a therapeutic standpoint because
20:08 --> 20:10it turns out certain chemotherapeutic
20:10 --> 20:12agents in certain drugs can actually
20:12 --> 20:14be more helpful in patients who
20:14 --> 20:15have those mutations.
20:15 --> 20:16So one of the things that's
20:16 --> 20:19emerged is that as we sequence more
20:19 --> 20:20and more pancreatic cancers,
20:20 --> 20:22we're finding that we're starting
20:22 --> 20:25to find more and more of these DNA
20:25 --> 20:26repair gene mutations in those cancers
20:26 --> 20:29such that we actually believe as
20:29 --> 20:31a community that everyone who is
20:31 --> 20:32diagnosed with pancreatic cancer
20:32 --> 20:34should have their tumors looked
20:34 --> 20:36at for these particular mutations
20:36 --> 20:37with the hope of potentially using
20:37 --> 20:39that again to guide therapy.
20:39 --> 20:41Now there's a second class of mutations,
20:42 --> 20:42not germ line,
20:42 --> 20:44but these are mutations that
20:44 --> 20:46occur in individual cells in the
20:46 --> 20:48body at some point after birth,
20:48 --> 20:51and these are what we call somatic mutations.
20:51 --> 20:52These are mutations that can
20:52 --> 20:54drive the growth
20:54 --> 20:56and development of tumors.
20:56 --> 20:58One of these mutations that falls into
20:58 --> 21:01this class is the mutation in KRAS and
21:01 --> 21:03so these are mutations that we think are
21:03 --> 21:05integral to the formation
21:05 --> 21:06of particular cancer types.
21:06 --> 21:08KRAS and pancreatic cancer.
21:08 --> 21:11But they are not there from the very beginning.
21:11 --> 21:12From when you're born,
21:12 --> 21:15they emerged at a later time point,
21:15 --> 21:17but clearly play an important role in
21:17 --> 21:19cancer development and play a
21:19 --> 21:21potentially important role in
21:21 --> 21:22guiding treatment.
21:22 --> 21:24Again using targeted drugs that target these
21:24 --> 21:26specific mutations and you
21:26 --> 21:29make a very good point about
21:29 --> 21:31when you're diagnosed with cancer,
21:31 --> 21:32like pancreatic cancer,
21:32 --> 21:33getting that
21:33 --> 21:36evaluated to look for these genetic
21:36 --> 21:38mutations because there may be drugs
21:38 --> 21:40that can target that specifically.
21:40 --> 21:43You mentioned in lung cancer the
21:43 --> 21:46fact that we have drugs against
21:46 --> 21:48KRAS that have shown promise and
21:48 --> 21:51that the data are out in terms of
21:51 --> 21:53that fact with pancreatic cancer.
21:53 --> 21:55Are there clinical trials looking
21:55 --> 21:56at that?
21:56 --> 21:58There are clinical trials using those same
21:58 --> 22:01agents in a broad array of cancer
22:01 --> 22:03types that have KRAS mutations.
22:03 --> 22:05Specifically with that one particular
22:05 --> 22:08mutation, that G12C mutation, and so there are
22:08 --> 22:10clinical trials that might be available.
22:10 --> 22:12Again, it's not that common
22:12 --> 22:13in pancreatic cancer,
22:13 --> 22:16so a lot of patients would not be eligible.
22:16 --> 22:19There is clearly a push to
22:19 --> 22:21develop KRAS drugs that target a
22:21 --> 22:23larger number of KRAS mutations
22:23 --> 22:26and there is a tremendous
22:26 --> 22:28amount of research to develop this.
22:28 --> 22:30In fact, the National Cancer Institute
22:30 --> 22:32has a whole KRAS initiative which
22:32 --> 22:34is really focused on developing
22:34 --> 22:35more fundamental understanding.
22:35 --> 22:36of KRAS
22:36 --> 22:38and other proteins and trying to
22:38 --> 22:40develop new structures and drugs
22:40 --> 22:42that we can use to target these.
22:42 --> 22:43In the lab,
22:43 --> 22:45we've tried to model what would
22:45 --> 22:47happen if you inhibit KRAS using
22:47 --> 22:49genetic technologies because we did
22:49 --> 22:51not have these drugs for many years
22:51 --> 22:53and so we can actually use
22:53 --> 22:55genetic tricks to disrupt or knockout
22:55 --> 22:57all function.
22:57 --> 22:59And we've done that in pancreatic cancer.
22:59 --> 23:01We see that it can be quite
23:01 --> 23:03effective in reducing the growth of
23:03 --> 23:05many pancreatic cancer cell lines.
23:05 --> 23:07But a subset of them
23:07 --> 23:09seem to continue to survive
23:09 --> 23:11despite complete loss of KRAS,
23:11 --> 23:13suggesting that even with these drugs
23:13 --> 23:16there is likely to be some resistance now.
23:16 --> 23:17The encouraging
23:17 --> 23:20part is we can use these models to
23:20 --> 23:22study how cells aid KRAS inhibition,
23:22 --> 23:23how they resist,
23:23 --> 23:25how they continue to survive,
23:25 --> 23:27and using this data we can now
23:27 --> 23:29use that to bring it into our clinical
23:29 --> 23:31trials and try and design better
23:31 --> 23:33combination therapies that might
23:33 --> 23:35overcome the resistance mechanisms
23:35 --> 23:37that developed with KRAS.
23:37 --> 23:38Now we're excited
23:38 --> 23:40we finally have drugs that target
23:40 --> 23:42KRAS to really test these hypothesis
23:42 --> 23:44and really see whether we can
23:44 --> 23:45overcome resistance.
23:45 --> 23:47But because of the genetic studies
23:47 --> 23:50that we and others have done,
23:50 --> 23:52it gives us some advanced insight
23:52 --> 23:54into how to really combine drugs
23:54 --> 23:56into ways that might help patients
23:56 --> 23:58even earlier in terms of overcoming
23:58 --> 24:00resistance to KRAS inhibitors
24:00 --> 24:01as they continue to
24:01 --> 24:04emerge. So now that we have these inhibitors
24:04 --> 24:07against the G12 mutation of KRAS,
24:07 --> 24:10have you looked at mice who have that
24:10 --> 24:12mutation and see whether these drugs work?
24:12 --> 24:14Whether there is a significant
24:14 --> 24:16proportion of them that are resistant,
24:16 --> 24:19or whether most of them actually will
24:19 --> 24:21respond like the lung cancer patients have?
24:21 --> 24:23so there are studies that have
24:23 --> 24:25been done using human cell lines
24:25 --> 24:27that have particular disk error.
24:27 --> 24:29Gee, 12 Mutation and put them into
24:29 --> 24:31mice and then treated the mice with
24:31 --> 24:34the drugs and they can be quite
24:34 --> 24:36effective in shrinking the tumors.
24:36 --> 24:38Now we do see that again.
24:38 --> 24:40Subset of those tumors will recur,
24:40 --> 24:44and a lot of work is being done
24:44 --> 24:45now to try to identify those resistance
24:45 --> 24:47mechanisms and then hopefully
24:47 --> 24:49bring that quicker to the clinic.
24:49 --> 24:51That's something we've really learned
24:51 --> 24:52from targeting other mutations
24:52 --> 24:54and other cancer types like lung
24:54 --> 24:56cancer that cancers will often find
24:56 --> 24:58ways to escape the inhibition,
24:58 --> 25:00but we now know
25:00 --> 25:02and study that in advance and
25:02 --> 25:04hopefully design clinical trials
25:04 --> 25:06and better ways to bring
25:06 --> 25:07up those combination therapies
25:07 --> 25:09sooner and hopefully prevent
25:09 --> 25:12the emergence of resistance to these
25:12 --> 25:14drugs. So given the choice,
25:14 --> 25:16if a patient is diagnosed
25:16 --> 25:17with pancreatic cancer,
25:17 --> 25:18there are standard chemotherapy
25:18 --> 25:20regimens that are given,
25:20 --> 25:22and we know that these
25:22 --> 25:25may or may not be effective,
25:25 --> 25:27but if a patient has a particular
25:27 --> 25:29mutation and there is a clinical trial
25:29 --> 25:32that is offering them a medication
25:32 --> 25:34targeted against that mutation,
25:34 --> 25:36are they better off just
25:36 --> 25:38statistically to take the clinical
25:38 --> 25:40trial over the standard of care?
25:40 --> 25:43Or is it better to do the standard of care?
25:43 --> 25:44Wait till you fail and then
25:44 --> 25:46try a targeted therapy?
25:46 --> 25:47Many of these targeted therapies,
25:47 --> 25:49when their first initially
25:49 --> 25:50introduced and tested in patients,
25:50 --> 25:52are often used after the standard of
25:52 --> 25:54care is already been given and there may
25:54 --> 25:57be a point once we show that they are
25:57 --> 25:59efficacious or they work that they then
25:59 --> 26:01are brought up to earlier stages.
26:01 --> 26:02That's true for example,
26:02 --> 26:04in lung cancer and specific types of
26:04 --> 26:06mutations in lung cancer that we've observed.
26:06 --> 26:08But at this point most of these trials,
26:08 --> 26:11at least the early phase trials, are after
26:11 --> 26:12the standard of care,
26:12 --> 26:15so I think that right now standard of
26:15 --> 26:17care chemotherapy is really our best bet.
26:17 --> 26:19How we tailor which chemotherapy to
26:19 --> 26:22give it may depend a little bit
26:22 --> 26:24on whether there are mutations in DNA
26:24 --> 26:26repair genes that we can detect in cancer.
26:26 --> 26:29So I think it's important to talk
26:29 --> 26:31to your oncologist or doctor about
26:31 --> 26:32looking at the sequence,
26:32 --> 26:34because that could affect how you choose
26:34 --> 26:36the chemotherapies that we typically
26:36 --> 26:38give and then hopefully down the line
26:38 --> 26:40some of these targeted drugs will
26:40 --> 26:42make their way to where they might
26:42 --> 26:44be helpful in the first line
26:44 --> 26:46prior to what we have currently,
26:46 --> 26:48and maybe replace the current therapies
26:48 --> 26:50in terms of standard of care.
26:50 --> 26:52I don't think we're quite there yet,
26:52 --> 26:53and
26:53 --> 26:54pancreatic cancer for targeted therapies,
26:54 --> 26:56so when we talked about germline
26:56 --> 26:58mutations and some people may have,
26:58 --> 27:00for example a mutation,
27:00 --> 27:02are you using that information to
27:02 --> 27:04tailor your therapy as well and if so,
27:04 --> 27:06can you tell us a little
27:06 --> 27:09bit about that?
27:09 --> 27:11We do know that DNA repair pathways
27:11 --> 27:13are abnormal in patients who have
27:13 --> 27:16two mutations and it turns out
27:16 --> 27:18certain chemotherapy therapies that we give
27:18 --> 27:21can be more effective in that context.
27:21 --> 27:24Those cells can't repair the DNA
27:24 --> 27:26damage.
27:26 --> 27:28It actually induces, which leads them to be
27:28 --> 27:30more sensitive to those chemotherapies,
27:30 --> 27:33and so we are tailoring our chemotherapy a
27:33 --> 27:36little bit in terms of having that mutation.
27:36 --> 27:38We also know that there is a certain
27:38 --> 27:41class of drugs called PARP Inhibitors
27:41 --> 27:44that have been quite helpful in breast
27:44 --> 27:46and ovarian cancers with RCA mutations
27:46 --> 27:48that now have shown some efficacy
27:48 --> 27:50in patients who have be RCA germline
27:51 --> 27:53mutations in pancreatic cancer and
27:53 --> 27:55recently was FDA approved actually
27:55 --> 27:57for that indication in the last month.
27:57 --> 27:58And so again,
27:58 --> 28:00the knowledge of these mutations
28:00 --> 28:03and their presence in the tumors is
28:03 --> 28:05helping us guide how we treat our
28:05 --> 28:08patients.
28:08 --> 28:10Tell me how that impacts overall survival.
28:10 --> 28:12If we give standard chemotherapy,
28:12 --> 28:14how efficacious is it?
28:14 --> 28:16And if we can target something,
28:16 --> 28:18how much does that improve outcomes?
28:18 --> 28:19So in terms
28:19 --> 28:21of overall survival,
28:21 --> 28:22in standard of care chemotherapy,
28:23 --> 28:25in which we use really four drugs,
28:25 --> 28:27three of which are chemotherapies,
28:27 --> 28:30a regimen which
28:30 --> 28:32has been around now for nearly a decade,
28:32 --> 28:34is still the standard of care
28:34 --> 28:36and it was important when the initial
28:36 --> 28:38results came out nearly a decade ago,
28:38 --> 28:40because it really showed that
28:40 --> 28:41combinations of chemotherapy could be
28:41 --> 28:43better than a single chemotherapy.
28:43 --> 28:45In the 2000s,
28:45 --> 28:47we did a number of trials in which we
28:47 --> 28:48combined chemotherapies and none of
28:48 --> 28:51them were better than one drug alone,
28:51 --> 28:53and so that really showed us that
28:53 --> 28:54that combination chemotherapy can
28:54 --> 28:55be helpful in pancreatic cancer,
28:55 --> 28:58and I think those are still the
28:58 --> 28:59standard of care at this point.
28:59 --> 29:00Though again,
29:00 --> 29:02we can tailor a little bit based
29:02 --> 29:05on the sequencing and the presence
29:05 --> 29:07or absence of these general
29:07 --> 29:08permutation.
29:09 --> 29:11Deepak Muzumdar is an assistant
29:11 --> 29:13professor of genetics and medical
29:13 --> 29:15oncology at the Yale School of Medicine.
29:15 --> 29:16If you have questions,
29:16 --> 29:18the address is canceranswers@yale.edu
29:18 --> 29:20and past editions of the program
29:20 --> 29:22are available in audio and written
29:22 --> 29:23form at Yalecancercenter.org.
29:23 --> 29:26We hope you'll join us next week to
29:26 --> 29:29learn more about the fight against
29:29 --> 29:32cancer here on Connecticut public radio.

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June 7, 2020

Yale Cancer Center

visit: http://www.yalecancercenter.org

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