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Pancreatic Cancer Research

June 08, 2020
  • 00:00Support for Yale Cancer Answers
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  • 00:13Welcome to Yale Cancer
  • 00:15Answers with your host
  • 00:16Doctor Anees Chagpar.
  • 00:18Yale Cancer Answers features the
  • 00:20latest information on cancer care by
  • 00:22welcoming oncologists and specialists
  • 00:24who are on the forefront of the
  • 00:26battle to fight cancer. This week
  • 00:28it's a conversation about pancreatic
  • 00:30cancer with Doctor Mandar
  • 00:31Deepak Muzumdar. Doctor Muzumdar
  • 00:33is an assistant professor of
  • 00:35genetics and medical oncology
  • 00:36at the Yale School of Medicine
  • 00:38where Doctor Chagpar is a
  • 00:40professor of surgical oncology.
  • 00:42Maybe you can
  • 00:44start by telling us a little
  • 00:46bit about pancreatic cancer.
  • 00:47It's certainly not one of the Big 5.
  • 00:50We talk about breast
  • 00:52cancer and lung cancer and colon
  • 00:54cancer and prostate cancer.
  • 00:55Pancreatic cancer is a little bit rarer. Is
  • 00:57that right?
  • 00:59Yes, pancreatic cancer is
  • 01:00somewhere between the 10th and 11th,
  • 01:02most common cause of
  • 01:04cancer in the United States.
  • 01:05But it's rapidly contributing to
  • 01:07cancer deaths in the United States.
  • 01:09It's now the third leading
  • 01:10cause of cancer death in the
  • 01:11United States and is soon expected
  • 01:13to be the second leading cause
  • 01:15within the next few years.
  • 01:17So I think it's becoming a very
  • 01:20important cause of cancer that
  • 01:22we really have to deal with.
  • 01:24Yeah, and that's I guess
  • 01:25because pancreatic cancer,
  • 01:27although it may be rare,
  • 01:28is often pretty fatal. Is that
  • 01:31right?
  • 01:32Most patients with pancreatic cancer
  • 01:34are diagnosed at advanced stages.
  • 01:35Either it's beyond surgical resection,
  • 01:37which is our mainstay of
  • 01:39therapy for cure or it is
  • 01:41already spread to other organs,
  • 01:43making it exceedingly
  • 01:44challenging to treat at that
  • 01:46point. And so the idea is
  • 01:48to either find it early
  • 01:50or prevent it altogether.
  • 01:52So let's take each of those in turn.
  • 01:54I know that your lab is
  • 01:56really looking at prevention,
  • 01:57but maybe you can talk a little
  • 01:59bit before we get into that
  • 02:01as the bulk of our discussion today,
  • 02:03what are the signs and
  • 02:06symptoms that people should be aware
  • 02:08of so that they could try to catch it
  • 02:10a little bit earlier?
  • 02:11So pancreatic cancer unfortunately
  • 02:13is challenging to actually diagnose
  • 02:14early because many of the symptoms
  • 02:16that are associated with it are quite
  • 02:18nonspecific or associated with other
  • 02:20different more common conditions.
  • 02:21So some common symptoms include
  • 02:23abdominal pain or discomfort,
  • 02:24nausea, weight-loss.
  • 02:25Many of these things can be caused by
  • 02:28other factors that are more common,
  • 02:30such as reflux for example.
  • 02:31So that's one of the challenges
  • 02:33with diagnosing,
  • 02:34but I think that one of the things
  • 02:37that we do know is that there are a
  • 02:40number of risk factors associated
  • 02:42with pancreatic cancer,
  • 02:43in particular by 10% of all
  • 02:45pancreatic cancers,
  • 02:45are associated with some sort
  • 02:47of genetic
  • 02:48familial cause,
  • 02:49and so certainly in patients
  • 02:51who have first degree relatives with
  • 02:53a prior history of pancreatic cancer,
  • 02:55multiple family
  • 02:56members had pancreatic cancer
  • 02:57that should alert more complete
  • 02:59evaluation and discussion,
  • 03:00at least with their physicians.
  • 03:02But again,
  • 03:03it doesn't have very common
  • 03:04symptoms that are unique,
  • 03:06making it very challenging
  • 03:07to diagnose early.
  • 03:09A number of studies are being done now
  • 03:11to try to identify factors that
  • 03:13are involved in early detection.
  • 03:15Hopefully some of those will
  • 03:16lead to some blood based,
  • 03:18tests that we can actually do
  • 03:20to try to identify some markers
  • 03:22that might give us an inkling that
  • 03:24pancreatic cancer may be there.
  • 03:26That would allow us to do
  • 03:28some follow-up testing,
  • 03:30but we're still in the research
  • 03:31phases of that.
  • 03:32We're getting
  • 03:33there, but we're not quite there yet.
  • 03:35And so because the symptoms are so
  • 03:37non specific people I would presume
  • 03:39people don't pay attention to that.
  • 03:41And by the time things have
  • 03:43festered on for quite awhile.
  • 03:45They then present and have are found to
  • 03:48have disease that's gone and spread to other
  • 03:50organs making it more difficult to treat.
  • 03:52You talked a little bit about genetics and
  • 03:55you said that about 10% of all pancreatic
  • 03:57cancer patients have a family history.
  • 04:00That also means that 90% of people don't.
  • 04:04And so, even if you don't have a
  • 04:08family history of pancreatic cancer,
  • 04:10should you be paying attention
  • 04:12even to those non specific symptoms?
  • 04:15And if they don't go away,
  • 04:17or if they don't have a reason behind them,
  • 04:20maybe get checked out?
  • 04:21That's exactly right.
  • 04:22So if their symptoms that are
  • 04:24persistent or you don't have a great
  • 04:27explanation for, a discussion with
  • 04:28your doctor is always necessary.
  • 04:30It's always possible that it is pancreatic cancer.
  • 04:32But it's more likely
  • 04:34that something else is going on.
  • 04:35But it's better to be evaluated and
  • 04:37check to make sure that pancreatic
  • 04:40cancer wouldn't be a cause
  • 04:42of the symptoms.
  • 04:42Tell us a little bit more about
  • 04:45the genetics of pancreatic cancer.
  • 04:47I mean, when we talk about a
  • 04:49family history, is it something
  • 04:51that is age specific?
  • 04:53Should it run on one side
  • 04:55of the family or the other?
  • 04:57Are there multiple family members
  • 04:59who may be involved or should be
  • 05:02involved in order for you to
  • 05:04be a little bit more cautious?
  • 05:06Does it affect
  • 05:07other cancers? Tell us a little
  • 05:09bit more about that whole space of
  • 05:11the genetics of pancreatic cancer.
  • 05:13About 10%, like we discussed,
  • 05:15about 10% of all pancreatic cancers
  • 05:17are associated with some sort of family history.
  • 05:19And the things to be aware of,
  • 05:21are multiple first degree relatives,
  • 05:23so that is siblings, parents,
  • 05:25children with pancreatic cancer,
  • 05:26particularly first degree relatives
  • 05:28who are diagnosed prior to the age
  • 05:30of 50
  • 05:32found in your family.
  • 05:34There's a greater risk of
  • 05:35developing pancreatic cancer,
  • 05:36and there's a number of known gene
  • 05:38mutations that have been identified in
  • 05:40pancreatic cancer that are also seen
  • 05:42in other cancer types such as
  • 05:44colorectal cancer, breast cancer,
  • 05:46ovarian cancer.
  • 05:46So certainly,
  • 05:47if any of those have been
  • 05:49found in family members,
  • 05:51one should at least discuss with the
  • 05:53geneticists getting tested for
  • 05:55those types of mutations which might
  • 05:57alter how to actually screen or to try
  • 06:00and diagnose pancreatic cancer early.
  • 06:02And so some of those mutations I
  • 06:04know as a breast cancer surgeon,
  • 06:06things like BRCA,
  • 06:08we think of BRCA.
  • 06:10We think breast and ovarian
  • 06:12cancer but be RCA also increases
  • 06:14your risk of pancreatic cancer.
  • 06:16Prostate cancer.
  • 06:17So if you have a family history
  • 06:19of breast cancer and let's say one
  • 06:21of your family members has been
  • 06:24diagnosed with a BRC mutation,
  • 06:25you're at increased risk of
  • 06:27carrying that same mutation.
  • 06:28You go to a geneticists or genetic
  • 06:31counselor and you test because
  • 06:33testing now is pretty ubiquitous
  • 06:34and actually fairly cheap.
  • 06:36And if you carry that genetic mutation,
  • 06:38most people think about all of the
  • 06:40things that they can do to prevent
  • 06:43breast cancer or ovarian cancer,
  • 06:44and certainly prophylactic
  • 06:46surgery is in the cards.
  • 06:48But what about pancreatic cancer?
  • 06:49How do you prevent that?
  • 06:51You can't really remove your
  • 06:52pancreas.
  • 06:53There's no surgical removal of
  • 06:55the pancreas that would be used.
  • 06:57The prevention, though there are
  • 06:59certain screening programs that
  • 07:01one can get, a part of that would
  • 07:04help you to find it earlier.
  • 07:06That would include things like image Ng and
  • 07:08other things that can be done to find it.
  • 07:10There's also a number of non genetic
  • 07:12risk factors that we know can contribute
  • 07:14to pancreatic cancer and they likely
  • 07:16will cooperate with gene mutations,
  • 07:17and those are some of the lifestyle
  • 07:19things that can be done to try and
  • 07:22decrease your risk of pancreatic cancer.
  • 07:23For example,
  • 07:24we know for quite some time now that
  • 07:26smoking is associated with pancreatic cancer,
  • 07:28two and a half fold increased
  • 07:30risk of developing the disease
  • 07:31over the general population,
  • 07:32so quitting smoking might be
  • 07:34one thing to do.
  • 07:35We know there's several other
  • 07:37modifiable risk factors
  • 07:38including obesity,
  • 07:39which is soon
  • 07:41to surpass smoking as the leading
  • 07:43modifiable risk factor for pancreatic
  • 07:45cancer and its associated with
  • 07:46somewhere between 2 and a
  • 07:482 1/2 fold increased risk
  • 07:50again over the general population,
  • 07:52and so losing weight may be
  • 07:54helpful in terms of reducing risk.
  • 07:56There are a number of dietary
  • 07:58things that have been associated,
  • 08:00but none of them are convincing,
  • 08:02but there are lifestyle modifications in
  • 08:04terms of tobacco cessation, stopping smoking.
  • 08:06Or altering diets or losing
  • 08:08weight that might be helpful.
  • 08:09What about alcohol?
  • 08:10So there are some studies that
  • 08:12do see an association of alcohol
  • 08:14with pancreatic cancer.
  • 08:16Development of the studies
  • 08:17are not conclusive.
  • 08:18There's also an association
  • 08:20with excessive alcohol use.
  • 08:21An inflammation of the pancreas,
  • 08:23also known as pancreatitis
  • 08:25and certainly chronic pancreatitis.
  • 08:26That is inflammation that's recurrent,
  • 08:28can be a risk factor.
  • 08:33But in terms of limited exposures of alcohol,
  • 08:36there is some association,
  • 08:37though it's not necessarily as
  • 08:39strong as tobacco and or
  • 08:41obesity so
  • 08:42you make a good point.
  • 08:47We often talk about obesity and
  • 08:49sitting is becoming the new
  • 08:50smoking and the number of cancers
  • 08:53that are increased with obesity.
  • 08:55Your lab has been looking
  • 08:56at that in particular,
  • 08:58with pancreatic cancer. Tell
  • 08:59us a little bit more about the
  • 09:02research that you do.
  • 09:03We've become interested in
  • 09:05looking at non genetic factors
  • 09:07that might be contributed to
  • 09:09cancer development and this is
  • 09:11in part due to the fact that we
  • 09:13can study the cancer associated gene
  • 09:15mutations in animal systems or model
  • 09:18system such as the mouse and what
  • 09:20we found is when we engineer the
  • 09:22cancer associated mutations into mice
  • 09:23while they do get the human cancers,
  • 09:25we can engineer them in a large
  • 09:27fraction of the pancreas.
  • 09:29But we get very little tumor
  • 09:30that develops and even the tumors
  • 09:32that develop, most of them don't
  • 09:34progress to the advanced stages.
  • 09:36So this suggested to us perhaps
  • 09:38non mutational factors,
  • 09:39non genetic factors may
  • 09:41be driving it or
  • 09:42the environment or some other factors
  • 09:44within the person might be contributing.
  • 09:48And so we actually turned to
  • 09:50epidemiological studies that had actually
  • 09:52shown risk of increased pancreatic
  • 09:54cancer development in obese individuals,
  • 09:56and this has been known
  • 09:57now for nearly two decades,
  • 09:59in fact.
  • 10:00Obesity is associated with 13
  • 10:02different cancer types,
  • 10:03including many of the cancers in
  • 10:05the gastrointestinal tract,
  • 10:06including pancreatic cancer,
  • 10:07and our research is really focused
  • 10:09on trying to understand how
  • 10:11obesity might contribute to cancer
  • 10:13development in hopes of maybe
  • 10:15identifying new ways of preventing
  • 10:16and or treating the disease.
  • 10:18And what we've found actually in
  • 10:21studying obesity in mice in which
  • 10:23we can engineer the mice to be
  • 10:25obese or give them a high fat diet,
  • 10:28for example, to make them dietarily,
  • 10:30obese,
  • 10:30that the obesity
  • 10:32itself can actually cooperate
  • 10:34with gene mutations to promote
  • 10:35the development and progression
  • 10:37of pancreatic cancer.
  • 10:38And we can actually do studies in
  • 10:40mice to make them lose weight using
  • 10:43either genetic or again dietary tricks,
  • 10:45and we've found that if you do
  • 10:47that at an early stage prior to
  • 10:49the development of advanced tumors,
  • 10:52you can actually use that as a
  • 10:54preventative strategy
  • 10:55to actually prevent the
  • 10:57emergence of advanced pancreatic
  • 10:58cancer.
  • 11:00So what you're basically telling us
  • 11:01is that obesity kind of is
  • 11:03synergistic with genetic mutations
  • 11:04in pancreatic cancer in their
  • 11:06progression and in their development.
  • 11:08And so if you have a BRC mutation,
  • 11:11one of the things you can do before you
  • 11:13ever get pancreatic cancer as soon as
  • 11:16you know about that genetic mutation,
  • 11:19or even when you just have a
  • 11:21family history is to lose weight
  • 11:23because you will reduce your risk
  • 11:24of getting pancreatic cancer,
  • 11:27or at least having the pancreatic cancer
  • 11:29be as aggressive as it otherwise could be.
  • 11:32That's right, that's what
  • 11:33our studies are suggesting,
  • 11:35both in humans from the epidemiology
  • 11:37and also in our mouse models
  • 11:38that actually weight loss might
  • 11:40be helpful in reducing the
  • 11:42risk of pancreatic cancer.
  • 11:47And so does the
  • 11:49same thing apply to quitting smoking?
  • 11:51That is less well studied in
  • 11:53the realm of pancreatic cancer.
  • 11:55We do know, for example,
  • 11:57in heart disease that quitting smoking
  • 11:59can have a dramatic improvement in
  • 12:01reducing the risk of heart disease.
  • 12:03And losing weight or reducing obesity
  • 12:05also has cardiovascular benefits.
  • 12:07So in terms of heart disease
  • 12:09as well as cancer,
  • 12:14and as challenging
  • 12:17as it may be to reduce or stop
  • 12:19smoking and to lose some weight
  • 12:21it might be very helpful in terms of
  • 12:23not only improving general health,
  • 12:25including cardiovascular disease,
  • 12:26but also might play a role
  • 12:28in cancer prevention.
  • 12:29Yeah, it sounds like
  • 12:31those two things
  • 12:33if you want to live longer and better
  • 12:36are two things that should be at the
  • 12:38top of the ticket. You talked about
  • 12:41genetically or doing
  • 12:44dietary tricks to get mice to lose weight
  • 12:46and so we can make mice lose weight,
  • 12:49it's harder to get people to lose weight.
  • 12:52Do you have any tricks or tips on
  • 12:54studies that have been done that may
  • 12:57have helped people to lose weight?
  • 12:59So this is a big
  • 13:00problem. And how do we get
  • 13:02people to lose weight?
  • 13:04And a lot of it is genetics?
  • 13:07Some of it can be genetic,
  • 13:09some of it is trying to maintain the weight
  • 13:12when people have already lost weight.
  • 13:14I can't speak to any specific tricks
  • 13:17or tips that would be very helpful.
  • 13:19There are clinics now,
  • 13:21including here at Yale,
  • 13:22obesity clinics that do use
  • 13:24adjunctive medications that can be
  • 13:26very helpful in reducing weight
  • 13:28and keeping the weight off.
  • 13:29and I would suggest that for those
  • 13:32individuals that are having a hard time
  • 13:34through just altering their diet or
  • 13:36exercising to lose weight that trying to
  • 13:38take advantage of some of
  • 13:39these opportunities,
  • 13:40including potentially going to some of
  • 13:41these clinics might be very helpful.
  • 13:45There's a lot of focus from a public
  • 13:47health standpoint in reducing obesity.
  • 13:49I don't think anyone has a
  • 13:51Magic Bullet,
  • 13:51but I do think that there are dietary,
  • 13:53exercise as well as medications that might
  • 13:55be helpful for large fraction of people.
  • 13:57And as I've discussed already,
  • 13:59I think that is really important,
  • 14:00not only for a general health outcomes,
  • 14:02but I think it actually plays an
  • 14:04important role for cancer prevention.
  • 14:06For again, a large fractions of cancers.
  • 14:08Well thank you
  • 14:09so much for that. We are going to
  • 14:11take a quick break for a medical
  • 14:13minute please stay tuned to learn
  • 14:16more about pancreatic cancer,
  • 14:18the role of genetics and the environment with
  • 14:21my guest doctor, Mandar Deepak Muzumdar.
  • 14:24Support for Yale Cancer Answers
  • 14:27comes from AstraZeneca, dedicated
  • 14:30to advancing options and providing
  • 14:33hope for people living with
  • 14:33cancer. More information is at astrazeneca-us.com.
  • 14:35This is a medical minute about lung cancer.
  • 14:38More than 85% of lung cancer diagnosis
  • 14:41are related to smoking and quitting even
  • 14:44after decades of use can significantly
  • 14:46reduce your risk of developing lung
  • 14:49cancer. For lung cancer patients,
  • 14:51clinical trials are currently under
  • 14:53way to test innovative new treatments.
  • 14:55Advances are being made by utilizing
  • 14:58targeted therapies and immunotherapies.
  • 15:00The battle 2 trial aims to learn if
  • 15:02a drug or combination of drugs based
  • 15:05on personal biomarkers can help to
  • 15:08control non small cell lung cancer.
  • 15:11More information is available at
  • 15:14yalecancercenter.org.
  • 15:14You're listening to Connecticut public radio.
  • 15:18Welcome
  • 15:19back to Yale Cancer Answers.
  • 15:20This is doctor Anees Chagpar and
  • 15:23I'm joined tonight by my guest doctor
  • 15:25Mandar Deepak Muzumdar.
  • 15:27We're discussing pancreatic
  • 15:28cancer and the role of genetics
  • 15:30and the environment in cancer,
  • 15:31and one of the things that we talked
  • 15:34about right before the break is that
  • 15:36while pancreatic cancer is pretty rare,
  • 15:3810th or 11th,
  • 15:39most common cancer in the United States,
  • 15:42it is rapidly becoming one of the most
  • 15:44common causes of cancer related death.
  • 15:46Getting up there into the second
  • 15:48or third leading cause of
  • 15:50cancer related deaths.
  • 15:51So something really to think
  • 15:53about and what you had mentioned
  • 15:56was that there are a number
  • 15:58of things that increase our risk.
  • 16:01Some things we can't control.
  • 16:03Our genetics, our family history.
  • 16:05Some things we can control,
  • 16:07quitting smoking,
  • 16:08losing weight
  • 16:10to reduce your risk
  • 16:12of developing pancreatic cancer
  • 16:14and reducing the stage at which
  • 16:16it's likely going to present at.
  • 16:18But I wanted to go back and
  • 16:21talk about genetics.
  • 16:22We had talked about
  • 16:24the fact that people
  • 16:26have a family history.
  • 16:27They may have a genetic mutation.
  • 16:29Tell us a little bit more about
  • 16:31the work that you've been doing
  • 16:33looking at genetics and pancreatic
  • 16:35cancer and and how that
  • 16:37might actually affect people.
  • 16:38So a number of mutations have
  • 16:40been identified in pancreatic
  • 16:41cancer and specific cancer genes
  • 16:43and that's given us a great
  • 16:44understanding in terms of how
  • 16:46pancreatic cancers develop.
  • 16:47One of the hallmark genes
  • 16:49in the disease is really
  • 16:50the gene KRAS which
  • 16:53is mutated in more than 90% of
  • 16:55all human pancreatic cancers.
  • 16:57And it's clear that it's important in
  • 16:59the development of pancreatic cancer
  • 17:01when we engineer mice with KRAS,
  • 17:03mutations in the pancreas,
  • 17:04they get pancreatic cancers that look
  • 17:06and behave just like the human disease.
  • 17:08We also know that KRAS mutations
  • 17:11can promote the growth and development
  • 17:13of tumors in many other organs,
  • 17:15including the lungs and the colon.
  • 17:17In fact,
  • 17:1930% of lung cancers and in about 50%
  • 17:22of colon and rectal cancers.
  • 17:23And we know from cell studies
  • 17:25that KRAS really promotes
  • 17:27cell proliferation,
  • 17:28their ability to duplicate themselves is
  • 17:29a hallmark of cancer development.
  • 17:32Now
  • 17:32importantly,
  • 17:33KRAS has
  • 17:36been known for nearly four decades now,
  • 17:39and we know from other tumor types in
  • 17:42which we've identified the hallmark
  • 17:43genetic mutations that we can often target
  • 17:46those mutations with therapies
  • 17:48that can be quite effective.
  • 17:50Unfortunately,
  • 17:50for KRAS
  • 17:51it's actually been very hard to develop
  • 17:54drugs that can block its function,
  • 17:56and so one of the things that is actually
  • 17:59emerged recently is new developments in
  • 18:02drugs and one of those is a specific
  • 18:05drug that targets a specific
  • 18:06flavor or mutation of KRAS
  • 18:08which we call the G12C Mutation,
  • 18:10which is found in about 14%
  • 18:12of all lung cancers,
  • 18:14but only about 2 to 3% of pancreatic cancers.
  • 18:17Nonetheless, this
  • 18:19class of drugs is now being tested
  • 18:21in clinical trials and in lung cancer
  • 18:24at least the data are quite
  • 18:26promising that they can lead to
  • 18:28shrinkage of the tumors in
  • 18:30a large fraction of patients.
  • 18:32Now it remains to be seen whether the
  • 18:34effect will be true in pancreatic cancer,
  • 18:37but we're excited that now for
  • 18:39the first time,
  • 18:40we actually have a drug that
  • 18:42can target at least a specific
  • 18:43mutation in pancreatic
  • 18:45cancer, so I just wanted to clarify
  • 18:47for our listeners out there,
  • 18:48there's a difference in terms of
  • 18:50genetics that are germline genetics
  • 18:52and cancer genetics. Can you
  • 18:53clarify that a little bit?
  • 18:56Because I think when we've
  • 18:57talked about genetics,
  • 18:58we've talked about, you know,
  • 19:00going and if you have a family history,
  • 19:02seeing a geneticists and seeing if you
  • 19:05carry a genetic mutation like BRC and so on,
  • 19:08and then we kind of transitioned and we
  • 19:10talked about looking at cancer genetics,
  • 19:12the genetic mutations of a cancer cell.
  • 19:15Can you talk about and clarify
  • 19:17that difference just so that
  • 19:18I make sure that everybody out
  • 19:20there understands that difference?
  • 19:22Absolutely so germline genetics is really
  • 19:24based on mutations that are rise from
  • 19:26the very beginning that you inherit or
  • 19:28have been there from the very start.
  • 19:31So those are mutations that are
  • 19:33found in all of your cells.
  • 19:35And we think some of them predispose
  • 19:37to cancer development because they
  • 19:39affect the ability of your body to
  • 19:41maintain fidelity or to maintain the
  • 19:43DNA without creating new mutations.
  • 19:44So these are what we call DNA repair genes
  • 19:47they get when they get mutated.
  • 19:49Now when the cells duplicate themselves
  • 19:51during development, they make errors.
  • 19:53And new mutations can occur.
  • 19:54So that includes genes such as BRCA1
  • 19:56and 2 has been discussed,
  • 19:59as well as other genes
  • 20:00that are involved in DNA repair pathways
  • 20:02and we've gotten to actually be able
  • 20:05to take advantage of these mutations.
  • 20:07from a therapeutic standpoint because
  • 20:09it turns out certain chemotherapeutic
  • 20:11agents in certain drugs can actually
  • 20:12be more helpful in patients who
  • 20:14have those mutations.
  • 20:15So one of the things that's
  • 20:17emerged is that as we sequence more
  • 20:19and more pancreatic cancers,
  • 20:21we're finding that we're starting
  • 20:22to find more and more of these DNA
  • 20:25repair gene mutations in those cancers
  • 20:27such that we actually believe as
  • 20:29a community that everyone who is
  • 20:31diagnosed with pancreatic cancer
  • 20:33should have their tumors looked
  • 20:34at for these particular mutations
  • 20:36with the hope of potentially using
  • 20:38that again to guide therapy.
  • 20:40Now there's a second class of mutations,
  • 20:42not germ line,
  • 20:43but these are mutations that
  • 20:45occur in individual cells in the
  • 20:47body at some point after birth,
  • 20:49and these are what we call somatic mutations.
  • 20:51These are mutations that can
  • 20:53drive the growth
  • 20:55and development of tumors.
  • 20:56One of these mutations that falls into
  • 20:58this class is the mutation in KRAS and
  • 21:01so these are mutations that we think are
  • 21:04integral to the formation
  • 21:05of particular cancer types.
  • 21:07KRAS and pancreatic cancer.
  • 21:08But they are not there from the very beginning.
  • 21:11From when you're born,
  • 21:13they emerged at a later time point,
  • 21:15but clearly play an important role in
  • 21:18cancer development and play a
  • 21:20potentially important role in
  • 21:21guiding treatment.
  • 21:22Again using targeted drugs that target these
  • 21:25specific mutations and you
  • 21:27make a very good point about
  • 21:29when you're diagnosed with cancer,
  • 21:31like pancreatic cancer,
  • 21:33getting that
  • 21:34evaluated to look for these genetic
  • 21:36mutations because there may be drugs
  • 21:39that can target that specifically.
  • 21:40You mentioned in lung cancer the
  • 21:43fact that we have drugs against
  • 21:46KRAS that have shown promise and
  • 21:49that the data are out in terms of
  • 21:51that fact with pancreatic cancer.
  • 21:53Are there clinical trials looking
  • 21:55at that?
  • 21:57There are clinical trials using those same
  • 21:59agents in a broad array of cancer
  • 22:02types that have KRAS mutations.
  • 22:04Specifically with that one particular
  • 22:06mutation, that G12C mutation, and so there are
  • 22:09clinical trials that might be available.
  • 22:11Again, it's not that common
  • 22:13in pancreatic cancer,
  • 22:14so a lot of patients would not be eligible.
  • 22:17There is clearly a push to
  • 22:19develop KRAS drugs that target a
  • 22:21larger number of KRAS mutations
  • 22:23and there is a tremendous
  • 22:26amount of research to develop this.
  • 22:28In fact, the National Cancer Institute
  • 22:30has a whole KRAS initiative which
  • 22:32is really focused on developing
  • 22:35more fundamental understanding.
  • 22:36of KRAS
  • 22:37and other proteins and trying to
  • 22:39develop new structures and drugs
  • 22:40that we can use to target these.
  • 22:43In the lab,
  • 22:43we've tried to model what would
  • 22:45happen if you inhibit KRAS using
  • 22:47genetic technologies because we did
  • 22:49not have these drugs for many years
  • 22:51and so we can actually use
  • 22:54genetic tricks to disrupt or knockout
  • 22:55all function.
  • 22:58And we've done that in pancreatic cancer.
  • 23:00We see that it can be quite
  • 23:02effective in reducing the growth of
  • 23:04many pancreatic cancer cell lines.
  • 23:06But a subset of them
  • 23:07seem to continue to survive
  • 23:10despite complete loss of KRAS,
  • 23:12suggesting that even with these drugs
  • 23:14there is likely to be some resistance now.
  • 23:16The encouraging
  • 23:17part is we can use these models to
  • 23:20study how cells aid KRAS inhibition,
  • 23:22how they resist,
  • 23:23how they continue to survive,
  • 23:25and using this data we can now
  • 23:27use that to bring it into our clinical
  • 23:30trials and try and design better
  • 23:32combination therapies that might
  • 23:34overcome the resistance mechanisms
  • 23:35that developed with KRAS.
  • 23:38Now we're excited
  • 23:39we finally have drugs that target
  • 23:41KRAS to really test these hypothesis
  • 23:43and really see whether we can
  • 23:45overcome resistance.
  • 23:46But because of the genetic studies
  • 23:48that we and others have done,
  • 23:50it gives us some advanced insight
  • 23:52into how to really combine drugs
  • 23:54into ways that might help patients
  • 23:56even earlier in terms of overcoming
  • 23:59resistance to KRAS inhibitors
  • 24:00as they continue to
  • 24:02emerge. So now that we have these inhibitors
  • 24:05against the G12 mutation of KRAS,
  • 24:08have you looked at mice who have that
  • 24:10mutation and see whether these drugs work?
  • 24:13Whether there is a significant
  • 24:15proportion of them that are resistant,
  • 24:17or whether most of them actually will
  • 24:19respond like the lung cancer patients have?
  • 24:22so there are studies that have
  • 24:24been done using human cell lines
  • 24:26that have particular disk error.
  • 24:27Gee, 12 Mutation and put them into
  • 24:30mice and then treated the mice with
  • 24:32the drugs and they can be quite
  • 24:34effective in shrinking the tumors.
  • 24:36Now we do see that again.
  • 24:39Subset of those tumors will recur,
  • 24:41and a lot of work is being done
  • 24:44now to try to identify those resistance
  • 24:46mechanisms and then hopefully
  • 24:47bring that quicker to the clinic.
  • 24:49That's something we've really learned
  • 24:51from targeting other mutations
  • 24:53and other cancer types like lung
  • 24:55cancer that cancers will often find
  • 24:57ways to escape the inhibition,
  • 24:58but we now know
  • 25:00and study that in advance and
  • 25:02hopefully design clinical trials
  • 25:04and better ways to bring
  • 25:06up those combination therapies
  • 25:08sooner and hopefully prevent
  • 25:10the emergence of resistance to these
  • 25:12drugs. So given the choice,
  • 25:14if a patient is diagnosed
  • 25:16with pancreatic cancer,
  • 25:17there are standard chemotherapy
  • 25:19regimens that are given,
  • 25:20and we know that these
  • 25:23may or may not be effective,
  • 25:25but if a patient has a particular
  • 25:27mutation and there is a clinical trial
  • 25:30that is offering them a medication
  • 25:32targeted against that mutation,
  • 25:34are they better off just
  • 25:36statistically to take the clinical
  • 25:38trial over the standard of care?
  • 25:40Or is it better to do the standard of care?
  • 25:43Wait till you fail and then
  • 25:45try a targeted therapy?
  • 25:46Many of these targeted therapies,
  • 25:48when their first initially
  • 25:49introduced and tested in patients,
  • 25:50are often used after the standard of
  • 25:53care is already been given and there may
  • 25:55be a point once we show that they are
  • 25:57efficacious or they work that they then
  • 25:59are brought up to earlier stages.
  • 26:01That's true for example,
  • 26:03in lung cancer and specific types of
  • 26:05mutations in lung cancer that we've observed.
  • 26:07But at this point most of these trials,
  • 26:09at least the early phase trials, are after
  • 26:11the standard of care,
  • 26:13so I think that right now standard of
  • 26:16care chemotherapy is really our best bet.
  • 26:18How we tailor which chemotherapy to
  • 26:20give it may depend a little bit
  • 26:22on whether there are mutations in DNA
  • 26:24repair genes that we can detect in cancer.
  • 26:27So I think it's important to talk
  • 26:29to your oncologist or doctor about
  • 26:31looking at the sequence,
  • 26:32because that could affect how you choose
  • 26:35the chemotherapies that we typically
  • 26:36give and then hopefully down the line
  • 26:38some of these targeted drugs will
  • 26:40make their way to where they might
  • 26:43be helpful in the first line
  • 26:45prior to what we have currently,
  • 26:47and maybe replace the current therapies
  • 26:49in terms of standard of care.
  • 26:51I don't think we're quite there yet,
  • 26:53and
  • 26:53pancreatic cancer for targeted therapies,
  • 26:55so when we talked about germline
  • 26:57mutations and some people may have,
  • 26:59for example a mutation,
  • 27:00are you using that information to
  • 27:02tailor your therapy as well and if so,
  • 27:05can you tell us a little
  • 27:07bit about that?
  • 27:09We do know that DNA repair pathways
  • 27:12are abnormal in patients who have
  • 27:14two mutations and it turns out
  • 27:17certain chemotherapy therapies that we give
  • 27:19can be more effective in that context.
  • 27:21Those cells can't repair the DNA
  • 27:24damage.
  • 27:26It actually induces, which leads them to be
  • 27:28more sensitive to those chemotherapies,
  • 27:30and so we are tailoring our chemotherapy a
  • 27:34little bit in terms of having that mutation.
  • 27:37We also know that there is a certain
  • 27:39class of drugs called PARP Inhibitors
  • 27:41that have been quite helpful in breast
  • 27:44and ovarian cancers with RCA mutations
  • 27:46that now have shown some efficacy
  • 27:49in patients who have be RCA germline
  • 27:51mutations in pancreatic cancer and
  • 27:53recently was FDA approved actually
  • 27:55for that indication in the last month.
  • 27:58And so again,
  • 27:59the knowledge of these mutations
  • 28:01and their presence in the tumors is
  • 28:03helping us guide how we treat our
  • 28:06patients.
  • 28:08Tell me how that impacts overall survival.
  • 28:11If we give standard chemotherapy,
  • 28:13how efficacious is it?
  • 28:14And if we can target something,
  • 28:17how much does that improve outcomes?
  • 28:19So in terms
  • 28:20of overall survival,
  • 28:21in standard of care chemotherapy,
  • 28:23in which we use really four drugs,
  • 28:26three of which are chemotherapies,
  • 28:28a regimen which
  • 28:30has been around now for nearly a decade,
  • 28:32is still the standard of care
  • 28:34and it was important when the initial
  • 28:37results came out nearly a decade ago,
  • 28:39because it really showed that
  • 28:40combinations of chemotherapy could be
  • 28:42better than a single chemotherapy.
  • 28:44In the 2000s,
  • 28:45we did a number of trials in which we
  • 28:47combined chemotherapies and none of
  • 28:49them were better than one drug alone,
  • 28:51and so that really showed us that
  • 28:53that combination chemotherapy can
  • 28:54be helpful in pancreatic cancer,
  • 28:56and I think those are still the
  • 28:58standard of care at this point.
  • 29:00Though again,
  • 29:01we can tailor a little bit based
  • 29:03on the sequencing and the presence
  • 29:05or absence of these general
  • 29:07permutation.
  • 29:10Deepak Muzumdar is an assistant
  • 29:11professor of genetics and medical
  • 29:13oncology at the Yale School of Medicine.
  • 29:16If you have questions,
  • 29:17the address is canceranswers@yale.edu
  • 29:18and past editions of the program
  • 29:20are available in audio and written
  • 29:22form at Yalecancercenter.org.
  • 29:24We hope you'll join us next week to
  • 29:27learn more about the fight against
  • 29:29cancer here on Connecticut public radio.