Pancreatic Cancer Research

June 08, 2020

Information

June 7, 2020

Yale Cancer Center

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00:00Support for Yale Cancer Answers
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00:08with personalized medicine.
00:09Learn more at astrazeneca-us.com.
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.