Melanoma and Brain Metastases

Transcript

00:00 --> 00:02Funding for Yale Cancer Answers
00:02 --> 00:05is provided by Smilow Cancer
00:05 --> 00:07Hospital and AstraZeneca.
00:07 --> 00:09Welcome to Yale Cancer Answers
00:09 --> 00:12with host Dr Anees Chagpar.
00:12 --> 00:14Yale Cancer Answers features the
00:14 --> 00:16latest information on cancer care by
00:16 --> 00:17welcoming oncologists and specialists
00:17 --> 00:20who are on the forefront of the
00:20 --> 00:22battle to fight cancer. This week,
00:22 --> 00:24it's a conversation about Melanoma and
00:24 --> 00:27brain metastases with Doctor Thuy Tran.
00:27 --> 00:29Dr Tran is an instructor of
00:29 --> 00:30medicine in medical oncology at
00:30 --> 00:32the Yale School of Medicine,
00:32 --> 00:34where Dr Chagpar is a
00:34 --> 00:35professor of surgical oncology.
00:36 --> 00:38Doctor Tran, maybe we can start off
00:38 --> 00:40by you telling us a little bit
00:40 --> 00:41about yourself and what you do.
00:42 --> 00:45Absolutely, I am a translational
00:45 --> 00:47researcher at Yale Cancer Center.
00:47 --> 00:49I did my residency and fellowship
00:49 --> 00:52in heme/onc here and I'm happy to
00:52 --> 00:54be involved in the Melanoma team
00:54 --> 00:56treating patients with advanced
00:56 --> 00:58malignancies and skin cancers.
00:58 --> 01:00I do a lot of translational research,
01:00 --> 01:03which means that I am working at the
01:03 --> 01:05bench but also take what we find out
01:05 --> 01:07at the bench straight to the clinic
01:07 --> 01:08so that we can effect real change
01:08 --> 01:10in how we treat this disease.
01:11 --> 01:12So tell us a little bit
01:12 --> 01:13more about your research.
01:13 --> 01:17I mean you work in the Melanoma team,
01:17 --> 01:19how exactly does the translational
01:19 --> 01:22research part fit in and what
01:22 --> 01:24specifically are you looking at?
01:24 --> 01:27I've been spending the past couple
01:27 --> 01:28years really looking at innate
01:28 --> 01:30immunity in the brain and how we
01:30 --> 01:32can really capitalize on stimulating
01:32 --> 01:35those cells and in conjunction with
01:35 --> 01:36our currently available
01:36 --> 01:39therapies to try to improve
01:39 --> 01:41disease outcomes for our patients.
01:41 --> 01:42So just to give you an example.
01:42 --> 01:45One of the projects that I'm
01:45 --> 01:47highly involved with is trying to
01:47 --> 01:49target the blood brain barrier.
01:49 --> 01:51The blood brain barrier
01:51 --> 01:53has been a really understudied but
01:53 --> 01:55very clinically relevant and highly
01:55 --> 01:58impactful way for cancers to really
01:58 --> 02:00gain an advantage and to metastasize
02:00 --> 02:03and grow in the brain and so really
02:03 --> 02:05trying to focus on the blood brain
02:05 --> 02:07barrier and try to get these drugs
02:07 --> 02:10into the brain has been an
02:10 --> 02:11area of ongoing interest.
02:11 --> 02:13Just to give you an example.
02:13 --> 02:15So one of our currently active
02:15 --> 02:18projects is looking at targeting Veg F,
02:18 --> 02:20which stands for vascular
02:20 --> 02:21endothelial growth factor.
02:21 --> 02:24It's a subtle kind that really
02:24 --> 02:25stimulates blood vessel development,
02:25 --> 02:28and sometimes these tumors and the
02:28 --> 02:30immune cells surrounding them will
02:30 --> 02:32secrete this cytokine to help stimulate
02:32 --> 02:35tumor growth and so how can we
02:35 --> 02:37target this protein as well as maybe
02:37 --> 02:40target the endothelial cells themselves to
02:40 --> 02:43help decrease tumor growth in the brain.
02:43 --> 02:44And so we have a couple of
02:44 --> 02:45interesting targets,
02:45 --> 02:47one of which is currently an active
02:47 --> 02:50clinical trial within our Melanoma group
02:50 --> 02:52looking at Melanoma and lung cancer
02:52 --> 02:54patients who have brain metastases.
02:54 --> 02:56And so this clinical trial is
02:56 --> 02:58a phase two study looking at
02:58 --> 03:00the combination of bevacizumab,
03:00 --> 03:02which is our anti veg F drug
03:02 --> 03:04to help minimize blood vessel
03:04 --> 03:06development in combination with
03:06 --> 03:08an immune stimulating agent,
03:08 --> 03:10the checkpoint inhibitor pembrolizumab,
03:10 --> 03:12which targets another pathway
03:12 --> 03:15to help stimulate our own bodies
03:15 --> 03:17immune system to help fight cancer.
03:18 --> 03:21We're also going to be developing a
03:21 --> 03:23second clinical trial of pembrolizumab
03:23 --> 03:26or immune stimulating agent in
03:26 --> 03:27combination with Lenvatinib,
03:27 --> 03:29which instead of targeting the
03:29 --> 03:29cytokine itself,
03:29 --> 03:33targets the veg F receptors on the
03:33 --> 03:34endothelial cells and hopefully we
03:34 --> 03:38can get even a more dramatic immune response.
03:38 --> 03:41So today I want to take a step back
03:41 --> 03:43here and just kind of talk a little bit
03:43 --> 03:45about the blood brain barrier itself.
03:45 --> 03:49What exactly is it and how
03:49 --> 03:51does it affect cancer cells?
03:51 --> 03:53As we're always learning more
03:53 --> 03:55and more about the blood brain barrier,
03:55 --> 03:57it's not as simple as we first thought
03:57 --> 04:00where it's just comprised of the
04:00 --> 04:02blood vessel and death elial cells,
04:02 --> 04:03the blood brain barrier is
04:03 --> 04:04actually much more complicated.
04:05 --> 04:06It's composed of not only
04:06 --> 04:07the endothelial cells,
04:07 --> 04:09but all these supportive cells
04:09 --> 04:10adjacent to them,
04:10 --> 04:13and so this includes parasites
04:13 --> 04:14which control vasoconstriction
04:14 --> 04:17or the ability of these blood
04:17 --> 04:18vessels to contract and dilate.
04:18 --> 04:21It also includes all the supportive
04:21 --> 04:23astrocytes which have their
04:23 --> 04:25little processes in and feet
04:25 --> 04:27on the endothelial cells.
04:27 --> 04:29It includes interneurons,
04:29 --> 04:31it includes microglia,
04:31 --> 04:32microglia are considered,
04:32 --> 04:34sort of the innate immune cells
04:34 --> 04:36that reside within the brain.
04:37 --> 04:39How come the cancer cells can get
04:39 --> 04:41into the brain but the drugs can't?
04:41 --> 04:44You know the blood brain barrier
04:44 --> 04:47in normal states without any
04:47 --> 04:49pressure related to metastasis is
04:49 --> 04:52a very intact endothelial layer,
04:52 --> 04:55meaning that there are these specific
04:55 --> 04:56interconnections within or
04:56 --> 04:58between the endothelial cells
04:58 --> 05:00that prevent any other molecules,
05:00 --> 05:04such as drugs such as immune cells from
05:04 --> 05:07infiltrating or getting beyond them.
05:07 --> 05:09They typically are described
05:09 --> 05:10as the soldiers.
05:10 --> 05:12Remember the Roman soldiers
05:12 --> 05:15if you ever watch one of those
05:15 --> 05:17movies with all their Shields up
05:17 --> 05:20so they form an impenetrable
05:20 --> 05:22barrier to help prevent things
05:22 --> 05:24from getting past that layer.
05:24 --> 05:26And that's what's really
05:26 --> 05:27caused a lot of issues.
05:27 --> 05:28For example,
05:28 --> 05:31in breast cancer therapy where
05:31 --> 05:32chemotherapies that traditionally
05:32 --> 05:34work in breast cancers can't
05:34 --> 05:35penetrate into the brain,
05:35 --> 05:38and so we're seeing a lot more of late
05:38 --> 05:41relapses in the brain because these
05:41 --> 05:43cancer effective therapies are not
05:43 --> 05:45able to penetrate and circulate there.
05:45 --> 05:48So why can the cancer cells get
05:48 --> 05:49through those those Roman Shields?
05:49 --> 05:52I mean, it sounds like that should really be,
05:52 --> 05:55as you say, an impenetrable barrier.
05:55 --> 05:57And yet, cancer cells can seem to
05:57 --> 05:58sneak their way through.
05:58 --> 06:03Cancer cells when they metastasize,
06:03 --> 06:07they go through a very complex process,
06:07 --> 06:10basically giving them the ability to
06:10 --> 06:12invade through normal tissue and during
06:12 --> 06:15that process they adopt a different shape,
06:15 --> 06:17a different morphology.
06:17 --> 06:19They become migratory.
06:19 --> 06:20They get enter the bloodstream,
06:20 --> 06:22and when they circulate,
06:22 --> 06:25they essentially get into the brain.
06:25 --> 06:27And either lodge at Branch points
06:27 --> 06:30within those blood vessels in the
06:30 --> 06:32brain and cancer cells have all
06:32 --> 06:34sorts of different proteins and
06:34 --> 06:37things that they up regulate or
06:37 --> 06:40express to help them survive and
06:40 --> 06:42proliferate during this process,
06:42 --> 06:45and a few of those proteins include
06:45 --> 06:47things like matrix metalloproteases
06:47 --> 06:50where they can break apart different
06:50 --> 06:52elements of the tumor stroma,
06:52 --> 06:54or the tumor microenvironment,
06:54 --> 06:55and this allows them
06:55 --> 06:58essentially to break apart those tight
06:58 --> 07:00junctions within this endothelial cells.
07:01 --> 07:04Wedge themselves in between these
07:04 --> 07:07cells and eventually be able to set up
07:07 --> 07:08shop and grow there.
07:09 --> 07:11So I guess just to
07:11 --> 07:13press the point further,
07:13 --> 07:16my question is if the tumor cells can kind
07:16 --> 07:19of finagle their way through this barrier,
07:19 --> 07:23either they make holes in the barrier,
07:23 --> 07:26they kind of distort and try to get through,
07:26 --> 07:29then are those changes to
07:29 --> 07:32the blood brain barrier that allow
07:32 --> 07:34the cancer cells to get through,
07:34 --> 07:36those don't seem to be permanent enough
07:36 --> 07:38to allow our drugs to get through.
07:38 --> 07:41Or is there another thing at play?
07:41 --> 07:43Are the drugs too large?
07:44 --> 07:46Is it that they can't squish
07:46 --> 07:48through the little spaces?
07:48 --> 07:50Or is this more than simply
07:50 --> 07:51a mechanical problem?
07:51 --> 07:54I think the answer is actually a little
07:54 --> 07:56complicated to address and we don't
07:56 --> 07:58really at this point fully understand
07:59 --> 08:01how our current effective therapies
08:01 --> 08:03really penetrate to get into the brain.
08:03 --> 08:04So one hypothesis
08:04 --> 08:07is that actually when we give immune
08:07 --> 08:09therapy these immune stimulating
08:09 --> 08:12drugs that help educate our own
08:12 --> 08:14immune system to fight the cancer,
08:14 --> 08:16we're doing that below the
08:16 --> 08:18neck so peripherally,
08:18 --> 08:21so these educated immune cells can
08:21 --> 08:23then subsequently migrate through
08:23 --> 08:26the circulation into the brain.
08:26 --> 08:29They have a much easier ability
08:29 --> 08:31to transmigrate through the
08:31 --> 08:33endothelial layer and get into
08:33 --> 08:35the tumor to where they can have
08:35 --> 08:37antitumor effect,
08:37 --> 08:39the other component of this is maybe
08:40 --> 08:42the defects that lead to
08:42 --> 08:45forming a tumor in the brain caused
08:45 --> 08:47vessel leakiness and vessel damage,
08:47 --> 08:50and such that you have this
08:50 --> 08:53chronic adima or loss of vessel
08:53 --> 08:56integrity and that therefore
08:56 --> 08:58allows these large monoclonal
08:58 --> 09:01antibodies which are essentially
09:01 --> 09:02our immune checkpoint drugs,
09:02 --> 09:06to actually access
09:06 --> 09:06into the tumor
09:06 --> 09:09ecause these vessels are already so leaky.
09:09 --> 09:11That's really great
09:11 --> 09:13news on the immunotherapy front,
09:13 --> 09:15knowing that these therapies
09:15 --> 09:17can get into the brain,
09:17 --> 09:20I guess the next question is, well,
09:20 --> 09:22how come chemotherapy drugs can't do that?
09:22 --> 09:25I mean, we give them
09:25 --> 09:27peripherally into a vein below the neck,
09:27 --> 09:29right into a hand,
09:29 --> 09:31they get into a blood vessel.
09:31 --> 09:34How come they can't follow the same
09:34 --> 09:36kinds of path?
09:37 --> 09:40Yeah, so our blood brain barrier
09:40 --> 09:41through our development
09:41 --> 09:44has upregulated a lot
09:44 --> 09:48of drug efflux pumps and so these
09:48 --> 09:50endothelial cells that constitute
09:50 --> 09:53the blood brain barrier they have
09:53 --> 09:55these specialized pumps that whenever
09:55 --> 09:57drug does penetrate into the cells,
09:57 --> 09:59they pump them right back out
09:59 --> 10:01into the circulation.
10:01 --> 10:05And so that's what limits the effectiveness
10:05 --> 10:07of standard chemotherapy and
10:07 --> 10:10it's really not a very good treatment
10:10 --> 10:13option for patients with brain metastases.
10:14 --> 10:16OK, I get all of that.
10:16 --> 10:18So now let's talk a little
10:18 --> 10:19bit more about this.
10:19 --> 10:21Veg F that you were
10:21 --> 10:22mentioning just a moment ago,
10:22 --> 10:24this vascular endothelial
10:24 --> 10:26growth factor is that something
10:26 --> 10:28that is present on particular
10:28 --> 10:30cancer cells that these
10:30 --> 10:32therapies now are attacking?
10:32 --> 10:35Veg F is upregulated in a lot
10:35 --> 10:37of different cell types, and
10:37 --> 10:39one of those being Melanoma,
10:39 --> 10:41where we have found that circulating
10:41 --> 10:44veg F is actually a poor prognostic
10:44 --> 10:47marker in patients, so they
10:47 --> 10:48say essentially they have worse
10:48 --> 10:50outcomes when they have elevated
10:50 --> 10:52circulating levels of this protein.
10:52 --> 10:55So the protein is in the circulation.
10:55 --> 10:56It's not necessarily on the
10:56 --> 10:58tumor cells, or is it on both?
10:58 --> 11:02It's very ubiquitously expressed.
11:02 --> 11:05It can be expressed by the tumor cells
11:05 --> 11:08themselves and have a local effect in that
11:08 --> 11:10increased regulation or increased
11:10 --> 11:14expression of VEGF can also
11:14 --> 11:17appear as circulating levels.
11:17 --> 11:20Tumor cells, in addition to immune cells,
11:20 --> 11:23can also increase veg F levels too.
11:23 --> 11:24So, for example,
11:24 --> 11:26a specific type of immune cell
11:26 --> 11:29which essentially gobble up a lot
11:29 --> 11:32of tumor cells or cell debris.
11:32 --> 11:34One of those is macrophages.
11:34 --> 11:37So macrophages are able to secrete
11:37 --> 11:39high levels of veg F as well.
11:40 --> 11:42And so that makes me think that
11:42 --> 11:45these anti VEGF therapies that you're
11:45 --> 11:48looking at in clinical trials,
11:48 --> 11:49they might be
11:49 --> 11:52something not specific
11:52 --> 11:55for particular patients that they might
11:55 --> 11:57be more ubiquitously used rather than
11:57 --> 12:00some of the therapies that come out
12:00 --> 12:02where you really need to check the
12:02 --> 12:04tumor cells to make sure that
12:04 --> 12:06particular protein or that particular
12:06 --> 12:08receptor is on the tumor cell.
12:08 --> 12:10It sounds like this is something that
12:10 --> 12:12could be used for most patients.
12:12 --> 12:13Is that right?
12:14 --> 12:15That's correct. So actually,
12:15 --> 12:18even recently within the past couple
12:18 --> 12:20weeks we've had another FDA approval
12:20 --> 12:22for the combination of pembrolizumab
12:22 --> 12:24and lenvatinib,
12:24 --> 12:27being one of our veg F receptor
12:27 --> 12:29targeting drugs in addition to other
12:30 --> 12:32receptors that it does block as well.
12:32 --> 12:35So that was actually just in
12:35 --> 12:37advanced renal cell carcinoma.
12:37 --> 12:39The combination is already
12:39 --> 12:41been also approved in
12:41 --> 12:43advanced endometrial cancer,
12:43 --> 12:46and then actually Merck,
12:46 --> 12:50the company that produces pembrolizumab
12:50 --> 12:53is currently investigating this combination
12:55 --> 12:57in the first line and second line
12:57 --> 12:59setting for Melanoma patients as well.
13:00 --> 13:02Wow, all really interesting
13:02 --> 13:04developments which we will need
13:04 --> 13:06to investigate more when we take
13:06 --> 13:08a brief break for medical minute.
13:08 --> 13:10Please stay tuned to learn
13:10 --> 13:11more about Melanoma
13:11 --> 13:12and brain metastases with
13:12 --> 13:14my guest doctor Thuy Tran.
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13:29 --> 13:31The American Cancer Society
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13:47 --> 13:49Clinical trials are currently
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14:29 --> 14:31Welcome back to Yale Cancer Answers.
14:31 --> 14:34This is doctor Anees Chagpar and I'm
14:34 --> 14:37joined tonight by my guest Doctor Thuy Tran.
14:37 --> 14:39We're talking about the care of patients
14:39 --> 14:41with Melanoma and brain metastases,
14:41 --> 14:45and right before the break we were
14:45 --> 14:47talking about some of the techniques,
14:47 --> 14:50some of the new trials that are ongoing,
14:50 --> 14:53especially looking at use of anti
14:53 --> 14:56veg F therapies and immunotherapy
14:56 --> 14:59for patients with Melanoma,
14:59 --> 15:00who had brain metastases.
15:00 --> 15:04So I thought we'd take a step back and talk a
15:04 --> 15:06little bit more about patients with Melanoma
15:06 --> 15:08who have brain metastases.
15:08 --> 15:11So I think all of us know that Melanoma
15:11 --> 15:14is one of the deadliest skin cancers.
15:14 --> 15:17But how common is Melanoma?
15:19 --> 15:21Many patients get Melanoma.
15:21 --> 15:23What proportion of them will
15:23 --> 15:25actually develop brain metastases?
15:26 --> 15:29Melanoma over the past couple decades
15:29 --> 15:31it's actually the incidence
15:31 --> 15:35that's increasing more recently about 75,000
15:35 --> 15:38new cases are diagnosed each year and
15:38 --> 15:41it's a malignancy that is driven by both
15:41 --> 15:45genetic as well as environmental causes,
15:45 --> 15:48some of which are related to non
15:48 --> 15:52UV exposure and so really a lot of
15:52 --> 15:56Melanoma develops as we grow older in
15:56 --> 15:59our fifth generation or fifth decade.
15:59 --> 16:01And so it does have a higher
16:01 --> 16:03dominance in men,
16:03 --> 16:06and there are certain mutations
16:06 --> 16:07associated with it.
16:07 --> 16:1050% of melanomas will contain
16:10 --> 16:13a BRAF mutation that we can actually
16:13 --> 16:16target with effective BRAF inhibiting
16:16 --> 16:18drugs as well as MEC inhibiting drugs
16:18 --> 16:21that also help boost that response.
16:21 --> 16:23So just to pick up on
16:23 --> 16:25the genetic element for a second
16:25 --> 16:28one of the things that you said,
16:28 --> 16:29which I found really interesting
16:29 --> 16:32and I think our listeners will be
16:32 --> 16:35interested to learn about as well is
16:35 --> 16:37that there are a lot of melanomas
16:37 --> 16:40that are not related to UV exposure.
16:40 --> 16:41That may be genetic,
16:41 --> 16:44so by that do you mean that we should
16:44 --> 16:47know about our family history in terms
16:47 --> 16:49of our risk of developing Melanoma?
16:49 --> 16:53And when you talk about BRAF mutations,
16:53 --> 16:55are you talking about germline
16:55 --> 16:57mutations or are these more
16:57 --> 16:59somatic mutations that you'll find in a tumor?
17:00 --> 17:05The BRAF mutations are new mutations.
17:05 --> 17:07Sometimes we actually see
17:07 --> 17:09these mutations present but not
17:09 --> 17:11associated with any malignancy.
17:11 --> 17:14But when they do appear associated
17:14 --> 17:16with advanced Melanoma,
17:16 --> 17:18it is something that we can actually target.
17:18 --> 17:20Now these BRAF mutations
17:20 --> 17:21are not unique to Melanoma.
17:21 --> 17:23They're actually present in
17:23 --> 17:26certain types of colon cancers.
17:26 --> 17:28And as well as lung cancers.
17:28 --> 17:30And so the same drugs apply they're
17:30 --> 17:32as effective in those other types
17:32 --> 17:35of cancers as they are in Melanoma.
17:36 --> 17:38And so some people, even if they wear
17:38 --> 17:40sunscreen and they make sure
17:40 --> 17:42that they're not getting a lot of
17:42 --> 17:44UV exposure and so on and so forth.
17:44 --> 17:47They can still get Melanoma because of
17:47 --> 17:48these genetic mutations. Is that right?
17:49 --> 17:52Yes, in terms of the non sun
17:52 --> 17:54exposed related melanomas, we typically
17:54 --> 17:57think of those as a acreal melanomas.
17:57 --> 17:59Meaning they form between the hands,
17:59 --> 18:01the webs of the hands and
18:01 --> 18:03the feet on her extremities,
18:03 --> 18:05and so these are typically places
18:05 --> 18:06that you know aren't basking
18:06 --> 18:09in the Sun and other places
18:09 --> 18:12that melanomas can evolve from,
18:12 --> 18:15is the mucosal lining of
18:15 --> 18:18our upper oral pharanx
18:18 --> 18:20as well as the anal rectal region.
18:20 --> 18:24Vulvar melanomas from the reproductive tract,
18:24 --> 18:27as well as uveal melanoma's also
18:27 --> 18:29from the pigmented layers of the eyes.
18:29 --> 18:30So Melanoma, in essence,
18:30 --> 18:33is a cancer of the melanocytes.
18:33 --> 18:36These pigmented cells and so anywhere
18:36 --> 18:39where we have pigment there are
18:39 --> 18:41melanocytes associated with them.
18:42 --> 18:44When you think
18:44 --> 18:45about these genetic mutations,
18:45 --> 18:48now that we know more and more about them,
18:48 --> 18:53certainly you know people who have a
18:53 --> 18:56genetic mutation who are at increased risk,
18:56 --> 18:58they may want to take additional precautions.
18:58 --> 19:00You know making sure that
19:00 --> 19:02they're really getting
19:02 --> 19:04a good dermatologic exam,
19:04 --> 19:05and staying out of the sun,
19:05 --> 19:07and so on and so forth.
19:07 --> 19:08But one of the questions that I
19:08 --> 19:11have is for some genetic mutation,
19:11 --> 19:15for example for the RET proto oncogene,
19:15 --> 19:18which predisposes to thyroid cancers,
19:18 --> 19:20these are things that newborn
19:20 --> 19:22babies have tested,
19:22 --> 19:23whereas other mutations like
19:23 --> 19:26BRCA for example is something
19:26 --> 19:28that we don't generally test
19:28 --> 19:30until you know somebody comes
19:30 --> 19:31up to us and says,
19:31 --> 19:33you know I have a family history of
19:33 --> 19:36breast cancer and so should I get tested.
19:36 --> 19:38Where does BRAF kind of
19:38 --> 19:40fit into the grand scheme of things?
19:40 --> 19:44It's less clear whether having
19:44 --> 19:46a pre-existing BRAF mutation
19:46 --> 19:49ultimately will induce cancer.
19:49 --> 19:51A lot of the times it doesn't,
19:51 --> 19:54and it's just something that we
19:54 --> 19:57pick up that's not prognostic or
19:57 --> 20:01indicative of any future malignancy.
20:01 --> 20:02It's really something that we
20:02 --> 20:04find later on once the cancer is
20:04 --> 20:06developed that we can potentially
20:06 --> 20:08target as an effective therapy.
20:08 --> 20:10And you mentioned, BRCA mutations
20:10 --> 20:13in a very small
20:13 --> 20:15subset of patients can
20:15 --> 20:17contribute to increased risk of
20:17 --> 20:20Melanoma as well as pancreatic cancer.
20:20 --> 20:22So really it depends on family
20:22 --> 20:24history and it really depends
20:24 --> 20:26on your personal history too.
20:26 --> 20:29If you have a patient with multiple
20:29 --> 20:31melanomas with a strong family
20:31 --> 20:33history of multiple immediate
20:33 --> 20:36kin with Melanoma cancers,
20:36 --> 20:38that's when we typically
20:38 --> 20:40flag and refer
20:40 --> 20:42these patients to genetic counseling
20:42 --> 20:45to see if there are indeed these
20:45 --> 20:47generalized mutations that predispose
20:47 --> 20:49these patients to developing Melanoma
20:49 --> 20:51as well as other malignancies.
20:51 --> 20:53And so it really has an
20:53 --> 20:54impact on family members,
20:54 --> 20:55particularly children.
20:55 --> 20:59When we see patients in the clinic,
20:59 --> 21:02we always counseled them about preventive
21:02 --> 21:05measures that they can do to limit
21:05 --> 21:08additional UV damage and sun exposure risk,
21:08 --> 21:09but also,
21:12 --> 21:13seeing the dermatologist regularly,
21:13 --> 21:16making sure that they have full
21:16 --> 21:17body skin exams and making sure
21:17 --> 21:19that their family and their next
21:19 --> 21:21of kin are also screened with
21:21 --> 21:24full body skin exams as well.
21:25 --> 21:28Sadly there isn't anything that we can
21:28 --> 21:31do that will kind of reverse that,
21:31 --> 21:33but certainly taking additional precautions
21:33 --> 21:36like all of us should be in terms of
21:36 --> 21:38avoiding sun exposure and wearing
21:38 --> 21:40sunscreen and avoiding tanning salons and
21:40 --> 21:42things like that are really good ideas.
21:42 --> 21:46I wanted to take us back to the
21:46 --> 21:48whole concept of brain metastases so
21:48 --> 21:51we know that Melanoma, as you said,
21:51 --> 21:53the incidence is increasing.
21:53 --> 21:55People are getting this as they get older.
21:55 --> 21:58But what proportion of patients with
21:58 --> 22:01Melanoma actually will get brain metastases?
22:01 --> 22:04So about 40% of patients with
22:04 --> 22:06advanced Melanoma at some
22:06 --> 22:08point get a brain metastasis.
22:08 --> 22:11Now, as we're using a lot of
22:11 --> 22:12better imaging modalities,
22:12 --> 22:14mainly MRI of the brain,
22:14 --> 22:17we're catching a lot of
22:17 --> 22:18asymptomatic brain metastases,
22:18 --> 22:19so these are very small
22:19 --> 22:22metastases that are not associated with
22:22 --> 22:24significant edema around them,
22:24 --> 22:25and so we're able to treat
22:25 --> 22:29these smaller metastases earlier so that
22:29 --> 22:32they don't later become a larger issue.
22:32 --> 22:35There's a lot of toxicity
22:35 --> 22:38related to symptomatic brain metastases
22:38 --> 22:40because the brain itself is,
22:40 --> 22:43you know, encased in a very thick
22:43 --> 22:45structural support system,
22:45 --> 22:46which is the skull,
22:46 --> 22:49and so there's not a lot of
22:49 --> 22:51room for any lesions to expand
22:51 --> 22:53or any swelling to occur,
22:53 --> 22:56and so you have a very finite
22:56 --> 22:57window to address growing
22:57 --> 23:00lesions in the brain and so that's why
23:00 --> 23:03we've come up with alternative and
23:03 --> 23:05adjunctive therapies to help achieve
23:05 --> 23:07local control in the brain better.
23:07 --> 23:09And that includes not in
23:09 --> 23:10addition to immune therapy,
23:10 --> 23:13but also adding radiation to that
23:13 --> 23:16plan to help boost that immune response.
23:16 --> 23:19I want to get to the
23:19 --> 23:21treatments and what we can do
23:21 --> 23:23about brain metastases in a minute.
23:23 --> 23:26But that 40% number,
23:26 --> 23:27that seemed high to me.
23:27 --> 23:30So is that 40% of people who present
23:30 --> 23:33with advanced Melanoma or any Melanoma? NOTE Confidence: 0.928736929523809
23:33 --> 23:34For example,
23:34 --> 23:36let's suppose you were going
23:36 --> 23:38to your dermatologist and you
23:38 --> 23:41know they happen to find a small
23:41 --> 23:43Melanoma on the back of your hand.
23:43 --> 23:46Would you automatically get a brain MRI and
23:46 --> 23:49is your risk still 40% of
23:49 --> 23:50getting a brain metastases?
23:51 --> 23:54No, just to correct that
23:54 --> 23:57number really only applies to
23:57 --> 23:59those with advanced Melanoma,
23:59 --> 24:01so Melanoma that has metastasized
24:01 --> 24:05to other areas of the body,
24:05 --> 24:06typically, for staging for Melanoma
24:06 --> 24:09we really rely on tumor thickness and
24:09 --> 24:12whether or not it's gone to lymph nodes.
24:12 --> 24:14When it's gone to the lymph nodes,
24:14 --> 24:16that makes you a stage three Melanoma
24:16 --> 24:18and at the initial visit we usually
24:18 --> 24:20scan the brain to just make
24:20 --> 24:22sure that it isn't a stage four
24:22 --> 24:24Melanoma that we aren't catching,
24:24 --> 24:27and under diagnosing what would
24:27 --> 24:30have been metastatic disease.
24:30 --> 24:33So that 40% really reflects those with
24:33 --> 24:35advanced disease that spread beyond
24:35 --> 24:38the lymph nodes to other distant sites.
24:38 --> 24:42Got it and so if you do have a brain
24:42 --> 24:44met it could be asymptomatic.
24:44 --> 24:47It could be picked up on an MRI or it
24:47 --> 24:50could be symptomatic at presentation.
24:50 --> 24:55Tell us a little bit more about how exactly
24:55 --> 24:59you treat these patients?
24:59 --> 25:03So if you presented with symptoms are
25:03 --> 25:06you likely to resolve those symptoms?
25:06 --> 25:08How good are our treatments?
25:09 --> 25:12The treatments themselves over the past
25:12 --> 25:16five years have just magically improved.
25:16 --> 25:18Not only do we have better systemic therapies
25:18 --> 25:21that we know are effective in the brain,
25:21 --> 25:25but we also are better at timing in terms
25:25 --> 25:28of when to go in and resect symptomatic
25:28 --> 25:32brain metastases or radiate them in
25:32 --> 25:35conjunction with her systemic therapies.
25:35 --> 25:36So, for example,
25:36 --> 25:39if a patient presents to the emergency room
25:39 --> 25:41with nausea, vomiting,
25:41 --> 25:43some dizziness and balance issues,
25:43 --> 25:46they get a brain scan in the emergency room
25:46 --> 25:49are found to have new lesions in the brain,
25:49 --> 25:52if those lesions are large and associated
25:52 --> 25:55with significant edema, and that is
25:55 --> 25:56what's contributing to the symptoms,
25:56 --> 25:59oftentimes we have to get our
25:59 --> 26:01neurosurgery colleagues involved to
26:01 --> 26:03rapidly address that lesion and
26:03 --> 26:06the most rapid way is via surgery.
26:06 --> 26:08You know, it's a morbid procedure,
26:08 --> 26:09but the outcomes are typically
26:09 --> 26:11very good and people have
26:11 --> 26:13a very fast recovery.
26:13 --> 26:15If, for example,
26:15 --> 26:19the lesion is amenable to what we
26:19 --> 26:21call stereotactic radiosurgery,
26:21 --> 26:23which is very high radiation but
26:23 --> 26:26very focused radiation to try to
26:26 --> 26:28spare the normal surrounding brain
26:28 --> 26:30tissue and therefore limit the side
26:30 --> 26:32effects of radiation in the brain,
26:32 --> 26:36that itself is also a very effective therapy.
26:36 --> 26:38It's considered definitive, however,
26:38 --> 26:40it can only really be treated
26:40 --> 26:44for lesions that are less than 3 centimeters,
26:44 --> 26:45if you have a lesion greater
26:45 --> 26:46than 3 centimeters,
26:46 --> 26:48surgery is the best option.
26:48 --> 26:50If you have multiple lesions,
26:50 --> 26:52basically multiple small lesions,
26:52 --> 26:56too many to be individually treated
26:56 --> 26:58with what we call stereotactic
26:58 --> 27:00radiosurgery or gamma knife,
27:00 --> 27:03then the next option is whole
27:03 --> 27:06brain radiation which used to be very
27:06 --> 27:09neurotoxic long term because these patients
27:09 --> 27:13would develop cognitive decline later on.
27:13 --> 27:16Memory issues very similar to dementia.
27:16 --> 27:18Nowadays we have additional options
27:18 --> 27:21where we can spare the hippocampus.
27:21 --> 27:23This learning and memory center
27:23 --> 27:26in our brain and so we can try to
27:26 --> 27:28avoid some of these late chronic
27:28 --> 27:30sequella of radiation therapy.
27:30 --> 27:32Other options are to actually use some
27:32 --> 27:35of the drugs that have been known to be
27:35 --> 27:37effective in treating Alzheimer's patients
27:37 --> 27:40while they get whole brain radiation to try
27:40 --> 27:43to have a neuroprotective effect to spare
27:43 --> 27:45the normal brain from receiving
27:45 --> 27:48some of the detrimental long
27:48 --> 27:50term side effects of radiation.
27:51 --> 27:53I mean it sounds like there's
27:53 --> 27:55a lot of potential for
27:55 --> 27:57therapies for brain metastases,
27:57 --> 28:00but just in our last 30 seconds.
28:00 --> 28:02So if you have a brain
28:02 --> 28:04metastasis and it's been treated,
28:04 --> 28:06what's your overall prognosis?
28:06 --> 28:08So we're finding with the combination
28:08 --> 28:11of radiation and immune therapies,
28:11 --> 28:13prognosis can be actually very good.
28:13 --> 28:16Before it was three to six months
28:16 --> 28:18for anyone with brain metastases.
28:18 --> 28:20Now we're talking years out.
28:20 --> 28:22If you have a tumor that
28:22 --> 28:23responds to these treatments,
28:23 --> 28:26and so the overall survival,
28:26 --> 28:28the prognosis is much more bright
28:28 --> 28:30than what it was ten years ago.
28:31 --> 28:33Doctor Thuy Tran is an instructor
28:33 --> 28:34of medicine in medical oncology
28:34 --> 28:36at the Yale School of Medicine.
28:37 --> 28:38If you have questions,
28:38 --> 28:40the address is cancer answers at
28:40 --> 28:43yale.edu and past editions of the
28:43 --> 28:45program are available in audio and
28:45 --> 28:47written form at yalecancercenter.org.
28:47 --> 28:49We hope you'll join us next week to
28:49 --> 28:51learn more about the fight against
28:51 --> 28:53cancer here on Connecticut Public
28:53 --> 28:55radio funding for Yale Cancer
28:55 --> 28:56Answers is provided by Smilow
28:56 --> 29:00Cancer Hospital and AstraZeneca.

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October 3, 2021

Yale Cancer Center

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