Triple Negative Breast Cancer (TNBC)

Name: Triple Negative Breast Cancer (TNBC)
Uploaded: 2024-10-08T17:30:19.3733333Z
Duration: 29 min 22 s

October 08, 2024

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ID: 12185
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04:24Wait. That would be all
04:25just
04:27Okay. Good. Great. Thank you.
04:31So here's this is one
04:32of these slides that I
04:33think doctor Weiner was warning
04:34us about,
04:36early in his talk. Since
04:37the problem with triple negative
04:39breast cancer is it's a
04:40much more aggressive cancer on
04:42average.
04:42And people with triple negative
04:44breast cancer don't do as
04:45well as people who don't
04:46have triple negative breast cancer
04:47in the long run. It's
04:48largely because
04:50our treatments aren't as good.
04:51We don't have as many
04:52treatments, but also
04:54the cancer itself is much
04:55more aggressive.
04:58And now I can't advance
04:59my slides.
05:01Fantastic.
05:02I'm gonna get them.
05:05Stop. Moral of the story
05:06like, there's stagnation.
05:08Moral of the story is
05:10that we really need better
05:11therapies,
05:12especially for this more aggressive
05:14subtype of cancer.
05:17So we talked about hormone
05:19based therapies. There are HER2
05:20based therapies, but in triple
05:21negative breast cancer, we can't
05:23use them. And what we've
05:24got is chemotherapy.
05:26And so chemotherapy is the
05:27backbone of the treatment for
05:29triple negative breast cancer. And
05:30there are a lot of
05:31them. There's a huge arsenal
05:33of chemotherapy,
05:34but as you probably know,
05:36chemotherapy
05:37has a lot of potential
05:38side effects. It can be
05:39pretty toxic.
05:41It can affect almost any
05:43part of the body,
05:45from the brain all the
05:47way down to the bones
05:48and the skin and the
05:49muscles,
05:51and in anything in between.
05:54It's inconvenient.
05:55It requires,
05:56in most cases,
05:58IV treatments that people have
06:00to come in to clinic
06:01and infusion to get those
06:03treatments. That can be a
06:04problem for child care. It
06:06can be a problem for
06:07transportation.
06:10And if you have to
06:11get repeated IV therapies, that
06:13can affect your blood vessels,
06:15which makes it very difficult
06:16to even give blood or
06:18get blood for for blood
06:19tests.
06:21People can't work as much
06:23if you have to come
06:23in all the time for
06:24treatments, and that can lead
06:26to financial toxicity or or
06:28financial problems. And and all
06:30kinds of effects on mental
06:32health have been described over
06:33time.
06:34And this is work that
06:35I've done,
06:37now a while back twenty
06:38nineteen. It's pre COVID, like,
06:40a whole different lifetime.
06:42But what we know is
06:43that more than half of
06:44patients report difficulties with nonphysical
06:47concerns. So I think when
06:49you think about chemotherapy, you
06:50think about nausea, and you
06:52think about all of the
06:52physical side effects, but there
06:54are all kinds of other
06:55things that this sort of
06:56treatment impacts.
06:58I'm just trying to make
06:59the case that we need
07:00better therapies.
07:03So
07:04you have likely heard of
07:06this concept of immunotherapy,
07:08which is
07:10the latest and greatest in
07:11all kinds of cancers that's
07:12used in lung cancer and
07:13melanoma and bladder cancer and
07:15renal cell cancer. And it's
07:17kind of all over all
07:18the the
07:19lay press in terms of
07:20cancer treatments. Well, what is
07:22it?
07:23Immunotherapy
07:25takes the brakes off the
07:27immune system.
07:28So immunotherapy,
07:32when when there is an
07:33immune cell, and in this
07:34case, this is an immune
07:35t cell,
07:37the cancer cell
07:38comes along and kind of
07:40tells the t cells to
07:41stop working.
07:43It puts the brakes on
07:45the the immune system. So
07:46the immune system is not
07:47fighting the cancer. But these
07:49immunotherapies
07:50and here I've listed some
07:51here. We call them checkpoint
07:52inhibitors or immunotherapies or immuno
07:54oncologics.
07:57They
07:58put they they take the
07:59brakes off. So they allow
08:01the the immune system to
08:02kind of get back in
08:04gear and fight the cancer
08:06and start attacking the cancer
08:07cells. So it's harnessing the
08:09own power
08:10of your of a patient's
08:12own immune system to help
08:13combat the cancer.
08:16And we
08:18now are using immunotherapy
08:20as part of the standard
08:21of care for treatment of
08:24patients that have triple negative
08:25breast cancer.
08:27And this is,
08:29a slide from
08:30the initial presentation of a
08:32study called the keynote three
08:33fifty five study.
08:35Keynote,
08:37is a a series of
08:38studies that studied Keytruda, very
08:40cleverly named, and they're like
08:42a thousand of them. I
08:43only have I only know
08:44a couple. I only need
08:45to know a couple, but
08:46there are a whole bunch
08:47of them. But this is
08:48keynote three fifty five. And
08:49what it showed was that
08:51when we add the drug
08:52Keytruda
08:53to chemotherapy,
08:55we actually
08:57pro that that combination
08:59prolongs the time that patients
09:01can stay on those treatments
09:03and prolongs the time to
09:05the cancer growing and having
09:07to switch therapies
09:08from
09:09and
09:10furthermore, it actually prolongs how
09:13long people live.
09:15And in this case, it
09:16was in the the three
09:18fifty five study, it was
09:19a difference in overall survival
09:20of seven months.
09:24And what we
09:25when when the the people,
09:27the very smart people, not
09:28me, very smart people,
09:30did
09:31these studies,
09:33they found that the particular
09:34people who benefit
09:36were people who have certain
09:37levels of a of a
09:38protein called PDL one.
09:42So immunotherapy
09:43is kind of the latest
09:44and greatest. Yes, please. Great
09:46question.
09:48So
09:49people with higher levels of
09:51PD L1 benefit More. More.
09:54Mhmm. People with lower levels
09:56of PD L1 benefit a
09:57little bit?
09:59They they the cutoff of
10:00this
10:01it's a special test called
10:03the CPS
10:04where the cutoff is ten.
10:05People who had a CPS
10:06of less than ten did
10:07not seem to benefit,
10:09which is unfortunate.
10:11But
10:12I'll I'll kind of direct
10:13you to
10:14our next talk after this,
10:16which is from doctor Khan,
10:17who's gonna be talking about,
10:20phase one and early phase
10:21clinical trials. That doesn't mean
10:23that they may not benefit
10:24from some other combination
10:26of immunotherapy plus another drug
10:29or some other
10:30creative,
10:32approach
10:32to kind of using the
10:34immune system to target triple
10:35negative breast cancer. And we've
10:37got trials that are looking
10:38at that, and I bet
10:39you're gonna talk about it
10:40more. Yes.
10:42Is that CPS ten the
10:43same as the blood tumor
10:45burden?
10:46Oh, great question. Great question.
10:48It's not. So
10:50the CPS is looking specifically
10:53at PD L1,
10:55which is
10:56when we think about,
10:58the immune system interacting with
11:00cancer cells, there's an interaction
11:02between a protein called PDL
11:04one and PD one. That's
11:06Lynn.
11:07So they're looking for a
11:08specific marker
11:10on the cancer.
11:12Tumor burden or,
11:15circulating tumor DNA. Is that
11:17I think because there's The
11:18one in the blood. The
11:19one in the the one
11:20in the blood. There are
11:21a lot of different blood
11:22tests that we can do,
11:23but certain Foundation.
11:24But found so foundation is
11:26one thing. Signatera is another.
11:27Let's talk about both.
11:30Sign so foundation,
11:34is a blood test that
11:37looks at the DNA
11:39of the cancer
11:41and what are the mutations
11:43inside that DNA. What is
11:44making cancer cancer?
11:46So
11:48cells are normally controlled by
11:49your DNA.
11:50And and
11:52under normal circumstances,
11:53normal DNA, it makes proteins
11:56and cells grow
11:57and stop growing in a
11:59regulated fashion.
12:01But when you've got abnormal
12:03DNA, there's a mutation.
12:05That's one of the things
12:06that can make cancer cancer.
12:07So you're looking for specific
12:09mutations in genes
12:12of the of the cancer
12:13cell itself.
12:14And why do we do
12:15that? Well,
12:16we actually have some drugs,
12:18not necessarily in too much
12:20in my talk today, but
12:21in other other talks and
12:23certainly in doctor Khan's world,
12:25where when we see certain
12:26mutations,
12:28it may suggest
12:29that we have a drug
12:30that can target that mutation,
12:32which is one of the
12:33reasons why we check foundation.
12:35There's another test called Signatera,
12:37which is looking just at
12:39circulating tumor DNA to
12:42to kind of give us
12:43a sense of how much
12:44cancer is around.
12:47Not usually used too much
12:49in this in this, scenario.
12:54Other questions? Oh, yeah. Great.
12:56On a prior slide, you
12:57had no other immunotherapies
12:59listed. Are those all
13:01cheap, using standard of care,
13:03or is it just the
13:03intruder?
13:05In terms of standard of
13:07care for breast cancer Triple
13:08negative. For triple negative breast
13:10cancer and breast cancer in
13:12general, but triple negative breast
13:13cancer, Keytruda is the only
13:15one that's approved right now.
13:17The drug Tecentriq or atezolizumab
13:19was approved a while back,
13:21but that FDA,
13:23indication got pulled.
13:25The others are all FDA
13:27approved and are being studied.
13:29There have been studies that
13:30have been looking at,
13:32nivolumab and evolimumab, Mopdevo, Nirvoy.
13:35There are an, we have
13:36a number of studies
13:38that look at durvalumab,
13:40or in
13:43school names these things. I
13:44know. Infinzi.
13:47Sometimes it's harder than the
13:50brand name's harder
13:51than the generic. There's a
13:52funny formula about how they
13:54come up with these. It's
13:55three zero four syllables, and
13:56it can't sound like another
13:58drum. That's right. And I
13:59think they get bonus points
14:00if they have q's and
14:01z's.
14:04So,
14:06anyway, the, so it's just
14:08heat treated as z's. So
14:10what is the to determine
14:12the PDL?
14:13Because I thought that was
14:14tumor burden.
14:16Yeah.
14:17PDL
14:19is not tumor burden. Tumor
14:20burden kind of speaks to
14:23the volume of
14:25of cancer. Feel free. If
14:26you if you have a
14:27a better way of explaining
14:28what it is, please chime
14:30in.
14:33PDL is a it's measuring
14:35whether a protein is present
14:37on the tumor cells, so
14:38not how much cancer there
14:40is. What'd you say the
14:41test was for that CSP?
14:42It's CBS. It's the
14:46CBS tamper. Combine
14:48Combined. Prob
14:50prob prognostic store, prob prob
14:52something like that. Okay. It's
14:54a special it it's a
14:55test,
14:56that looks at how much
14:59is there and then what
15:00strength,
15:01is a particular,
15:05branded test that's associated
15:07with the key truth, and
15:08they were kind of approved
15:09together. I can try to
15:11do it maybe in a
15:11different language just to see
15:12if Yeah. So the the
15:14Portuguese. The
15:16cps or PDL one testing
15:18or or PD one test.
15:20So those the pathologist, which
15:22is the doctor that has
15:23a microscope,
15:24they get a piece of
15:25the tumor, they slice it,
15:27They get it into his
15:28face. He puts this dye,
15:30like, PDL dye, and then
15:31he throw throws it. And
15:33then if he does have
15:34those receptors get in the
15:36dye, he catches it. And
15:37then when he looks into
15:38the microscope, he says, oh,
15:39I see everything is kind
15:40of lining up from this
15:41PDL one receptor.
15:43That's a test that is
15:44easier or easy easily done
15:46in the hospital. Okay? Pathologists
15:48can put it in the
15:48microscope, throw the dye, and
15:50see if it catches it.
15:51And then it looks to
15:52see, do you have those
15:53markers that are gonna show
15:55that the immune cells are
15:56gonna engage with the cancer
15:57cells and and that some
15:58Higgs and Mel was more
16:00shown to work.
16:01That is the CPS combined
16:03positive score or the PDL
16:04one hundred and ten, and
16:05that's all under just a
16:06microscope.
16:07Then we have the tumor
16:08mutation BERT. Remember she was
16:10talking about the how the
16:11tumor is made and this
16:12DNA code. So I think
16:13of that as like a
16:14barcode. You have a barcode
16:16at the grocery store. You
16:16read it. It tells you
16:17something. That's how we know
16:19the cancer cells has it's,
16:20like, all of the bunch
16:22of random letters and codes
16:23that that turns into some
16:25sort of message
16:26that can be read. If
16:27you have a lot of
16:28changes in the barcode, like
16:29the barcode is all, like,
16:31full of mistakes,
16:32that's what they call mutation
16:33burden. How many mutations do
16:35you have? Just one mutation
16:36or have thirty mutations?
16:38And then that is something
16:39that they see when they
16:40read a whole DNA barcode
16:42of this cancer, which is
16:43the foundation test. That's a
16:45more expensive fancier test. They
16:46need to look at the
16:47coding on both the cancer.
16:49And then they say, I
16:50have a few mutations. Your
16:51tumor mutation burden is gonna
16:52be low. If you have
16:54a ton of different mutations
16:55in the barcode is full
16:56of mistakes, then the tumor
16:57mutation burden is high.
16:59And that's another marker for
17:00immunotherapists to work. Immunotherapists
17:02like tumors that have a
17:04ton of mutations that look
17:05gangrier and then immune cells
17:07can recognize that better and
17:08cure. And the cutoff is
17:10interestingly and confusingly the same.
17:12So cps of ten and
17:14tumor mutation burden of ten,
17:16both have two totally different
17:18tens, but the number is
17:20the same. But if you
17:21have a TMD, your tumor
17:22mutation burden higher than ten,
17:24mutations per megabase of the
17:26DNA reading, then you can
17:28get Keytruda regardless of your
17:30tumor type. If you have,
17:32CVS or PDL one ink
17:34test that is super inky,
17:36like, super positive and colorful,
17:39more than ten,
17:40then you see they also
17:41can benefit from the case
17:42scenario. So it's just different
17:44tests, but that ten to
17:45ten makes things confusing.
17:47Thank you for that clarify.
17:48I'm sorry. I'm gonna cut
17:49you off because we got
17:49nothing here. But, no, thank
17:50you for
17:51thank you for the clarification.
17:52I was there was a
17:53disconnect there. So you totally,
17:55I think, answered the question
17:56much better than I did.
17:57So thank you for being
17:58here.
18:01The, the really quickly because
18:03we're down to eight minutes.
18:05I I suspect that Renee
18:06is gonna come in and
18:07tell us that we have
18:08to stop. But,
18:10lots of people,
18:12with triple negative breast cancer,
18:14higher percentage than people without
18:16triple negative breast cancer, have,
18:19a a mutation in the
18:20genes BRCA one or b
18:22r BRCA
18:23two.
18:24And those folks can develop,
18:26have a very high chance
18:27of developing breast cancer in
18:28the lifetime in their lifetime.
18:30And in triple negative breast
18:32cancer, it makes up about
18:33almost a quarter.
18:37BRCA
18:38leads to lots of errors
18:40in DNA replication. That's kind
18:42of how cancer is formed,
18:44and I'm not gonna get
18:45too much into why
18:47like, how this happens.
18:50But people who have BRCA
18:52one and BRCA two mutations,
18:55cancers,
18:56associated with those mutations are
18:58very sensitive to drugs called
19:00PARP inhibitors. So we use
19:01PARP inhibitors a lot
19:03in people, with these types
19:05of mutations and particularly,
19:07in people with breast cancer,
19:09triple negative breast cancer.
19:11The pill, generally well tolerated,
19:13and and it's an yet
19:15another
19:16drug that we can put
19:17in the arsenal against this
19:19cancer.
19:20And, again,
19:21these are these are called
19:22Kaplan Meier curves. If you've
19:24not seen these, basically, it
19:25tells us
19:26what what's happening with patients
19:28on the y axis and
19:30how long out,
19:32we go. And the longer
19:34this tells us how many
19:35patients are alive in a
19:37big clinical trial and duration
19:39so that you want the
19:41curves to be as flat
19:42as possible. So a curve
19:44that comes in that's a
19:45little much shallower is better
19:46than a curve that drops
19:48off.
19:49But this tells us these
19:51these curves, these graphs are
19:52telling us that the drug
19:54olaparib in the top and
19:56the drug talozaparib
19:57in the bottom,
19:58both are very effective or
20:00more effective
20:01in people with BRCA mutations
20:03than not using these drugs.
20:07There's another really cool class
20:09of medications called antibody drug
20:09seeking missiles because they're antibodies,
20:10which are looking for a
20:11particular protein.
20:22They attach to a particular
20:23protein, but riding along with
20:25the with the antibody
20:27is a drug.
20:29And
20:30so when the antibody finds
20:32the tumor antigen that it's
20:33looking for, it delivers the
20:35chemotherapy drug right to that
20:37area.
20:38So it's it's,
20:40a very
20:41exciting,
20:44group of drugs. We've got
20:45a couple of them in
20:46breast cancer,
20:48that we use very routinely.
20:52In fact, the first antibody
20:54drug conjugate,
20:55was
20:56in breast cancer was approved
20:58for people with triple negative
20:59breast cancer. This is a
21:00drug called sacituzumab,
21:02or Trodelvie is the other
21:03name.
21:05And it was based on
21:06a a phase three
21:08large clinical trial of five
21:10hundred and thirty patients and
21:11found that people who received
21:13sacituzumab,
21:15or TRODELV
21:16did better
21:17than people who had just
21:19single agent regular chemotherapy
21:22that's really nonspecific.
21:24So where are we moving?
21:26You've got a we've got
21:27to fine tune our treatments
21:29for metastatic triple negative breast
21:31cancer.
21:32So everybody with metastatic triple
21:34negative breast cancer gets genetic
21:36testing.
21:37What's the DNA that they
21:38are born with?
21:40We're looking for BRCA one,
21:42BRCA two mutations as well
21:44as some other mutations
21:45that might suggest
21:47that people would respond to
21:49a PARP inhibitor.
21:51We're looking at PD L1
21:52status, which we've we've talked
21:54about. We look at HER2
21:56status.
21:56So even though triple negative
21:58breast cancers by definition
22:00are HER2 negative,
22:03There is a class of
22:05HER2
22:06low, which I'm not gonna
22:07get into, but
22:09depending on if patients have
22:11a little bit of HER2
22:13expression, they could benefit from
22:15this drug called nHER2, which
22:16you may have heard about.
22:18We also look at mutational
22:20burden. We look at deficient
22:22mismatch repair, microsatellite instability. These
22:24are all markers of
22:26lots of mutations,
22:28that suggest that those patients
22:30may benefit from drugs like
22:32Keytruda.
22:33And then more genomic and
22:35molecular pro profiling like foundation
22:37to see if the if
22:39patients are eligible for,
22:41importantly, clinical trials, but there
22:43are other couple of other
22:45mutations that we look for
22:46that we have specific drugs.
22:50This is a really complicated
22:51slide that I probably can't
22:52explain,
22:53give it and give it,
22:55the the explanation that it
22:57deserves.
22:58But this is a map
23:00of all of the different
23:01pathways that are that are
23:04used in some cancers, and
23:06it's not even all of
23:06them, it's just some of
23:08the pathways.
23:09And these red lines with
23:11the kind of stop sign,
23:12these are the drugs that
23:14we have that are either
23:15in development or approved already
23:18that
23:19may
23:20work against those particular proteins
23:22and and pathways.
23:24These are all it's
23:25cell growth is a series
23:27of light switches, and it's
23:29like a circuit, and you
23:30gotta block the circuit in
23:31order to tell certain in
23:33order to tell cancer cells,
23:36to to stop growing.
23:38So I know I told
23:39you that I didn't change
23:40any any of the the
23:42slides. This is Eleanor.
23:44She had her biopsy. It
23:46confirmed that she had metastatic
23:48breast cancer.
23:49She did we did check
23:50her PDL one, and it
23:52did come back positive,
23:54greater than ten.
23:56And so she started on
23:58chemotherapy
23:59with Keytruda.
24:01And you can see that
24:03spot in the liver, that
24:04dark area of the liver,
24:06just the the whole thing
24:07on the on the left
24:08side there.
24:09And her most recent scans
24:12show
24:13almost a complete resolution of
24:14metastatic lesions. So she's basically
24:17got no evidence of cancer
24:19on her scans,
24:21and then we dropped the
24:22chemotherapy. She's been hanging out
24:24on Keytruda. This is her
24:26most recent liver scan. Well,
24:27no. This was her most
24:28recent liver scan last year.
24:29So her her scan this
24:30year looks exactly the same.
24:33But
24:34that that cancer has completely
24:37resolved on the CAT scan.
24:38She's doing great. She has
24:40a man friend. She won't
24:41call him a boyfriend,
24:43because he's a man.
24:45And she retired from her
24:47job. She sees her friends.
24:48She goes to visit her
24:49family in Portland,
24:51multiple times a year, and
24:53they're going to the Caribbean.
24:54They go someplace fantastic every
24:56year with her man friends.
24:57So she's, like, living her
24:59best life.
25:01And it's it's it's just
25:03one of the success stories
25:05that I
25:06think, you know, she is
25:08really enjoying every day.
25:10She's been living with metastatic
25:11triple negative breast cancer now
25:13for over three years
25:15doing fantastic, and I don't
25:16see that changing anytime in
25:18the near future. And,
25:20hopefully, by if if her
25:21cancer ever does
25:23make an appearance again, we'll
25:25have even more exciting options
25:27for.
25:29That is
25:30it is time to see
25:32on the dot. I wanna
25:34exercise it.
25:36What
25:37can I answer other questions?
25:41Anything else kind of come
25:42up
25:43in this yes, please. Asking
25:45for in folks who have
25:46the aesthetic look at
25:49does the KEYTRIA work better
25:50if it's in different parts
25:52of the body? You know,
25:53liver versus lung versus brain?
25:56Bones, you know.
25:58I I don't I am
25:59not aware of any data
26:00that suggests that it does
26:02work better in any particular
26:04part of the body,
26:07with the exception of it
26:08doesn't get to the brain
26:10all that well.
26:12And some of these drugs
26:13do penetrate
26:15what we call the the
26:16blood brain barrier
26:18better than others. And and
26:19Keytruda is a big drug,
26:21It's a big antibody, so
26:22it doesn't penetrate as well.
26:26In my experience, people
26:29people with bone only disease,
26:31and triple negative breast cancer
26:33don't tend to respond as
26:34well, but they also don't
26:35tend to be CVS positive.
26:37So it's again, even triple
26:39negative breast cancer is
26:41a spectrum
26:43of diseases with not everybody's
26:45cancer behaving exactly the same
26:47way.
26:51So if it's bone and
26:53then it's hard to do
26:54the test on
26:55bone biopsies
26:56Yes. So you kinda have
26:58to keep repeating, you know,
26:59if it's just only your
27:00bone and it spreads around.
27:02Yes. And so bone only
27:05cancer is challenging for a
27:06number of reasons. It's a
27:07little bit harder to follow
27:09on scans, and
27:11you you may be there
27:12are PET scans and bone
27:13scans and CAT scans, and
27:15then they don't always,
27:18follow the disease activity for
27:20one. Second is biopsies are
27:22challenging because you've gotta get
27:24to the bone, and then
27:25it has to be decalcified.
27:26And and sometimes you can
27:28lose some diagnostic material
27:30in that process.
27:33But oftentimes,
27:34because people with breast cancer
27:36do well for a long
27:37time
27:38and the mutation
27:40the mutational profile can change
27:42over time,
27:43people can develop new things,
27:44we do biopsy
27:46sometimes people
27:47multiple times throughout the course
27:49of their their treatment to
27:50see if
27:52there's something new that's developed
27:54over time because cancers can
27:56develop resistance to things and
27:59create new mutations and and
28:01that all of a sudden
28:02we may have a new
28:02drug
28:07for. Yeah. Is there a
28:08concern of,
28:11of number of scams that
28:12a person a patient should
28:14be subject to?
28:16There's always kind of that
28:17concern about radiation exposure and,
28:19you know, are we scanning
28:21somebody too often or not
28:22often enough?
28:25And I think there's no
28:27standard answer to that question
28:29because every patient's different.
28:32And sometimes
28:34we do need to scan
28:35someone every six weeks or
28:37two months because we're really
28:39looking for a particular we're
28:41we're watching them very closely.
28:42Other times, we might do
28:43it less frequently.
28:45There's certainly financial considerations as
28:47well and
28:49and convenience considerations.
28:50So there's no
28:52set answer to that. Typically,
28:54we do something every three
28:56months,
28:59subject to change depending on
29:00a patient's particular situation.
29:05Thank you all so much
29:07for being here.
29:09I really I appreciate the
29:10questions. I'm sorry for the
29:12miss
29:13my my lack of understanding
29:15earlier questions, but,
29:18please don't hesitate to reach
29:20out if other things come
29:21up. My
29:22ask your