The Second Century in the Land of Small Tumors

Transcript

• 00:00Good afternoon, everybody.
• 00:01I think we'll go ahead and get started.
• 00:03So greetings to everybody in
• 00:05the room and to everyone online.
• 00:08And welcome to Yale Cancer Center,
• 00:10Grand Rounds. My name is Pam Koons.
• 00:12I'm the director of the
• 00:13Center for GI Cancers,
• 00:14for those of you who do not know me.
• 00:16And it is a great honor to introduce
• 00:19my friend Doctor James Yao as the
• 00:22Norbert Schnog Endowed Lecturer.
• 00:23So Doctor Yao is a Professor and
• 00:25Chair in the Department of GI
• 00:28Medical Oncology at the University
• 00:30of MD Anderson Cancer Center,
• 00:32and he received his medical degree
• 00:34from Baylor College of Medicine and
• 00:37completed his fellowship at MD Anderson.
• 00:40So for the last two decades, Dr.
• 00:42Yao and colleagues have really transformed
• 00:44the field of neuroendocrine tumors.
• 00:46So that is how I know him and he has led
• 00:50practice changing randomized clinical trials,
• 00:53specifically the family of radiant clinical
• 00:56trials that include the drug everolimus
• 00:58that led to FD approvals for pancreatic net,
• 01:02lung net and GI and undercon tumors.
• 01:05Doctor Yeah,
• 01:05I was also a strong advocate
• 01:07of mentoring and education.
• 01:08He is a founding member and past
• 01:10chairman of the North American
• 01:12Neuroendocrinic Tumor Society of which
• 01:14I am the president of this year.
• 01:16And then through that society can helped
• 01:19establish two young investigator awards
• 01:21that fund early career investigators.
• 01:23He's also the past chair of the
• 01:25NCIA and under consumer task force.
• 01:27And during his tenure,
• 01:29early career and female investigators
• 01:31led more than 50% of the multicentered
• 01:33clinical trials developed through
• 01:35that net task force.
• 01:36I've known doctor Yes since I was a fellow.
• 01:40I am one of those early career
• 01:42investigators who benefited from his
• 01:43mentorship and scholarship and had
• 01:45the opportunity to lead one of the
• 01:47randomized trials through the net task force.
• 01:49So I'm grateful for you coming today
• 01:52and joining us to speak on the 2nd
• 01:54century of the land of small tumors.
• 01:56So thank you,
• 02:02Thank you so much for that kind introduction
• 02:05and very glad to be here with you today.
• 02:07So today I'm going to talk a little
• 02:10bit about your endocrine tumors,
• 02:12where we've been and some of the challenge
• 02:15remains and for you know what we need to.
• 02:18Make the next century even better
• 02:20than the what we've done so far and
• 02:24it's a plug for nanettes this this
• 02:27rainbow at this photograph was from
• 02:29one of the nanettes meetings which
• 02:31we held at the at the the Grand Tea
• 02:35Towns National Park and let's see
• 02:42here's my disclosures.
• 02:44So the field of neuroendocrine tumor
• 02:47started with open door for first
• 02:50described this entity about in 1907 he
• 02:53described this group disease is cancer
• 02:56like or part of what tumors are more slow
• 03:00growing than the typical carcinomas.
• 03:03The 1st century of net has been a a
• 03:06century where we've learned a lot about
• 03:08the Natural History of the disease.
• 03:10Understand a lot of the endocrine
• 03:13manifestations of neuroendocrine tumors
• 03:15and we also learn a lot about epidemiology
• 03:19of disease in semester biology.
• 03:22However, the number of therapeutic
• 03:25introduced over this period is
• 03:28actually relatively sparse prior to I
• 03:32would say the more recent approvals.
• 03:35There was only one drug that was FDA
• 03:37approved for oncologic control and that
• 03:40streptosis dosen for pancreatic net.
• 03:43There were two drugs approved for hormonal
• 03:46control of the neuroendocrine tumors.
• 03:51This is certainly not for lack of effort.
• 03:54This is a classic lecture by Chuck
• 03:57Mortell where he talks about his
• 03:59odyssey in the land of small tumors as
• 04:01you can see on the table on the right.
• 04:03There's been numerous agents that
• 04:06were studied but these chemotherapy
• 04:09agents did not really have that
• 04:11much activity with the exception of
• 04:15DTIC and streptozosin in pancreatic
• 04:19neuroendocrine tumors.
• 04:20Another thing you'll see is that
• 04:22that because you know this disease
• 04:24was thought to be rare and he that's
• 04:27why he used the the the term land
• 04:30of small tumors.
• 04:31The studies were actually very small and I
• 04:35think that really limited the the progress.
• 04:38These were all single arm studies
• 04:40and some of them only containing
• 04:42less than a handful of patients.
• 04:48So one of the first things I think we
• 04:50needed to understand about neuroendocrine
• 04:52tumors is that the disease is probably
• 04:55actually more common than we think.
• 04:57One of the analysis we did in from
• 05:00the SEAR database and we showed that
• 05:04comparing to other malignant neoplasms
• 05:07diagnose incidence of neuroendocrine
• 05:09tumor is continually rising and since
• 05:12this we have a kind of updated the data
• 05:15and in you know when when it was in 2004
• 05:20the incident was about 5 per 100,000,
• 05:242012 about the.
• 05:267 to per 100,000 and more more
• 05:29recent data would happen publish
• 05:32it is well above 8 per 100,000.
• 05:35Another thing that's different about
• 05:37this disease is because the disease
• 05:39is more slower growing patient live
• 05:41a lot a lot longer with the cancer.
• 05:44So essentially the prevalence
• 05:46statistic which is the number of
• 05:49patients who are potentially in
• 05:51need of care because there are life
• 05:53with disease is actually higher.
• 05:55So if you did limited duration
• 05:58prevalence analysis which we did from
• 06:00the SEAR data it the US prevalence
• 06:03last we looked was above 170,000.
• 06:06So certainly this is still at least
• 06:10for the moment below the 200,000 cut
• 06:13off which the FDA uses this definition
• 06:17of rare disease and certainly if you
• 06:19further divide you're in the consumer
• 06:22into a subtypes that will remain.
• 06:24Rare for quite a quite a long time.
• 06:27So one of the question to think about is,
• 06:30was this rising incidence and so
• 06:32forth is what's going on here.
• 06:35There are environmental factors that
• 06:37are increasing the incidence of
• 06:39neuroendocrine tumor or perhaps this is
• 06:42just better recognition of the disease.
• 06:45Certainly we are seeing more
• 06:47neuroendocrine tumors in some case
• 06:50related in the gastric urine the consumer.
• 06:53Related to use of PPI's,
• 06:56but I think for the most part these
• 06:59neuroendocrine tumor has always been there.
• 07:01So here are a couple of classic
• 07:03studies in two in,
• 07:04in,
• 07:05in Carcino tumors are really talking
• 07:08about intestinal neuroendocrine
• 07:10tumors are two studies that included
• 07:1215,000 autopsies and these tumors
• 07:15are found in about 1% of autopsies.
• 07:18So these are patient who died
• 07:21from unrelated causes.
• 07:23And most mostly lift out their natural
• 07:26lifespan without having them diagnosed.
• 07:29So really the question is not so
• 07:31much whether they're increasing in
• 07:35and what are environmental factors,
• 07:37but what transforms some of these nine
• 07:40small tumor into malignant ones but
• 07:43pancreatic neurin different tumors.
• 07:44There's one study that was in Hong Kong,
• 07:47again 11,000 autopsy one in 1000.
• 07:51Autopsy specimen had a pancreatic urine.
• 07:53The consumer,
• 07:54if you look for them compare this
• 07:57to a diagnosed instance more like
• 07:59in the range of maybe three to five
• 08:02per million per year.
• 08:04That tells you probably less than
• 08:071% of pancrea and urine.
• 08:09The consumers that are present
• 08:12and in patients eventually become
• 08:15clinically relevant.
• 08:16This is posing a challenge for
• 08:18us as we move forward.
• 08:20Because the increased use of
• 08:23imaging nowadays you can hardly
• 08:25go to the ER with abdominal
• 08:27pain without leaving the ER with a CT scan.
• 08:30So we're finding a lot of small tiny
• 08:33pancreatic neuroendocrine tumors,
• 08:35some of them in the head of pancreas
• 08:38where if you try to operate on them may,
• 08:41may, may be a quite a morbid
• 08:43and higher risk procedure.
• 08:44So understanding which of these can be
• 08:47left alone and patients are going to.
• 08:50Essentially lived with disease
• 08:52in their natural lifespan,
• 08:53which one is near to near that
• 08:55really needs to intervene on is
• 08:58going to be important going forward.
• 09:00So the other thing that the with you know
• 09:04this information about the incidence
• 09:06and prevalence in your endocrine tumors
• 09:08is that the patient advocacy groups,
• 09:12you know in the past decades
• 09:14has really got engaged.
• 09:16There are the stories of
• 09:18patients who have had.
• 09:19Long history of symptom maybe
• 09:22that went undiagnosed for decades.
• 09:24So there's a there was a strive to see
• 09:27whether we can recognize the symptoms
• 09:30earlier and diagnose the cancer earlier.
• 09:33But the challenge is the symptoms that are
• 09:36associated with these tumors are fairly
• 09:39vague and common in the general population.
• 09:42So this is study we did
• 09:45from CR Medicare database.
• 09:46Essentially, looked at the year prior
• 09:49to their neuron cancer diagnosis,
• 09:51what kind of doctor do they go visit and
• 09:54what sort of symptoms do they complain of?
• 09:58You can see, well,
• 09:59statistically significant for most of these.
• 10:02There are differences in
• 10:04rates of hypertension,
• 10:05abdominal pain, heart failure,
• 10:08diarrhea, and peripheral edema.
• 10:09But if you try to look at a positive
• 10:12predictive value of these symptoms
• 10:13when you're in the current tumor.
• 10:15They're all very,
• 10:16very low because they're very
• 10:18common in the general population.
• 10:23The newer endocrine field also is
• 10:25a field where the very terminology
• 10:27we or she used to describe the
• 10:30disease has been evolving in the
• 10:33in in the over the past decades.
• 10:35In the older time frame,
• 10:38the worst like carcinoy eyelid
• 10:40spells were commonly used.
• 10:42And it's moved to newer endocrine
• 10:46neoplasms and there's grading
• 10:48initially just grade 1-2 and now
• 10:51differentiation is added to add a
• 10:54historical context on why the the
• 10:56constant change almost feels like
• 10:59in terminology is that this field
• 11:01you know at the time when these
• 11:04terminologies classification created was.
• 11:06Relatively.
• 11:07I think people didn't really know where
• 11:09the right cutoff is in terms of the disease.
• 11:12It's more based on consensus and
• 11:15recurrence and relate the true biology.
• 11:18What beginning to understand is
• 11:21clearly there's two different group
• 11:23of diseases well differentiated,
• 11:25you're in the consumer grade 1-2 and
• 11:28three and they're mostly grade 1-2 and
• 11:30numerically and then the essentially
• 11:33the poorly differentiated urine carcinomas.
• 11:36Which is a completely different disease
• 11:38that has nothing to do with the other,
• 11:41right.
• 11:42And there are also differences
• 11:44in terms of the primary site.
• 11:47We'll talk a little bit about the
• 11:49molecular landscape and genomics
• 11:51of the different primary sites,
• 11:53but they are characterized by
• 11:56relatively low tumor mutational burden,
• 11:59but these tumor actually has high
• 12:02high rates of chromosomal instability.
• 12:05You see instead of point mutations,
• 12:08a large scale chromosomal changes
• 12:11lung neuro endocrine tumor.
• 12:13The most common mutation see is M
• 12:17EM1 and the same with pancreas M EM1.
• 12:19But here you also see DAX and ATRX and
• 12:23intestinal relatively few somatic mutations,
• 12:28but you see frequent loss of chromosome 18,
• 12:31the poorly differential
• 12:32neuro endocrine tumor.
• 12:34It's probably really a mixed bag a
• 12:36lot of time these are essentially
• 12:39transformed versions of adenocarcinoma,
• 12:42occasionally transformed lower grade
• 12:44tumor after certain types of therapy,
• 12:48but they're characterized by a very
• 12:50fast growth rate and mutation in TP53
• 12:53and RV are the most common mutations.
• 12:58So if you understand the genomics
• 13:00of neuroendocrine tumors,
• 13:01so one of the things we did is leverage
• 13:04our large phase three clinical trials.
• 13:07We did a series of trials called radium
• 13:10trials looking at everolimus where
• 13:12over about 1000 patients across you
• 13:15know four studies were were enrolled
• 13:17and where we can get the tumor.
• 13:19We did a whole genome analysis.
• 13:25We saw relatively few somatic mutations,
• 13:28but what what is striking is the amount
• 13:32of largescale chromosomal changes
• 13:34that you see chromosomal gain and
• 13:37chromosomal loss and these actually
• 13:39have very significant prognostic value.
• 13:42So for example in pancreatic
• 13:45neuron different tumors,
• 13:47patient with high chromosomal instability
• 13:49actually have a much better prognosis
• 13:52in the advanced disease setting.
• 13:54And we'll talk about a little bit
• 13:56in the next few slides why that
• 13:59is because it is a specific you
• 14:01know carcinogenesis pathway that's
• 14:04this this is implying here.
• 14:06And then we see also those patients
• 14:10with intestinal neuroendocrine tumor
• 14:12with loss of chromosome 18 also have a
• 14:15far better prognosis than those who do
• 14:18not have a loss of chromosome 18
• 14:21whereas the loss of chromosome 3.
• 14:23On the lung neuron, different tumors
• 14:27pertains to a poor prognosis.
• 14:30So one of the things that really always
• 14:33short struck me is really what's going on
• 14:35with pancreatic neural in the consumer.
• 14:37It's really one of my favorite
• 14:39diseases in the sense there's so much,
• 14:41so much stuff here.
• 14:43So you see here when we sequence
• 14:46the pancreatic neural in the tumors.
• 14:49They roughly fall into three categories
• 14:51when you look at the host whole genome
• 14:54in terms of chromosomal changes.
• 14:57In the first group here, Group One,
• 14:59they lose one copy of 11 of
• 15:03the 22 chromosomes.
• 15:05In the second group,
• 15:07there's loss of 1 copy of the 11 chromosomes,
• 15:1211 one copy of 11 chromosomes.
• 15:14And gain on the complementary 11
• 15:18chromosomes and then there's a
• 15:21group that are relatively stable in
• 15:24terms of chromosomal abnormalities.
• 15:26And on the bottom panel is little small.
• 15:28So I'll just talk through it a
• 15:30little bit and it's important in
• 15:32the sense that you can actually
• 15:35link these chromosomal changes to
• 15:37specific mutations that are present
• 15:39in if you look at this.
• 15:42The chromosomal instability tumors
• 15:44so that that's these are in Gray and
• 15:48in red are essentially are in rich
• 15:51for patients with M EM1 mutations.
• 15:54So what's the link between M EM1
• 15:58mutation and and this and the M EM1
• 16:02mutations is also linked with DAX
• 16:05mutations whereas the ATRX mutations.
• 16:10Essentially also involved in a TRX and
• 16:12DAX are involved in alternative links.
• 16:15Near telomeres can be associated with
• 16:19chromosome instability in absence of M EM1.
• 16:23So the ATRX by itself the mutation
• 16:27seems to drive this phenomenon.
• 16:30So so So what we see here is then
• 16:32you see DAX and ATRX mutations
• 16:36associated chromosomal instability.
• 16:38And you have,
• 16:39you know loss of 1 copy of 11 chromosome
• 16:42and gain on the complementary 11
• 16:45chromosomes and the strong association
• 16:47between men one mutation and DAX
• 16:49in the combination of men one DAX
• 16:52mutation with chromosome instability.
• 16:54So what's going on here?
• 16:56Why are we losing one copy of
• 16:5911 chromosome and gaining on the
• 17:02complementary 11 chromosomes?
• 17:05For whatever reason,
• 17:06you're essentially what's actually
• 17:08going on is you're losing one copy of
• 17:1211 chromosomes and this in some patients,
• 17:14probably due to happily insufficiency,
• 17:17is leading to whole genome duplication.
• 17:20So essentially these are copy neutral LOH.
• 17:25They are occurring essentially in the
• 17:29game because the whole genome duplication.
• 17:32Is occurring in the
• 17:34complementary 11 chromosomes.
• 17:36So what's the story here?
• 17:38While the most common mutation in your
• 17:42endocrine tumor is man one specifically
• 17:44linked to pancreatic neuroendocrine
• 17:47tumors occurring roughly about 40%
• 17:50of patients and also associated with
• 17:53lung neuroendocrine tumors.
• 17:55What do we know about man one biology?
• 17:59It is certainly is epigenetic
• 18:01regulators involved in modulating
• 18:04P27 and it's actually involved
• 18:07in controlling endocrine mass.
• 18:09So this is a study done at Stanford
• 18:13where the group looked at men
• 18:15and in in mice doing pregnancy
• 18:19and you can see that men and
• 18:22expression goes down during pregnancy
• 18:24and goes back up post pregnancy.
• 18:27Associated with that is turning on cell
• 18:32cycle and increase in endocrine mass.
• 18:35And so there is a, you know there's
• 18:40important biology here in prevention of
• 18:43gestational diabetes related to men in
• 18:48men in turns out is also an
• 18:52important regulator of telomeres.
• 18:54In the Nurses in the Prostate, Lung,
• 18:59Colorectal Ovarian Cancer Screening
• 19:01Trial and Nurses Health Study that
• 19:04involved about 3600 patients,
• 19:06the group this group evaluated 743
• 19:09snips and try to correlate that with
• 19:13essentially peripheral blood telomere lens.
• 19:16The only gene that fell out to be
• 19:19important was actually men and.
• 19:21It was the most important implicated
• 19:24in control of telomere lens
• 19:27for for in in the study.
• 19:31So the story of telomeres,
• 19:34you know as you know the telomeres are
• 19:37in the caps and end of our chromosomes
• 19:39and Menon is driving cell cycle in here.
• 19:43The telomere lens is going to get
• 19:46short as telomere lens gets short.
• 19:49Essentially usually the cancer
• 19:51cell dies where you need to turn
• 19:54on some way of maintenance of
• 19:56telomere or Linston telomeres.
• 19:58For most cancers this is essentially
• 20:02activation of telomeres,
• 20:03but in a few cancers and in in
• 20:07pancreatic neuroendocrine tumors,
• 20:08the mechanism that's gets gets gets activated
• 20:13as alternative linsing of telomeres.
• 20:17How do we know this?
• 20:18This is some slice courtesy of
• 20:21Christopher Heefy where he showed
• 20:24essentially in neuro endocrine tumor
• 20:27that has well typed Dax ATRX you see
• 20:31fairly normal telomere lens and when
• 20:35there is Dax or a TRX alterations
• 20:39you see these bright pink spots
• 20:42which are telomere specific fish.
• 20:45Showing a classic pattern associated
• 20:50with alternative listening of telomeres,
• 20:55the story on essentially alternative
• 20:59listening telomeres and DAX ATRX mutations
• 21:02is actually complex in terms of prognosis.
• 21:06Earlier on I showed you a slide
• 21:09where essentially the the.
• 21:11Mutation of DAX ATRX and and turning
• 21:17out ELT was associated with good
• 21:19prognosis in patients with advanced
• 21:22pancreatic neuroendocrine tumor.
• 21:25The situation is actually
• 21:27reversed in the earlier disease.
• 21:29Essentially what's going on is that
• 21:32advanced disease the the DAX ATRX mutation.
• 21:38Is marking a group of pancrea urine
• 21:41the consumer who goes down a very
• 21:44specific carcinogenic pathway,
• 21:46whereas in in the earlier disease
• 21:49this actually the IT pretends
• 21:51to be a worst prognosis.
• 21:54So this is a great study
• 21:56that was done in men,
• 21:57one families.
• 21:58So these are patients with
• 22:01familial mutations in M EM1.
• 22:04What they're able to show is that.
• 22:07When the tumors are small,
• 22:09you usually don't see DAX ETRX
• 22:13mutations and the DAX ETRX mutations
• 22:16occurs in tumors that are larger
• 22:20in this case and I think they
• 22:22use a cutoff about 3 centimeters
• 22:24and also happens in patients
• 22:27who have lymph node metastasis.
• 22:29So likely what's going on is
• 22:33that as the these tumor.
• 22:35Are driven by men one to
• 22:38proliferate these benign tumors.
• 22:41The tilar mirrors are getting shorter
• 22:44and the ones who are able to turn on
• 22:47tilar mirror maintenance throughout
• 22:49are the ones that gets larger and
• 22:52then lead to regional metastasis.
• 22:59So again, this is just showing
• 23:02the same in terms of A.
• 23:05In a recurrencefree survival graph,
• 23:08those who are turning on health
• 23:10in the localized setting where
• 23:12they have three section have
• 23:15a little bit poor prognosis.
• 23:21Next I'm going to shift gear a little
• 23:22bit and talk about essentially on the
• 23:25clinical side the development of new
• 23:28novel therapies for neuroendocrine tumors.
• 23:31So essentially prior to 2007,
• 23:35we only had Streptozosin for your
• 23:37in the contumor of the pancreas.
• 23:40And since then you really have
• 23:42seen a lot of new agents showing
• 23:45activity getting FDA approved for
• 23:48having positive phase three trials.
• 23:51And I think a key thing here that
• 23:55happened really related to one of the
• 23:58meetings in Pam you were involved with.
• 23:59Was the first in a CTPM meeting sponsored
• 24:03by NCI and the importance of that
• 24:06meeting is really to come to consensus.
• 24:09What is the right kind of clinical trial
• 24:12design when you're in the consumers,
• 24:14what are the correct endpoints?
• 24:17There's a recognition progression,
• 24:19free survival is probably the
• 24:21right endpoint or in,
• 24:23but the phase three trials
• 24:26are are recommended.
• 24:27Overall survival trials,
• 24:29neuroendocrine tumors,
• 24:31we came that out in doing the meeting
• 24:34and realized they will require a
• 24:36probably about two to 3000 patients
• 24:39and probably 8 to 10 years to execute.
• 24:43So that that's why you will see
• 24:47in the subsequent slide most of
• 24:50the approved agents are able to
• 24:52then demonstrate PFS benefit.
• 24:54But we don't have quite a
• 24:56large sample size needed that
• 24:57demonstrates survival benefit
• 25:02going going into the the systemic
• 25:04randomized space free trials are you
• 25:07know we you're going to talk to them
• 25:09a little bit about different targets.
• 25:12So the first targets we'll talk
• 25:14about is the Smestan receptor.
• 25:16For a long time prior to this Smestan
• 25:19receptor targeting was Octreotype.
• 25:22Was approved for control of Carson
• 25:24syndrome it relief flushing and diarrhea
• 25:26in probably about 70% of the patients.
• 25:29But there are a lot of back and
• 25:31forth debate as to whether actually
• 25:33or not is slow cancer grows and it
• 25:36was almost like a little religion
• 25:39people either believe it or we they
• 25:41they didn't but what was important
• 25:43is you just need to actually do the
• 25:45trial it turns out and in this phase
• 25:48three trial that's done by the.
• 25:51A multicenter German trial in in patients
• 25:56were relatively newly diagnosed with
• 26:00small bowel neuroendocrine tumor.
• 26:02They were able to demonstrate
• 26:04improvement progression free survival.
• 26:06A similar trial was land Realty
• 26:09was conducted as a larger trial
• 26:12and included a broader group of
• 26:14patients including pancreatic and
• 26:16rectal neuroendocrine tumors.
• 26:18And again showing significant benefit
• 26:20in terms of progression free survival.
• 26:23Notice however the hazard ratio
• 26:25for the octerotized study was a
• 26:28little bit lower than the hazard
• 26:30ratio for the land real time study.
• 26:33This is probably a by byproduct in terms
• 26:37of the way the trial were executed.
• 26:41It turns out the octerotized study
• 26:44was permanent terminated early.
• 26:46At interim analysis and in there's
• 26:50been subsequent publications and
• 26:53analysing analysis of popular population
• 26:55of studies that can demonstrate
• 26:58while when you terminate a study
• 27:01early for outstanding efficacy,
• 27:03you tend to overestimate the the
• 27:06magnitude of the treatment effect.
• 27:08And that's just a you know a byproduct
• 27:12of our early termination because
• 27:14when you terminate a study early.
• 27:16You preserve your ability to
• 27:19test the hypothesis,
• 27:21but not the ability to estimate
• 27:23the magnitude of treatment benefit.
• 27:27Another way to term to target
• 27:30some mass and receptor is PRRT,
• 27:33which really has become very well,
• 27:36you know, widely used at this point.
• 27:39Again, in the earlier
• 27:41development of PRRT it was not.
• 27:43It was a lot of a single single
• 27:48institution studies and you have
• 27:50these publications in high impact
• 27:52journals where they purportedly report
• 27:55a phase two study of 1000 patients.
• 27:59And you know,
• 28:00but actually what was needed for
• 28:02really demonstrating benefit and
• 28:03approval is a randomized phase three
• 28:06trial which you can do actually was
• 28:08far fewer than thousand patients.
• 28:11So this takes advantage of the
• 28:13fact that semastin receptors are
• 28:15present on your endocrine cancer
• 28:17cells in 7080% of the cases.
• 28:20Specifically for semastin receptor
• 28:222 when the lichen binds to
• 28:25the receptor is internalized.
• 28:27So.
• 28:28So these agents essentially takes a
• 28:32Lutetian 177 and taking into the cell
• 28:35and leading to very good efficacy.
• 28:41There's also a role for targeted
• 28:44therapy in neuroendocrine tumors.
• 28:46One of the drugs that we were involved
• 28:49in developing is everolimus of
• 28:51affinitor targeting the emptor pathway.
• 28:54The Radian 3 trial was the first
• 28:57to report out and for pancreatic
• 29:00neuroendocrine tumors and here you saw
• 29:03a benefiting progression free survival
• 29:05from median 4.6 months to 11 months.
• 29:10And hazard ratio was .35 here
• 29:13in overall survival because the
• 29:15crossover we did our PFST analysis
• 29:18rank preserving structure failure
• 29:20time showing like there's a likely
• 29:22benefit in overall survival,
• 29:24but in because of the the crossover
• 29:27these such studies and not these
• 29:30studies are really designed
• 29:31to evaluate overall survival.
• 29:37For Radian 4, this is the phase
• 29:39three study we did in lung
• 29:42and GI neuroendocrine tumors.
• 29:44Again patient were randomized to
• 29:47receive everolimus or placebo.
• 29:50The the the, the PFS improved from
• 29:543.9 months to 11 months with a
• 29:57hazard ratio of 0.48 and a trend
• 29:59to our overall survival benefit.
• 30:05Another targeted agent that's
• 30:07shown benefit is sunitnip.
• 30:09So Sunita was initially evaluated in a
• 30:12phase two study being that had two cohorts
• 30:15for intestinal neuroendocrine tumors and
• 30:18for pancreatic neuroendocrine tumors.
• 30:20All the responses were seen in the
• 30:23pancreatic neuroendocrine group.
• 30:25So it was taken into a phase three trial.
• 30:28The study actually terminated early
• 30:31at an unplanned interim analysis.
• 30:33Nonetheless there it was significant
• 30:36benefit demonstrating PFS and then that
• 30:39led to the FDA approval of the drug
• 30:43for pancreatic neuroendocrine tumors.
• 30:47We do believe VEGF inhibitors may
• 30:49have a role in extra pancreatic
• 30:52neuroendocrine tumor as well.
• 30:54This is a another phase three trial
• 30:56that I did early in my career,
• 30:59the SWAG O 518.
• 31:01And the in this study patients were
• 31:05randomized from octreotype plus interferon
• 31:08versus octreotype plus Bebasus MAP.
• 31:11Where we're able to show in this
• 31:13study is that although the response
• 31:15rate improved with Bebasusan MAP and
• 31:18toxicity was better was Bebasusan map,
• 31:21there was not any significant
• 31:24difference in progression free survival.
• 31:27So this is probably one of
• 31:28my regrets in the career.
• 31:30I probably should have done this
• 31:32study against placebo and we would
• 31:34have had had another drug available
• 31:36for neuroendocrine much earlier on.
• 31:40This is what the time point in my
• 31:43career where we weren't sure whether
• 31:45we can execute a placebo control trial.
• 31:47It's certainly a little bit harder to do,
• 31:49but often placebo control trial
• 31:52give you cleaner data.
• 31:54Especially when the comparator
• 31:56arm is not is not very carefully
• 32:00what is not well defined.
• 32:04So there has been others who evaluated
• 32:08veget inhibitors in your in the Contuber.
• 32:12This is a study conducted
• 32:14also in the cooperative group.
• 32:16The Pi is Emily Burksland and
• 32:19patient were randomly assigned to
• 32:22either pizopanit versus placebo.
• 32:24And there there was the benefit
• 32:26in terms of progression free
• 32:29survival also demonstrated in extra
• 32:32pancreatic neuroendocrine tumors.
• 32:34So potentially showing the importance
• 32:37of role of VEGF inhibitor outside
• 32:41beyond the pancreatic group in terms
• 32:45of phase three studies for extra
• 32:49pancreatic neuroendocrine tumor.
• 32:51And there's also a study that was
• 32:54performed in two studies that were
• 32:57performing in China with Serofatin NIP,
• 33:00another VEGF or multi kinase
• 33:03inhibitor demonstrating similar
• 33:05magnitude of benefit for Serofatin
• 33:08Nip both in pancreatic net and extra
• 33:11pancreatic net unfortunately the FDA.
• 33:13It's going to probably require
• 33:16the the company to redo the trial
• 33:19because it did not contain it was a
• 33:22purely Chinese population and the
• 33:24population may not fully represent
• 33:26the lines of prior therapy Western
• 33:29populations would have been exposed to.
• 33:34Next I'm going to mention while
• 33:36Doctor Kunz's trial Ecog 2211,
• 33:39this is actually a very important trial.
• 33:43Partially because the initial development
• 33:46of Timosolomite were essentially
• 33:48skipped the single agent step they were,
• 33:52you know most of the trials that
• 33:55were published were doublets.
• 33:57So always been a question to feel
• 33:59that whether you need doublets
• 34:01or you know where the agent is,
• 34:05Timosolomite by itself is a sufficient.
• 34:08Certainly there's rationale to
• 34:09look at this class of agents in
• 34:12pancreatic neuro in the consumers.
• 34:13If you dig back into Chuck
• 34:16Mattel's papers and so forth,
• 34:19DTIC is active in the disease.
• 34:21So this is a trial that compared Timosolomite
• 34:25to Tim Cape at the intern analysis.
• 34:28The study met its primary
• 34:31endpoint and showed improvement
• 34:33in progression free survival.
• 34:35For our patients with Tim Kay and I
• 34:39think another actually very important
• 34:42finding from this study is the
• 34:45prognostic and significance with
• 34:47association of the MGMT expression
• 34:51with the response in this is a
• 34:55DNA repair pathway when that often
• 34:59are methylated MGMT and leading
• 35:01to low expression and you can see.
• 35:03That for patients with low MGMT,
• 35:06the response rate is much higher than
• 35:09those who have intact MGMT expression.
• 35:14So if you look at the current treatment
• 35:16landscape for neuroendocrine tumor,
• 35:17we have come a long way.
• 35:20You know in the beginning historically we
• 35:22only have one agent for pancreatic net.
• 35:25Now you have number of phase three
• 35:28clinical trial covering many of the
• 35:31different in your endocrine tumors.
• 35:34Essentially these are clustered
• 35:36around agents that targets these.
• 35:39These are stable or early disease like
• 35:42TRILTY and then Realty in the pro
• 35:45Med and the CLARINET study and in the
• 35:49studies who tend to target patients
• 35:52was faster progressing disease PRT
• 35:55somewhere in the middle that required
• 35:58progression in the past three years.
• 36:00And most of the targeted agents
• 36:02require progression in the past one
• 36:05year when in the case of Radian 4
• 36:07progression within the past six months.
• 36:10So what are some of the remaining
• 36:13challenges and questions that we
• 36:14we have when you're in the current
• 36:17tumor at this point,
• 36:18one of the question I get asked
• 36:20the most is sequencing,
• 36:22what's the optimal sequencing of
• 36:25therapy for neuro in the current tumors?
• 36:29So it's kind of interesting
• 36:31because you're in the consumers,
• 36:33you had approval a lot of agents
• 36:35while in a short period span of time.
• 36:38So they were not really developing a way
• 36:42where they were specific align first line,
• 36:44second line, third line.
• 36:46Most the drugs were either approved
• 36:49for progressive disease or they
• 36:51were just approved for advanced
• 36:54disease but optimal sequencing.
• 36:56It's really talking about which sequence
• 36:59leads to the best overall longterm survival.
• 37:03This is actually extremely
• 37:05difficult question to answer.
• 37:08It's not about which agent when used
• 37:11first has the longest initial PFS,
• 37:14because if that agent,
• 37:16you know,
• 37:17essentially takes out your kidney or makes
• 37:21it difficult for you receive other agents.
• 37:24And it may not be the best agent
• 37:26to use initially.
• 37:28So almost certainly this is if you
• 37:30really want to answer this question,
• 37:32it needs overall survival endpoint.
• 37:35Well,
• 37:36here's the challenge right when for
• 37:39different indications you have different
• 37:42number of treatments available,
• 37:45the approved therapy for lung,
• 37:47there's only ever limus in peanut you
• 37:49have six agents that are available,
• 37:52approved you can use.
• 37:54A 7th agents demonstrated activity
• 37:56that that's probably works well.
• 38:00You can imagine trying to compare
• 38:04optimal sequences.
• 38:05There's 5040 sequences,
• 38:095040 arms for overall survival.
• 38:12This is not where we want to spend
• 38:14our energy and because I think
• 38:17likely before evening to solve a
• 38:20simpler question before you actually.
• 38:23To answer the question and complete a trial,
• 38:25the treatment landscape would
• 38:26have changed in the trial design
• 38:28will probably no longer be valid.
• 38:33And to give a actually example
• 38:34of attempt to do this,
• 38:36our European colleague
• 38:38contacted the secretor trial.
• 38:41The secretor trial look look to
• 38:44compare the sequence of Ever Linus
• 38:46followed by Streptozosin based
• 38:48chemotherapy or Streptozosin based
• 38:51chemotherapy followed by ever Linus.
• 38:53They weren't going to be quite ambitious
• 38:56to try OS as the primary endpoint.
• 38:58They were going to look at P FS2.
• 39:01So initially are due to a cruel
• 39:05issues that they had to do scale
• 39:08back their ambitions to look at
• 39:10P FS1 as the primary endpoint.
• 39:13So what did the study show?
• 39:16Yeah, actually showed that although
• 39:19Streptozosin set of toxic chemotherapy.
• 39:22Was a little bit more toxic but higher,
• 39:24had a higher response rate,
• 39:26but there was no difference in progression
• 39:29free survival between the two arms.
• 39:31So higher higher response rate may not
• 39:34necessarily lead to a better outcome.
• 39:38The second most frequent question I get
• 39:41asked about nearing the consumer these
• 39:43days is precision medicines and biomarkers.
• 39:46If you did a search on your end,
• 39:49the consumer and biomarkers on Pub Med.
• 39:52And you'll get thousands,
• 39:54probably near 10,000 results back.
• 39:57So what do we know about biomarkers
• 40:00for neuroendocrine tumors?
• 40:03I usually think about biomarkers
• 40:05as two classes.
• 40:06These are prognostic identifying
• 40:08those people who have a better
• 40:11or worse outcome and predictive
• 40:13meaning to actually sorting out
• 40:16individual who are more likely.
• 40:19But then similar individual without a
• 40:21biomarker to experience a favorable
• 40:23unfavorable benefit from an exposure to
• 40:26a medical product we environment agents.
• 40:28So the bottom line is who should get
• 40:31this treatment is really the important
• 40:34question for predictive biomarker.
• 40:36Another way to think about the importance
• 40:39of predictive biomarker is really
• 40:42thinking about like who's going to
• 40:44benefit from treatment if you have a
• 40:47treatment where everybody benefits.
• 40:50Predictive biomarker can almost becomes
• 40:52essentially a prognostic biomarker.
• 40:54It's probably of less clinical
• 40:58importance in the situation where
• 41:00half the patient will benefit.
• 41:02A predictive biomarker is super useful
• 41:06and it's even more important when a
• 41:08smaller group of patient have profound
• 41:11benefit, but most people don't.
• 41:14So what is actually the situation
• 41:16you are in different tumor which of
• 41:18these waterfall plot do we look like?
• 41:21Fortunately it looks like this whereas
• 41:23a most the patients benefiting from the
• 41:28treatment within their treatment indications.
• 41:34So the challenge of predictive
• 41:37biomarker is essentially you have to
• 41:39randomize more patient all patients.
• 41:41Including patients who doesn't have
• 41:44the biomarker because without that
• 41:46randomization is very difficult to
• 41:49understand which biomarker is important.
• 41:52You should do this when the marker
• 41:54is suspected to be predictive but not
• 41:57proven and you have reliable assay
• 42:00methodology and cut points and there's
• 42:03reason to expect benefit potentially
• 42:06in biomarker negative patients.
• 42:11Much more common we seeing oncology these
• 42:14days is this approach which is establishing
• 42:18a efficacy of biomarker population which
• 42:21means we only essentially randomize
• 42:24the biomarker positive population.
• 42:27So here you can prove the biomarker positive
• 42:30benefit patients benefit from new treatment.
• 42:34But it's best used when no benefit is
• 42:36expected in bowel marker negative population.
• 42:39You don't have any information gained
• 42:41about the bowel marker negative population.
• 42:47But often sometimes we get it wrong, right.
• 42:49We we don't initially fully understand this.
• 42:52The classic example in
• 42:54colon cancer is cetuximab.
• 42:57The initial FDA approval in
• 42:59clinical trial was for patients.
• 43:01Who had e.g. Fr expression on I HC?
• 43:06Turns out that has nothing to do
• 43:08with whether someone benefits from
• 43:10situximab or not in colorectal cancer.
• 43:14And the net example is really kind
• 43:16something I kind of lived through.
• 43:19After we started a phase three trial,
• 43:21a publication came out in science
• 43:23showing about 15% of the patients with
• 43:27pancreatic net at M Tor pathway mutations.
• 43:30So I I I will,
• 43:32I would gladly admit I was a very lucky
• 43:35not to know that when I started the trial.
• 43:38But because it turns out you
• 43:42know extra pancreatic net,
• 43:44none of the patients have
• 43:46mtor pathway mutations,
• 43:47quote mtor pathway mutations,
• 43:49but they all benefited from the therapy
• 43:52and even in the pancreatic net group
• 43:55those who had mtor pathway mutations.
• 43:58And didn't have M Tor pathway mutation
• 44:01have similar magnitude of benefit.
• 44:03That's not to say that it's not
• 44:06correct that you know what what
• 44:09was published is just means that
• 44:11I don't think we may sometimes
• 44:13know the full M Tor pathway or
• 44:16how these drugs actually work.
• 44:21Those are biomarkers.
• 44:23In neuroendocrine trials,
• 44:25the question often is asked about the
• 44:28semester and syntacriphy in for semester.
• 44:32And like octreotile and Realty,
• 44:35the prominence study actually
• 44:37allowed for both semester and
• 44:41receptor syntacrification of.
• 44:45And clarinet study only treated patient
• 44:54for semester and receptor positive.
• 44:58This one comes close to a predictive
• 45:01biomarker which is the degree of
• 45:03uptake and response and tumor
• 45:06shrinkage in in in for treatment
• 45:10with a peptide receptor radiotherapy
• 45:13as you can see that comparing
• 45:15to the using the craning scale.
• 45:17As the expression goes up,
• 45:19the response rate increase compared
• 45:22for peptide receptor radiotherapy.
• 45:26Another biomarker that was evaluated is
• 45:30is more like a pharmacodynamic biomarker.
• 45:34In early studies and single arm study
• 45:36it looked like those patient who had an
• 45:39early drop in pomegranate had a benefit
• 45:42for patients treated was everolimus.
• 45:45But this turned out actually not to be
• 45:48that useful when we took it to phase
• 45:51three because the placebo patient
• 45:52who had a 30% dropping from Granny
• 45:55A also had a better outcome as well.
• 45:58So likely this is pointing out some
• 46:01issues with the assay performance and
• 46:04also whether we're not you actually
• 46:05have to test these patient multiple
• 46:08times before you get a reliable results.
• 46:12Another BOW marker attempting to look
• 46:14at the predictive bow marker in terms of
• 46:18response is looking at profusion CT in
• 46:21patients treated with veg inhibitors.
• 46:23We're able to show that in patients treated
• 46:26with Bebasusan app is open in a flipper
• 46:29set that essentially baseline parameter
• 46:31and change after treatment correlated
• 46:34with the degree of tumor shrinkage.
• 46:37I think what we learned here is that
• 46:40these are very difficult to do.
• 46:42And very operator dependent.
• 46:44So it's was possible to do it in
• 46:47clinical trial taking it out to the
• 46:50wider clinical practice is challenging.
• 46:52So if you look at a biomarker
• 46:55landscape for neuroendocrine tumor,
• 46:57you see that in terms of understanding
• 47:01whether the treatment work in the in,
• 47:05in the indication we do pretty well.
• 47:08Whereas predictive biomarkers,
• 47:10there are a few promising ones
• 47:13like printing scale for
• 47:18PRT&MGMT for Timosolemai,
• 47:20However, we're still need a lot,
• 47:23lot more work to do in terms of
• 47:26getting real predictive biomarkers.
• 47:30So I mentioned earlier that we
• 47:32have a lot of approved therapy
• 47:34but most of these trial were not
• 47:36designed to ask a survival question.
• 47:39So you know has all this work been
• 47:42approval our patients doing better,
• 47:45we can look back into the SEAR
• 47:47database again and showing
• 47:49that the trend in improving,
• 47:51improving overall survival in
• 47:53patients with great one to two
• 47:56metastatic neuroendocrine tumors.
• 47:58Suggesting that what we did actually
• 48:01does actually make a real impact.
• 48:04So next what do you think we need
• 48:06to do to continue the progress
• 48:09in your endocrine tumors?
• 48:11I think clearly we one thing
• 48:13we learned is the use of robust
• 48:16randomized clinical trials and we
• 48:18shouldn't be shy about using placebo
• 48:21control trial in the right setting.
• 48:23We do need better availability of neuro
• 48:25in the model for translational research.
• 48:28I think we have a baseline group of
• 48:31therapy that works now to find the
• 48:33next pathway to target the next target.
• 48:36I think the the neuron models in
• 48:39the lab will really benefit us
• 48:42and we need to obviously explore
• 48:46novel therapeutic approaches.
• 48:47I'll just have two more slides
• 48:50on the modeling part so.
• 48:53There's a real challenge with
• 48:55developing models for well
• 48:56differentiating your endocrine tumors.
• 48:59There's been many attempt to generate
• 49:02cell lines, xenographs and organize.
• 49:04Principally they are limited by a
• 49:07slow growing nature of the tumor.
• 49:09So if you think about it in
• 49:12placebo arm of clinical trial,
• 49:14you see these tumors takes about
• 49:18somewhere between 5 to 18 months median.
• 49:21To show about a 20% increase in diameter,
• 49:24if you really had a representative Model 1,
• 49:28those models are very difficult
• 49:30to keep alive.
• 49:31Second, will take you years to run
• 49:33one single experiment in the lab.
• 49:35So it's it's very,
• 49:36very, very challenging.
• 49:37There are models out there,
• 49:40but many of them are altering in such
• 49:42a fundamental way that I don't think
• 49:45they represent your end of biology.
• 49:47So if you look at the published
• 49:50cell lines and.
• 49:51In in the the models out there,
• 49:55many of them highlighting yellow,
• 49:57have mutation that do not occur naturally.
• 50:00While differentiating Nets with P53 and RB.
• 50:05The remaining usually are
• 50:07unknown in terms of P53RB status.
• 50:11So here's the conundrum.
• 50:13You need a model that's grows
• 50:16fast enough to actually take.
• 50:18And can generate enough material
• 50:20that you can actually do experiments,
• 50:23but you still need to represent the the
• 50:27neuroendocrine slow growing biology.
• 50:30So how do we tackle this?
• 50:32One of the efforts we've been doing
• 50:35in our lab is using a genetically
• 50:37engineered patient derived organo way models.
• 50:40So what are we doing here?
• 50:42We know that if you alter P53 or RV.
• 50:45These these things will grow
• 50:47and take and proliferate,
• 50:49but you don't want the P53RB L you
• 50:52know altered when you're testing,
• 50:54studying new drugs or understanding the
• 50:59the biology of Nets.
• 51:01So we are using a lenty viral
• 51:04vector to introduce essentially
• 51:07doxycycline inducible alterations
• 51:10in key proliferation pathways.
• 51:13So the idea is you.
• 51:16Essentially putting a growth on
• 51:18and off switch into the patient
• 51:21tumor samples and then you control
• 51:24it with in this case doxycycline.
• 51:28We're using either SV40 large T antigen
• 51:32behind a the behind the promoter or
• 51:38a altered P53R273 because the P53.
• 51:42Acts as a tetramer when even one
• 51:45copy is is actually mutated.
• 51:47Is in Paris its function
• 51:51still a lot of work to do to
• 51:53figure this out because there
• 51:55are many different variations.
• 51:56You can do this.
• 51:58You can directly in fact the primary cells,
• 52:01you can grow them in organizing.
• 52:03In fact the organize and what's the right
• 52:07condition and how to solve this work.
• 52:10We're happy to show that
• 52:11we're making progress,
• 52:12that we can actually use the system to
• 52:15make your endocrine tumor organoids grow
• 52:20because the previous attempts to organize,
• 52:22while you can use growth
• 52:24factor to keep them alive,
• 52:25they don't really grow.
• 52:26So the only way you can study them is
• 52:29to have a constant stream of material
• 52:31coming from the operating room.
• 52:34But each time is a little bit different,
• 52:36right? So we're hoping that.
• 52:40Over the next month to year to fully
• 52:42characterize all the these organized
• 52:45that we're developing in terms
• 52:47of what what is staying the same,
• 52:49what is being altered and to what
• 52:52extent we can reverse the P53
• 52:55and and and SV40 induce changes,
• 53:00we show all the doxycycline to do
• 53:04drug screening or study the biology.
• 53:07So I'm going to end the talk here and
• 53:09maybe just a few minutes for questions.
• 53:11You
• 53:25can say it there. Any questions
• 53:27from the audience or from or online,
• 53:30maybe one, see if anyone in the chat,
• 53:34I'll, I'll ask the first question,
• 53:36what are you most excited about from a
• 53:39therapeutic standpoint in the next decade?
• 53:42That's a tough question.
• 53:45You know I I I think there's still a role
• 53:48for immunotherapy but probably not with
• 53:52existing checkpoint inhibitors but maybe
• 53:56within except for maybe subpopulations.
• 53:58That's one of the things we're
• 54:00learning is although tumor tumor
• 54:03mutational burden is generally low,
• 54:06you're in the patients live a long time.
• 54:09So that tumor mutation burden
• 54:11actually may change over time.
• 54:13If you look late in the course of disease,
• 54:16you may find you know patients will
• 54:19benefit from those those sort of
• 54:21treatments especially interesting is
• 54:23like your work with Timozola mine right,
• 54:26because these are Asians that tend
• 54:28to induce tumor mutations and and may
• 54:31increase tumor orientation will burden.
• 54:34So that's actually I think the
• 54:36relevant sequencing question.
• 54:37When you use that early,
• 54:38does that mean later on they have a
• 54:40high T MB and you can go back with I/O,
• 54:43that sort of things?
• 54:43Yeah.
• 54:43Kevin,
• 54:47thanks. Doctor Yellen,
• 54:49can you comment given the expanding
• 54:52armamentarian and systemic agents
• 54:54where you see the evolving role
• 54:58of surgical therapy fitting in?
• 55:00It's complicated historically?
• 55:03Depending on where you are
• 55:05and who you work with,
• 55:07what the landscape is and we have
• 55:11felt like surgical cyto reduction
• 55:15has a role in this disease.
• 55:19But I I don't know that that's
• 55:22as much the case the current
• 55:24era or it will be in the future.
• 55:26I think that's the great question.
• 55:28I think there's still be a very
• 55:30important role for cyto reduction
• 55:32in surgery in this disease.
• 55:34If nothing,
• 55:35it actually gives the patient a
• 55:37potentially a long treatment free
• 55:39interval from systemic therapy and
• 55:41although the time course here is long,
• 55:44so metastatic small bowel patients
• 55:47are living 8 to 10 years.
• 55:50But if you ask the patient they will
• 55:52say 8 to 10 years is not enough,
• 55:54right?
• 55:54So I think there's still room
• 55:56to use more modality including
• 55:58surgery and international
• 56:00radiology technique and so forth.
• 56:05The surgery of symptoms,
• 56:08it certainly can mean, yeah,
• 56:12you know there's many different
• 56:14ways it can in you know some
• 56:17cases patients have essentially
• 56:19abdominal discomfort from a local
• 56:21tumor with nodes and the surgical
• 56:24resection will bypass can be very
• 56:27important for them even though
• 56:29palliative and patients who have.
• 56:31Severe Carson syndrome sometime
• 56:33refractive therapy and benefit
• 56:35from the bulking all types
• 56:40should there's an increase in
• 56:42incidence but also survival.
• 56:43Are you able to kind of differentiate
• 56:46increased diagnosis of otherwise
• 56:47ability versus advances in therapy
• 56:50or you know parse this out? Yeah.
• 56:53So I think one of the ways we're looking
• 56:56at the survival changes is limiting our
• 56:58analysis to those with metastatic disease.
• 57:01There are still very much some limitations
• 57:03when you look at that sort of data.
• 57:05But I think the large registry is
• 57:08probably still the best way to look
• 57:10at the survival data because when
• 57:12you look at individual institutions,
• 57:14you have a lot of referral bias.
• 57:16You know, those patients who
• 57:18has surgery are cured,
• 57:19they don't come to tertiary centers, right.
• 57:21They're going on and living
• 57:23their normal lives.
• 57:24And so the large registry still
• 57:27have a very important role there.
• 57:29And the increase in incidence is happening
• 57:32in distinct areas like rectal is you
• 57:35know because the screen colonoscopy
• 57:37you're finding lot of tiny rectal,
• 57:41you're in the consumers which also
• 57:44is linked to specific race and
• 57:47ethnicity issues and in in in small
• 57:49pancreatic urine the consumer is
• 57:51going to be something we're going
• 57:52to have to deal with just the
• 57:54increase CT start getting done.
• 57:59Well, thank you so much
• 58:00Doctor Yao for coming today.