"A NET Gain: Establishing the Yale Neuroendocrine Tumor Program" and "Merkel Cell Carcinoma: Past, Present, and Future Directives"

January 12, 2022

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Yale Cancer Center Grand Rounds | January 11, 2022

Presentations by: Dr. Pamela Kunz and Dr. Kelly Olino

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00:00So our first speaker is Pam Kuntz,
00:02who is associate professor
00:04of medical oncology here,
00:05director of the Center for GI Cancer.
00:07As the chief of GI Medical Oncology
00:10and the Vice Chief of Diversity,
00:12Equity and inclusion for medical oncology,
00:14she received her medical degree
00:16from Dartmouth and Residency and
00:17Fellowship Training at Stanford,
00:19where she joined the faculty
00:21and she joined us now.
00:242020 She is an international leader
00:26in the clinical care of patients
00:28with neuroendocrine tumors conducting
00:30important clinical trials in this area.
00:34And as well as translational science
00:35for patients with this rare diagnosis,
00:37she's also a vocal advocate for women
00:40and underrepresented groups in medicine.
00:41And recently,
00:42the women leader in oncology named her the
00:452021 Women Women oncologist of the Year,
00:48so we're very happy to hear, and
00:50we'll hear about GI neuroendocrine tumors.
00:52I suspect from Pam.
00:54Thank you.
00:55Thanks, Dan.
00:57I can switch here.
00:59There has that looks OK all right excellent.
01:02So thanks so much for the
01:03opportunity to speak today.
01:04I will in fact be talking about
01:07neuroendocrine tumors and establishing the
01:09Yale and neuroendocrine tumor program.
01:12I'd like to highlight this is broadly
01:14part of the Center for GI cancers.
01:16We have a new Twitter handle
01:18and email which is here.
01:20These are my disclosures.
01:23I'm going to go over.
01:25I'm just a brief outline of epidemiology,
01:28nomenclature, and some key characteristics
01:30of Nets that impact treatment.
01:32We'll talk some about treatments,
01:35some clinical trials in which I've
01:36been involved over the last few years,
01:38and why we should create a.
01:40Net program at Yale,
01:41and then we'll finish with some future
01:44clinical and research opportunities.
01:47I like starting with a little bit of history,
01:49and I think this this one is
01:51especially important, so.
01:53Neuroendocrine tumors were recognized
01:55in the late 1800s and early 1900s.
01:59The term carcinoid,
02:01which means cancer like,
02:03has been attributed to doctor or
02:05Bender for a German pathologist.
02:07He felt that these had five key
02:10characteristics that they were small,
02:12and multifocal had undifferentiated
02:14cellular formations,
02:15well defined borders,
02:17no metastatic potential,
02:18and we're slow growing and harmless,
02:21though this was a very
02:22important contribution to the.
02:24Field we now know that these
02:26tumors are can in fact metastasize.
02:29They are in fact cancers,
02:31and unfortunately this
02:33really held back the field.
02:35In fact,
02:36for many many years these were
02:38not incorporated or included
02:39in cancer registries,
02:40and therefore it made epidemiologic
02:43and other studies very difficult.
02:45So we Fast forward to the 1980s
02:48when we developed streptozotocin
02:50and octreotide for the treatment
02:54of neuroendocrine tumors and
02:56hormone hypersecretion.
02:57And then there was really a desert
02:59of therapeutic and diagnostic
03:01advances for almost 30 years.
03:04And then you can see an explosion
03:07of research starting in 2011
03:09with a number of FDA approvals
03:11for everolimus and student Neb
03:13and pancreatic Nets and so on.
03:15I'm going to go into a little
03:17bit more detail on this.
03:18Up on the top we see that there are
03:21actually 3 new novel imaging modalities,
03:24three types of PET scans with
03:26different radioisotopes.
03:26Those have really completely
03:28replaced the use of octreoscan,
03:30so it's been an exciting time
03:32to be in the field.
03:34I'd like to also really dispel the
03:37myth that Nets are really that rare,
03:40so they are in fact low,
03:42have a low incidence rate,
03:44so that's the number of
03:45patients diagnosed per year,
03:46and we can see that in this figure
03:48from a seer epidemiologic study in
03:51yellow is the incidence of Nets the
03:53corresponding Y axis is on the left,
03:56so at present we have about 7 to
03:588 diagnosis per 100,000 patients
04:01in the United States.
04:03However, in the figure on the right.
04:05I like to also describe that these
04:07are a higher prevalent cancer
04:10than was previously recognized.
04:12The prevalence,
04:13meaning the number of patients
04:15alive at any
04:16given time and the net prevalence actually
04:19exceeds that of stomach and pancreatic
04:22adenocarcinoma combined, so I think
04:24it's a bigger public health problem.
04:25Many primary care,
04:27general oncologists will see these patients.
04:31Nets are epithelial neoplasms that
04:33are derived from neuroendocrine
04:35cells throughout the body.
04:37As Dan said, I may officially
04:39a card carrying GI oncologist,
04:41but they do in fact happen throughout
04:43the body GI tract most commonly
04:45followed by lungs and then other.
04:47And I actually see Nets of
04:49almost every primary site.
04:51I just saw a base of Skull net last week,
04:54so most grow slowly in comparison with
04:57their adenocarcinoma counterparts.
04:58The majority are sporadic with only
05:01the minority associated with inherited.
05:03Familial syndromes such as M1 MEN 2,
05:07von Hippel,
05:08Lindau and Neurofibroma Fibromatosis
05:10on pathognomonic for this disease
05:12or the presence of somatostatin
05:14receptors on the surface of the cells.
05:17There are five types and over 80% of
05:21Nets over express somatostatin receptor
05:23type 2 and we can take great advantage
05:26of this in terms of diagnostics and
05:29therapeutics and we'll talk about that also.
05:32And just a brief mention,
05:34this is a really cursory overview
05:36of net biology,
05:37but I did want to to bring this
05:40in large scale.
05:41Chromosomal alterations are common.
05:44Tumor mutation burden is low in the net,
05:47so that's the lower grade grade
05:491/2 nor underprint tumors.
05:51It's higher in neuroendocrine carcinomas,
05:53that's the Grade 3 or poorly
05:56differentiated recurrent somatic
05:57mutations are actually rare.
05:59There have been a number
06:01of fairly recent studies.
06:02So in pancreatic net,
06:03we will say somatic mutations
06:05in MN dachsund fate Terex we see
06:08mtor pathway gene mutations,
06:10mute YH,
06:11check two and bracket two and there
06:13are proposed or hypothesized at least
06:17four different molecular subtypes of
06:19pancreatic Nets and in small bowels
06:21we will see mutations in CDKN 1B.
06:25Tumor grade progression does
06:27occur in pancreatic Nets,
06:29and we have seen clonal
06:31evolution patterns as well.
06:32There was a very elegant study
06:34done by friends and colleagues.
06:35Doctors Nature Raj and Diane Reidy Lagunes
06:38at memorial that demonstrated this,
06:41and then germline alterations are also
06:43more common than previously thought.
06:45So in the Scarpa Nature Paper from 2017,
06:4917% of quote sporadic pancreatic
06:51Nets actually had germline mutations.
06:55In terms of the diagnostic work up,
06:57the mainstay of imaging is cross sectional,
07:00so either a multiphasic CT and that
07:03is key when you order a net CT.
07:06So you have to order it as multiphysics
07:09specifically with an arterial phase
07:11and or MRI somatostatin receptor
07:13imaging complements the cross sectional
07:16imaging octreoscan has been completely
07:18replaced by the gallium 60 Dota
07:21Tate or Copper 64 Dota Tate Pets.
07:24We still occasionally will use FTG.
07:27But that's really only for high grade,
07:29poorly differentiated disease.
07:31And as you can see in the figure on the left,
07:34this is a cross section through the liver
07:37with two hypervascular liver lesions shown
07:39in the arterial phase of the CT scan.
07:42So that's really important,
07:43as these can be missed if that
07:45arterial phase is not done.
07:47We also tissue diagnosis is important.
07:50We try to find the primary site as
07:52there are some differences in FDA
07:55approvals by primary site and then key
07:58minimum data elements on pathology
08:00include WHN grade Ki 67 mitotic
08:03index and degree of differentiation.
08:05Tumor markers are not all that
08:07helpful for Nets.
08:08In fact, Crimina, which has historically
08:10been used pretty widely,
08:12is in fact falling out of favor.
08:13I don't use it anywhere.
08:1624 hour urine 5.
08:17HIA,
08:18which is a metabolite of serotonin,
08:20is useful for those patients in
08:22whom it's elevated,
08:24and then they're all also other
08:26specific peptides.
08:26Any means which will speak about.
08:29So I like to think of six key patient
08:32characteristics that impact treatment
08:33will go over these briefly hormone
08:36status stage and burden of disease grade
08:39and differentiation pace of growth,
08:41primary site and somatostatin receptor
08:44status on these all yield potential
08:48clinical and research questions.
08:49So I I think it also helps frame
08:52the rest of the conversation today.
08:54So in terms of hormone status,
08:56we divide patients into functional
08:58and non functional.
09:00Functional refers to patients having
09:02symptoms from a measurable hormone.
09:04Carcinoid syndrome is the classic example,
09:07so this happens in about 10% of
09:09small intestine Nets and this is
09:11due to production of serotonin.
09:13Patients may have flushing and
09:15venous telangiectasia shown in
09:17the picture on the left.
09:18Patients are often misdiagnosed
09:20as having rosacea.
09:22They can have diarrhea, bronchospasm.
09:24Valvular fibrosis,
09:25as seen in that second picture
09:27which is fibrosis of the pulmonary
09:30and tricuspid valves?
09:32Pancreatic Nets can also secrete
09:34hormones in about 40 percent.
09:3640% of the time.
09:38Most commonly insulin,
09:39followed by gastrin,
09:40Glucagon and wezo intestinal polypeptide,
09:43and the symptoms are defined
09:45by the hormones to create it.
09:46And then nonfunctional Nets are patients
09:49who are asymptomatic or have symptoms
09:52that are not from hormone access.
09:55Stage and burden of disease.
09:56It's important to think about.
09:57Do they have localized or metastatic disease,
10:00liver,
10:01dominant,
10:01or widely metastatic or low volume
10:04or high volume and aren't new dodo
10:06pets really are the best tool to
10:09help us determine extent of disease?
10:11So as you can see on the left,
10:12this is a localized pancreatic net
10:14with you can see the pancreatic net
10:17here in the middle liver dominant
10:19disease with a liver really filled
10:22with with tumor metastatic disease.
10:24And then widely metastatic disease,
10:26and this is these are actually bone lesions
10:30throughout the axial skeleton. I'm a JCC.
10:33Staging follows other solid tumors,
10:35but the key point I want to make from
10:37this slide is that Nets were actually
10:39only added to the AJC staging as of 2010,
10:42so relatively new.
10:44Grade and differentiation is important,
10:47I just have highlighted the two
10:49most recent WHO classification
10:51for thoracic and digestive Nets.
10:54They are, I'd say loosely related,
10:58but there are some nuances and suffice
11:00it to say that the nomenclature and
11:03evolution of The Who classification and
11:05what we call these tumors is complicated
11:09and has changed a lot overtime.
11:11I'd like to just bring you to
11:13this right column of the 2019.
11:14Adjusted WHL classification so we now have
11:18well differentiated grade 1/2 and three Nets,
11:21and then a poorly differentiated carcinoma
11:24so that word carcinoma implies that it is
11:29grade 3 and has a Ki 67 greater than 20%.
11:33So piece of growth matters also,
11:35so I may need a patient who has
11:37had stable disease for many years,
11:39or I may meet a patient who has rapidly
11:42progressive metastatic disease and that
11:44matters in terms of how I select therapy.
11:47Primary site matters,
11:48as I'd mentioned some of our FDA approvals
11:51are really dependent on primary site,
11:54so for one example,
11:55sunitinib is only approved
11:57for pancreatic Nets,
11:58not for other primary sites.
12:02And then lastly of these characteristics,
12:04somatostatin receptor,
12:05is our newest characteristic that matters.
12:08This is just a really nice example of
12:10this same patient who had an octreoscan,
12:12so that's our older imaging tool.
12:15It required patients coming back
12:17to the facility two days in a row,
12:20and then our newer gallium 68 dotatate
12:22pet that has much higher resolution.
12:25I'll just highlight a couple
12:26of interesting points,
12:27so the pituitary gland is normally
12:29a little bit positive on this as is.
12:31Be or as are the liver has
12:34some normal background,
12:35but then spleen and that it's
12:37concentrated in the latter.
12:40So just a brief overview of what we have
12:42in terms of tools for hormone control.
12:45So somatostatin analogs are the mainstay
12:47of how we treat functional Nets,
12:51primarily carcinoid syndrome.
12:52There are two approved agents in the
12:55United States, octreotide and lanreotide.
12:57These are both approved for hormone control.
13:01They have the same affinity for
13:03somatostatin receptors 2 and five.
13:05The main difference is that octreotide has
13:08comes in both a short and a long acting form.
13:10It is an intramuscular injection whereas
13:13lanreotide only has a long acting,
13:154 minutes, a deep subq injection
13:18pass rate is a third form.
13:20It's approved in the US,
13:21in Europe for cushions.
13:23And then on the right is actually a new
13:27agent that is a was approved a few years
13:30ago on the basis of improving diarrhea
13:33for patients with carcinoid syndrome,
13:35diarrhea, telotristat blocks, TPH.
13:37It's the rate limiting enzyme in the
13:41conversion of tryptophan to serotonin.
13:44So I participated in this clinical
13:46trial when I was at Stanford and it
13:48reduces on average bound movements,
13:50about two per day.
13:51You may not think that is clinically.
13:54Important, but it often helps
13:55get patients out of the house,
13:57so it's again and it's oral,
13:59so that's great for patients.
14:03There are a number of
14:04tools for tumor control.
14:05They fall into four categories,
14:07somatostatin analogs, biologics,
14:10cytotoxic chemotherapy,
14:12and PRRT,
14:13which is peptide receptor
14:15radionuclide therapy.
14:17I am going to focus today just
14:18talking about two of these,
14:20so we're going to talk about
14:22tempos Olamide and capecitabine on
14:23the basis of a large randomized
14:25trial that I lead through the NC,
14:26TN and also the crescendo dictate,
14:29which is our sort of first and only so far.
14:33On peptide receptor radiotherapy
14:35for this disease.
14:37So this was a study and I think
14:38if there are any trainees on that,
14:40I started getting involved with E
14:42Cogen the national clinical trial
14:44network as a fellow and junior
14:47faculty it was a great opportunity
14:49for networking and mentorship.
14:51Through that I helped to develop this
14:53randomized study for patients with
14:55progressive, metastatic pancreatic Nets.
14:57Grade one and two half received
15:0010s Olumide alone and half received
15:02capecitabine and Thomas Alameda.
15:04Together,
15:04the maximum duration was 13 cycles
15:07to about one year,
15:09and the primary endpoint was
15:12progression free survival.
15:14So this study indicated a benefit
15:16of the combination arm with a
15:18median progression free survival
15:20of 22.7 months versus 14.4 months
15:23with a hazard ratio of .58.
15:27And the overall survival also showed a
15:31statistically significant difference.
15:33The median in the Thames Olumide
15:34alone arm was 38 months and it was
15:37not reached in the combination arm.
15:41And then in terms of response rate,
15:42this is actually a combination that
15:44yields one of the highest response
15:47rates of any available agent,
15:49so the response rate for the combination
15:51arm was 33% and the single agent arm 27.8%.
15:56These were not powered to determine
15:58a difference between the arms,
16:00but but I think another important
16:03takeaway is that both
16:04agents yield approximately a 30% record rate.
16:09So moving on to talk about Sonata Staten
16:13receptors also just a brief history.
16:15Somatostatin was sequenced in 1963.
16:19It's a naturally occurring peptide,
16:21but has a very short half life,
16:23so analogs were later developed in
16:26order to be clinically practical.
16:29There are two Nobel prizes on this list.
16:31The first is in the 1970s for
16:34doctors Gilman and Shelly on
16:36the discovery of somatostatin.
16:39And then later in 2012,
16:41doctors could Belka and Lefkowicz
16:43were awarded the Nobel Prize for their
16:45discovery of G protein coupled receptors
16:47to which somatostatin receptors belong.
16:51So I'd like to introduce you next
16:53to the concept of theranostics,
16:55and this is really important as
16:57we think about developing our
16:58yield or under consumer program.
17:00So imagine you have a group of
17:02patients you'd like to determine
17:04whether they have a specific target.
17:06You have a diagnostic imaging
17:08tool that actually helps select
17:10who in fact has that target,
17:12and then you have a targeted
17:14therapy that goes to that target.
17:16So Theranostics is using the
17:18same target for both therapy.
17:21And diagnostics.
17:23I like to think of this using
17:25a lock and key analogy,
17:26so the lock is that target,
17:29or the somatostatin receptor
17:30in the case of Nets,
17:32the key is the peptide or
17:35octreotide in our case,
17:37and the reporting unit is the
17:40payload or the radioisotope.
17:42So the diagnostics for Nets.
17:43I walked you through this a little bit,
17:46but it actually dates back to the 1980s,
17:48and using I won I won 23,
17:51labeled octreotide,
17:52but then it's been through this
17:55entire evolution of Indian 111
17:57which is Indian 111 octreotide.
18:00And so that's the octreoscan that
18:02was approved in 1994 and then in
18:05the 2000s we've had gallium 68,
18:07dotatate pet gallium 68 Doda
18:10talk pet and copper 64 dodat 8.
18:14So that and there is.
18:16I put the reference in here.
18:17There's a great article that's an
18:20appropriate use criteria for these
18:22somatostatin receptor imaging modalities.
18:25Therapy is similarly we can
18:26think about the lock and key.
18:28I use this analogy quite a
18:29bit when I talk to patients.
18:31So for peptide receptor radionuclide
18:33therapy there has also been an
18:35evolution first using Indian
18:37111 in the 2000s using yttrium
18:3990 and then later in the 2000s.
18:41Evaluation of lutetium 177 dooda tape.
18:45It was this clinical trial that I
18:47had the opportunity to lead while
18:49I was at Stanford and this was an
18:52international multicenter randomized trial.
18:55Get randomized patients with midgut
18:58or small intestine narendran tumors 2
19:01to one to receive 4 administrations.
19:03Ivy of this this radioisotope
19:06lutetium dotatate at 200 millicurie
19:10versus high dose octreotide.
19:13This was a positive study,
19:16so the primary endpoint was
19:18progression free survival.
19:19It showed a hazard ratio of .21 and
19:22this is one of our in the median.
19:26PFS was not reached at the time of the study,
19:28but is approximately 2 1/2 years.
19:31The overall survival had not
19:32been reached at the time of this
19:34initial publication.
19:35It's since has been reported actually.
19:37Just ask, oh,
19:38this year it did not officially
19:39meet statistical significance,
19:41but was a clinical difference.
19:43Of one year.
19:44So on the basis of this study,
19:46this was FDA approved in January of 2018.
19:48It was really fun to be part of
19:50a process of kind of a a novel
19:53class getting FDA approved,
19:54and then the clinical implementation of that.
19:58I'd also like to sort of
20:00postulate that's not a statin.
20:02Receptors are a perfect target,
20:05I'll just mention for other
20:06agents that are in very
20:08early phase studies.
20:09But Letitia Satureia tide is acineta
20:12Staten receptor antagonist so that
20:15Ludo date is actually an agonist.
20:18This was an early phase study
20:20that actually had quite a bit
20:22of grade 4K metalogic toxicity.
20:24They that led to some dose reductions and
20:26they are pursuing that in later phase.
20:28Committees PEN 221 is a peptide
20:31drug conjugate with DM,
20:32one that also just recently completed
20:35a small phase two trial and did
20:39not have a modest benefit rate.
20:41No PR's, but had an 88% on stable disease
20:46rate to do to Mab is a Sonata Staten
20:49receptor 2 CD 3 bispecific antibody
20:52also just completed a phase one study.
20:55Modest response rates but hadn't had a 55.
20:58Percent stable disease rate.
21:01Of note.
21:01I'll just mention I didn't go
21:02into detail in this today,
21:03but single agent checkpoint inhibitors
21:05do not work in low grade nor consumers.
21:08So the idea of trying to use
21:11combination approaches is very
21:12attractive and then led to 12 dot M.
21:15Tate is an alpha emitter.
21:17PRT alpha emitters are felt to be.
21:20I'm have fewer side effects and
21:22have more tumor cell killing.
21:24This just completed a phase or in
21:25the middle of a phase one trial.
21:27They just reported some.
21:29Early results,
21:30so in their first ten patients
21:32there was a response rate of 80%.
21:34So we are all very excited about
21:37the idea of alpha emitters,
21:39and so stay tuned on that.
21:41And then I did a tweet Oriel kind
21:43of on this medicine receptors as
21:46part of a Twitter tumor board.
21:49So what do we know about Nets
21:50as we start thinking about
21:52translational research questions?
21:53Well, we know there are chronic cancer.
21:55We know somatostatin receptors
21:57are unique target.
21:58Somatic mutations are rare.
22:00Tumor mutation burden is low and
22:02germline mutations are more common
22:05than was once appreciated and existing
22:07biomarkers or imperfect and we have a
22:10number of treatments that yield stability.
22:12Hodo dictates those progression
22:13and shrinks tumors in the optimal
22:15sequence of therapies is unknown and
22:17most patients receive therapies.
22:19From this experience years of toxicity.
22:22So how can we optimize PRT?
22:25How could we take better advantage of this?
22:27Meta Staten receptor?
22:28Can we identify resistance
22:30mechanisms and overcome them?
22:32And how can we develop predictive
22:34and prognostic biomarkers so
22:35the bar is low in the field?
22:37Needs your help,
22:38so this is part of my plea to the
22:40Cancer Center community to help me
22:42start thinking about translational
22:43questions as we develop teams for research.
22:46So one such team that I'm part of
22:50is the National Cancer Institute.
22:53Under Consumer task force that I chair,
22:55I had the opportunity to lead a
22:57clinical trial planning meeting
22:58this past year with.
23:00The objective was to really think
23:02about treatment in the era of PRT.
23:05I'll bring you down to the bottom here.
23:06Our deliverables are in manuscript
23:08that is in process.
23:09But really the deliverables are clinical
23:11trials and so we now out of this.
23:14Like many month process have a PRT re
23:18treatment clinical trial started or
23:20in development I should say and then
23:22we have working groups on looking at.
23:24PRT plus DNA damage repair PRT plus
23:28IO PRT and liver directed therapy
23:31ended in some dosimetry studies.
23:33So why build a net program at Yale?
23:35I hope I've shown you that there is
23:38a real renaissance in net research
23:40in terms of increased publications
23:42and clinical trials.
23:43The volume of net patients at
23:45YCC is increasing.
23:47There's significant downstream
23:48revenue of patients who have a high
23:50prevalent disease and are in our
23:52health care systems for a long time.
23:54We have the multidisciplinary
23:56expertise for metal, concert, junk,
23:58and endocrine and IR, a nuke Med.
24:00Our clinical trial portfolio is growing.
24:03There is philanthropic interest.
24:04I'd like to specifically thank
24:06the Alan and Cheryl Lipson fund
24:08for a generous and multi year gift
24:10that we have recently received.
24:12And really the timing is right.
24:14I think that with my arrival to
24:17Yale and really a convergence
24:19of all of this expertise,
24:21it's very exciting and we have
24:22identified Nets as one of our four key
24:25programs in the Center for GI cancers.
24:27So I have just a few minutes remaining.
24:29I'm going to kind of try
24:30to breeze through this,
24:31but our Yale net program is cold.
24:33By myself, dark crime.
24:35We are adding Doctor Mary McCoy
24:37and we have currently a monthly.
24:39Net support group and I'm sort
24:42of the anchor medical oncologist.
24:44And we are planning a PRT clinic.
24:47Some efforts around a nutrition education
24:49and a new theranostics program that
24:52Doctor Abovyan will be leading that
24:54will really have benefits beyond
24:57neuroendocrine to include Neuro and Gu.
24:59As I've mentioned,
25:00we have clinical trials.
25:01We just opened our first one and actually
25:03our first patient is enrolling on the
25:06net are two clinical trial this week.
25:08We have a biorepository enriched
25:09with net cases and we have a number
25:12of transitional team brands,
25:13one of which we just submitted last week.
25:16On looking at sex differences
25:18in neuroendocrine tumors.
25:20This is the net are two clinical trial.
25:22It's a randomized phase three
25:24trial for patients with advanced,
25:26well differentiated GI in order
25:28consumers that are slightly
25:30higher grade than the number one,
25:32and it's randomized loot 8 versus octreotide.
25:35I have a whole list of my wish
25:37list of other clinical trials.
25:39These are all NC TN trials that are in
25:42queue to hopefully open in the next year.
25:44This is a new alpha emitter as I'd
25:46mentioned where there's a lot of
25:48excitement about this and I serve on
25:50the steering committee for this study.
25:51So a shout out to the bio GI tumor
25:55biorepository led by Doctor John Kunstmann.
25:57It's been established for almost a decade,
26:00and I'd like to highlight that it's
26:02really enriched fernette cases,
26:03so we have 106 net tissue samples,
26:0670 of which are fresh frozen and you
26:09can see the breakdown of diseases
26:11and they're
26:11all associated with plasma,
26:13so a great opportunity for collaboration.
26:16And then lastly, in terms of education,
26:18we launched our Patient
26:20Education initiative in November.
26:21We have a CMU series planned and a
26:23number of trainees already involved.
26:25Carolyn Gordons of Pgy 2 who's helping
26:27to do a review paper on sex differences
26:30and or under commute classrooms.
26:32They shall shrikumar is helping with
26:35a pathology project in jamies Ang just
26:37completed a really wonderful JCO oncology
26:40practice review so please join us we
26:42have on Thursdays I'd like to highlight it.
26:45We have a great.
26:46In our series on Thursday
26:48afternoons from 4:15 to 5:00,
26:50and I think I'll end there.
26:52So, you know, we're really excited
26:54about building this program.
26:55I think our next step is
26:57really building on some of the
26:59translational research opportunities,
27:00so thanks.
27:02Thank you, Pam. Very exciting.
27:04Particularly these tremendous
27:06advances in therapy.
27:08Those are very impressive capital.
27:10Higher plots.
27:12So are there questions while
27:14we're waiting I-1 quick one.
27:16There's a huge increase since the 1970s.
27:19Is that just better diagnosis or is
27:21it incidents actually increasing?
27:23So that's a great question.
27:24I think that the diagnostics
27:26or have clearly improved.
27:28I think that we're seeing incidentally
27:30discovered GI Nets through colonoscopies
27:32to specifically rectal and colon,
27:35but I think that it
27:36probably goes beyond that,
27:37and so some hypotheses have been
27:39are there environmental risks
27:41that we have not yet picked up on.
27:42So I think some of its diagnostics,
27:44but some of it's something
27:45we don't yet understand.
27:48And you may have said this, but I missed it.
27:50Do you sometimes have patience with
27:52different primaries and different sites?
27:57That would be really infrequent,
27:58but can happen with some of our
28:01inherited syndromes, but usually
28:02they have a single primary site.
28:06Are there other questions in
28:08the chat or raise your hand?
28:15Well, I have another question we
28:17talk about briefly before we started.
28:19Has anyone looked for viruses in
28:22these tumors? I'm asking 'cause
28:24as we'll hear the next one,
28:25there is a virus involvement.
28:29So Dan, good question
28:30and not to my knowledge,
28:32and as I was sharing with you,
28:34I think that in this particular
28:37field the bar is pretty low.
28:39The the clinical science interestingly
28:41was way ahead of some of the basic
28:44understandings of the molecular biology,
28:46and in fact we knew that M Tor
28:48inhibitors worked clinically before.
28:50We knew that there were entire
28:52pathway mutations, somatic mutations.
28:54So I think there are a lot of
28:56really great questions we still
28:57need to ask in this field.
29:00Well, it's great that we have
29:01such a strong program here.
29:02Oh, thank you for doing that.
29:04I'm seeing whether questions we'll
29:05move on to our second speaker,
29:07so there's one quick.
29:09There is one question.
29:10I'm sorry.
29:11It just came in from Jeremy Jaycox.
29:14Do you see that?
29:18Yes. Had a dominant features of
29:21non STR Nets biologically and
29:23clinically compared to those that
29:25are somatostatin receptor positive,
29:27so that's another great question.
29:29I would say typically the patients
29:32who are noncitizen receptor avid
29:34have more aggressive disease.
29:36They tend to have lost.
29:37That's in Edison receptor
29:39as they differentiate,
29:41so it usually are the grade 3 poorly
29:43differentiated in order consumers.
29:45I'm as I mentioned,
29:46we can see great evolution over time,
29:48so sometimes a patient who may have
29:50initially been SSTR positive can lose.
29:52That
29:54and another question are there supportive
29:57services unique for this population?
30:02So so yes, and I actually,
30:05I'm really eager to work Terrace Hampton.
30:07I have talked some about this,
30:08but I think particularly for the
30:10grade one and two under consumers
30:12defined as a more chronic cancer,
30:14the chronicity of their
30:16survivorship issues, I think,
30:17is a really unique aspect that
30:19we need to pay more attention to.
30:20So hopefully we'll have
30:22more dedicated services.
30:25And and finally, what about
30:27differentiation therapy?
30:28Isaac Kim has a question on that point,
30:32yes, so in fact one wish list for
30:362022 is to actually bring together
30:39a multidisciplinary group of people
30:41to to examine new under condition
30:43ciation across specialties.
30:45So bringing GUGI thoracic
30:48folks together to release.
30:50Think about this as a team or
30:52underground differentiation.
30:53It can be an end differentiation
30:54for many cancer types and I think.
30:56We know very little about that.
30:59OK terrific, thank you for other people.
31:00Have questions.
31:01You should contact Pam directly.
31:04Our second speaker today.
31:07Get my little sheet out.
31:08Is is Kelly Olino from partement surgery?
31:11She's an assistant professor and
31:13received her medical training at Johns
31:15Hopkins and also residency there.
31:17Then a fellowship at
31:18Memorial Sloan Kettering.
31:20She came to Yale from the University of
31:22Texas Medical Branch and while in Texas,
31:24she was recognized as a Texas Rising Star,
31:27a Lone Star, a Provost,
31:29scholar and recipient of the
31:31Society for Surgical Oncology,
31:33Clinical Investigation Award.
31:34Interested in terminology including Melanoma.
31:37And her clinical specialties include
31:39treatment of patients with Melanoma,
31:41Merkel cell cancer which will hear
31:43about today and other other cancers
31:46and also interested in developing.
31:49Clinical trials,
31:50including immune therapy for
31:52these diseases and like what
31:54we just heard about merkle's,
31:55is a neuroendocrine tumor
31:57with the virus association,
31:58which makes it interesting to me.
32:00So I'm very interested in
32:01hearing what Kelly has to say.
32:05OK, it looks good.
32:07Great thank you.
32:09So, again, another neuroendocrine
32:12tumor and again another instance
32:14where it really was a here at Yale.
32:18Seeing more and more of a disease process
32:20and really relying on our skin cancer,
32:22spore and multidisciplinary networks
32:25actually build a relatively new
32:28program for a rare disease.
32:30So I have no disclosures,
32:32so today we'll talk about an update
32:34on the incidence, the management,
32:36and the treatment of Merkel cell carcinoma.
32:38And then we'll go into specifically
32:40some more recent work that we've
32:43done looking at our vast experience
32:45and benchmarking that against
32:47national guidelines,
32:48and then briefly.
32:49I'll mention some of the new
32:51research again supported through
32:52the score and through the the
32:54great relationships that we have
32:56through our skin cancer program.
33:01So. Merkel cell was first described as
33:05a true bickler carcinoma of the skin,
33:08and it wasn't until 1978 that it was first
33:11coined to even be a neuroendocrine tumor.
33:13However, at that time,
33:14thought to be derived from Merkel cells,
33:16which is actually not the case.
33:19It wasn't until 2008 that there
33:21was the discovery of a Merkel cell
33:23polyoma virus which is fairly endemic,
33:26as even being a causative factor in.
33:28In addition to UV radiation for this disease.
33:32And to be quite as we still don't
33:34even know what the cell of origin is,
33:37there's been some hypothesis that this
33:38may be from a pre pro fiesel which
33:41would fit somewhat with the increased
33:43incidence in patients with lymphoma.
33:45Other work is focused on dermal stem
33:47cells as well as dermal fibroblasts,
33:49but it's still a work in progress.
33:53As opposed to Melanoma,
33:55where we speak about the ABC's we
33:57use our vowels for Merkel cell.
33:59So it's the AEIOU's and these
34:02are known to be asymptomatic.
34:05They're not painful.
34:06The big thing with these and how they
34:08behave differently is their rate of growth.
34:11When we look about when we look at Merkel
34:12cell and the ones that I'm showing you here,
34:14one is an intransit picture on the right,
34:16but the other ones which are
34:18seeing we measure Merkel cells
34:20in centimeters versus Melanoma.
34:21We really measure that in.
34:23Millimeters or fractions of millimeters,
34:26so this expanding rapidly of a of a non
34:28pigmented mass really should open the
34:30thought that this could be a Merkel cell.
34:33It's more likely to be found in
34:35patients with immunosupression older
34:37patients and again can be associated
34:40with UV exposure and about if you
34:43one looks about 90% of each patient
34:45will have more than or equal to
34:47three of these characteristics.
34:52He immunohistological diagnosis
34:53is always based upon the primary
34:56skin lesion and generally speaking,
34:59most patients will present about 50%
35:01of the time with localized disease,
35:0435% with nodal disease,
35:05and about 15% of patients at
35:07the time of presentation with
35:09metastatic disease and up to 15%
35:12can present with an unknown primary.
35:16So as far as management for
35:20localized or Merkel cell carcinoma,
35:22it really is a surgical disease.
35:24So we recommend that we do a wide
35:26local excision with one to two
35:28centimeter margins when possible,
35:30you should perform a Sentinel node biopsy,
35:32again, with the caveat being the
35:35demographic population who can be high
35:37risk and elderly and may not be the
35:40best candidates for general anesthesia.
35:42Again, adjuvant radiation,
35:44which is very different than Melanoma.
35:46Merkel cells are exquisitely
35:48sensitive to radiotherapy,
35:49and again are much larger.
35:51The only times when we really don't
35:53consider radiation again for a given
35:55patient would be very small tumors,
35:57less than a centimeter,
35:59no lymphovascular invasion in
36:00the setting of a widely margin.
36:02Negative resection.
36:03There are times two that if a
36:06primary is unable to be respected.
36:08For example, very poor surgical candidate.
36:10You could have just local
36:13palliative radiation.
36:14Similar to Melanoma Sentinel,
36:17nodes are important prognostic value.
36:19Now, in the case of a
36:21clinically positive lymph node,
36:22so a patient presents with a
36:23lymph node that you can feel.
36:25In that case,
36:26the recommendation is that we still
36:28perform a therapeutic lymph node dissection,
36:30and it's controversial whether or
36:33not additional adjuvant radiation
36:35therapy is needed in that context.
36:38If someone undergoes a Sentinel
36:40lymph node procedure,
36:42if it's positive again,
36:43the options are to to go further.
36:46Surgical treatment.
36:48Or to actually undergo radiotherapy again,
36:52there's lots of series that are all
36:55retrospective in nature as we have
36:57no prospective data looking at this.
37:00And again, even if you're a central node,
37:01negative patient, again,
37:03fairly controversial radiotherapy.
37:05We typically would use here at Yale.
37:07There are some centers that still use that,
37:09and that really is,
37:10for instance,
37:11is particularly in head and neck cancers,
37:13where if you thought that your nodal
37:15mapping was poor or inaccurate that
37:17you could offer that to a patient
37:20adjutant therapy currently for Merkel
37:22still is just under investigation and
37:24actively ongoing clinical trials,
37:26including the stamp trial,
37:27which we have open at Yale.
37:31So for metastatic Merkel cell carcinoma
37:34used to be chemotherapy, first line
37:36with the topside and platinum agents.
37:38Those had very short lived responses,
37:41lots of toxicity, so we're abandoned
37:45beginning with two clinical trials that
37:48were completed and published both initially
37:51in 2016 and then updated in 2019 and 2020.
37:54Looking at pembrolizumab as frontline
37:58for metastatic disease with 50%
38:01overall response rates, which was.
38:03Which is fantastic compared to
38:05what we we saw historically with
38:07chemotherapy and then with PDL.
38:09One agents have a limo map with 33%
38:12just looking at the overall response
38:14rates and this again continues to grow
38:16and expand with additional clinical
38:18trials focused on immune therapy.
38:23So Merkel cell carcinoma is
38:26very interesting because of.
38:29The end product of your disease
38:31looks exactly the same.
38:33However, there are two completely
38:35distinct pathophysiology
38:37underlying the the tumorigenesis.
38:40Interestingly, as well,
38:41depending on where you live,
38:42for example, the US and Europe,
38:44about 20% of Merkel cell carcinomas are
38:46what we call what we think to be UV related,
38:49very different.
38:52Then Australia.
38:53In in the United States and Europe,
38:56again we see much more prevalent
38:59Merkel cell polyomavirus related
39:01disease and was interested
39:02again about this polyomavirus.
39:04It's really endemic it if you one
39:06looks from China to South America,
39:09it wouldn't were to swab patients.
39:11You know,
39:12usually this polyomaviruses found
39:14during childhood 6080% of people
39:17will be colonized if you take out a
39:19squamous cell or basal cell cancer.
39:21And if you look for Merkel cell polyomavirus,
39:23you'll see that in up to 25%
39:25of those samples.
39:25Even though it's not related to that
39:28Physiology, at least that we think.
39:31And again,
39:32any infection with a polyomaviruses really
39:34asymptomatic and we have patients come in.
39:36They're very,
39:36very concerned that they're going to
39:38give this to their spouse or their partner.
39:40But again,
39:40this is not something that that's really
39:43of concern as far as being contagious,
39:46and again,
39:47the UV mediated Merkel cell.
39:50Again, we don't know what the
39:51what the cell of origin is.
39:53However, what we know is that
39:55there's Burley mutations,
39:56particularly in RB one,
39:58and those become founder
40:01mutations in P53 and RB-1.
40:03And when we look at the metastases
40:06later in patients on autopsy study,
40:09we'll see that those are
40:10really clonal nature.
40:11However,
40:12for virally mediated polyomavirus
40:15associated Merkel cell,
40:17what you see is actually a critical
40:19event where there's viral integration
40:21and there's a small and a large
40:23T cell antigen and Merkel cell
40:25and what happens is that actually
40:27gets incorporate actually very
40:28close to where the the RB 1 gene
40:31is and what happens is that.
40:33Along T cell antigen as you look
40:36downstream that becomes truncated,
40:37it becomes a trophic factor and actually
40:41drives further growth of the tumor.
40:43Now,
40:43the things that are interesting in the
40:46UV associated Merkel cell carcinoma.
40:48This is very high in neoantigen
40:51burden as well as a high overall
40:53tumor mutational burden compared
40:54to that of the viral one.
40:56However,
40:56that has a viral T cell antigen expression,
41:00and interestingly,
41:01the responses to immune therapy are
41:04exactly the same regardless of the etiology.
41:09Why is this important?
41:10You know such a rare cancer is that
41:13it's actually growing and you know
41:15similar to the the question that was
41:18just asked of Doctor Kuntzman Dr.
41:21Kunz. We were actually really curious
41:23as to why we were seeing this.
41:26So this is a multidisciplinary
41:27effort really headed by Dan Jacobs,
41:30who is now a first year, head and neck.
41:33Surgical resident and this was done
41:36with myself or medical oncology group.
41:38Ben Judson from otolaryngology and Doctor
41:42Zhang from the School of Public Health.
41:44Really trying to answer the
41:46question so how we underwent this
41:48analysis is doing something called
41:50a age period cohort analysis,
41:53again similar to what's happening
41:54with neuroendocrine tumors
41:55and a lot of other cancers.
41:57Even thyroid cancer.
41:58When we're seeing increasing incidence,
42:00you want to say is this related to
42:02aging of the population which is?
42:03Really important for Merkel cell or
42:05as it related to the calendar period
42:08of diagnosis and the calendar period
42:10effect really is looking at well,
42:12are we better at detecting this?
42:14Are we more aware of the diagnosis
42:16and so that will affect equally affect
42:18people across all ages and then the
42:21last thing is really really important
42:23is the birth cohort and that really
42:25says are there real changes in risk factors?
42:27Is there something actually changing in
42:30the environment that's explaining the
42:31increase in incidence that we're seeing?
42:33In Merkel cell,
42:34we thought that this was a really
42:37important analysis to be done.
42:39Even though this is a rare disease,
42:41so we were able to do is we looked
42:43and use SEER data and we're able
42:46to get it over 3700 patients again.
42:48We saw what one would expect.
42:51Again,
42:51this is usually a male dominated disease,
42:53almost exquisite,
42:54almost exclusively found in
42:57Caucasians this year.
42:58Registry data becomes a little tricky
43:00'cause it just turns out by chance
43:02that the areas that are actually
43:04involved in this year registry happen
43:06to be some of the higher volume.
43:09Tertiary referral centres from
43:11Merkel cell in the country so you
43:14know that that data was was a
43:16little difficult to interpret,
43:18but again, we saw you know,
43:19head and neck primarily again
43:21just what we would expect to
43:24see localized regional disease.
43:26But the the APC analysis itself.
43:29What you can see here in panel
43:31A is what you would expect.
43:33So if we look at by the calendar
43:35period of diagnosis,
43:37right so that the the time that we've
43:39diagnosed and we look at age older patients,
43:42particularly with improving diagnostics,
43:44were seen in more age adjusted
43:48incidence rates happening.
43:49And we see that in men and women.
43:52More interestingly,
43:53if you look at panel C&D,
43:55when we look at the birth cohort effect now,
43:58compared by age and having looking
44:00at the age adjusted incidence,
44:03they're still seeing actually an important
44:05association due to the birth cohort,
44:08which really points to that.
44:09Despite that,
44:10the that we're better and more aware of
44:13diagnosing Merkel cell and that we
44:14know that this is a disease that's
44:17more prevalent in the aging population,
44:19there does appear to be something
44:22that has changed. Overtime,
44:23that's an environmental risk factor,
44:26although we don't know what that is.
44:31So and again, this is this is just part
44:33of the the conclusions of that paper.
44:35Once again, just saying that the
44:37the effect of how good we are at
44:39diagnosing this is really leveling out,
44:41yet the incidence is still going on going up.
44:44And that's not just explained by that.
44:47The aging of the population.
44:52So the second thing that I wanted
44:54to show again is some original
44:56work again put together by our
44:58multidisciplinary team here at Yale.
44:59Looking at our near 20 year experience
45:03taking care of this disease.
45:05And once again, this is work.
45:07Put together.
45:08The registry really brought together
45:10by Andrew Esposito who's one of our
45:13general surgery residents as well
45:15as Dan Jacobs who had worked on the
45:17other APC cohort analysis paper.
45:19And they really built this up.
45:21And then with the support of
45:23our Yale spore program,
45:25is also now the registry,
45:27being maintained by Ray Bowman,
45:29who who is a wonderful and really
45:31helps us with even our Melanoma program.
45:33So again, when we look at just our.
45:3520 year Yale experience.
45:37What we see are similar clinical
45:39pathologic features to what one
45:41would find at other centers when
45:43we look at the cause of death,
45:44what we see is only about 36%
45:46of our patients that we see are
45:49actually dying from Merkel cell.
45:51We see them recurring at rates
45:53that are similar to other centers.
45:55We do have a little bit more of an
45:57enriched in transit population,
45:59which may be due to how things
46:02are referred to us all. Be it.
46:04Even when we see patients who
46:05presented with de Novo disease,
46:07I do see more intransit disease
46:10than what I would expect if one
46:12were to compare that to Melanoma,
46:14and I think that Merkel cell does
46:16have very different biologic behavior.
46:18Again,
46:18when we look at our final
46:20pathologic stage again.
46:21We're seeing similar presentation as
46:24to what we would be seeing around
46:27the country at high volume centers.
46:30So the trends in treatment again with
46:32newer approvals, there's been very,
46:35very quick adoption of increasing
46:37frequency of immunotherapy for
46:39systemic therapy for patients who
46:42are eligible with the concomitant
46:44decrease in chemotherapy.
46:46The radiation therapy.
46:48Again, some of this,
46:51I think,
46:52is that we're having more patients
46:53who have better systemic treatment options.
46:56And some of the earlier patients
46:58who are seen because I think of
47:01improved recognition amongst the
47:03dermatologic community in the state.
47:05So I think that that explains a little bit
47:07of this decrease in the radiation receipt.
47:10But again,
47:11if we look at our initial nodal management.
47:14We're we're right on par with where
47:17we would expect our group to be.
47:20And our management is following yet again,
47:22national Trends 1 looks at
47:25surgical resection rates.
47:27The rates in which you're
47:29appropriately staging patients,
47:30nodal basins and those patients who
47:34are receiving non-surgical management.
47:36Again, what we're seeing here.
47:38And this is the data that we
47:40had pulled from SEER is is.
47:41We're very much on target with where
47:43we would expect our program to be,
47:45and in aligned with what's going on or
47:48across the nation in high volume centers.
47:51But one thing that that started to bother me,
47:54the more that I learned about Merkel cell,
47:57we thought it was a great
47:58opportunity when we were
48:00looking at our institutional
48:01series was there's many, many,
48:03many papers that were being published
48:06as retrospective series and they
48:09were really solely using overall
48:11survival as their outcome measure
48:14for trying to make conclusions.
48:17And we said, you know,
48:18this doesn't really sound right.
48:19We think there's competing
48:21causes of mortality.
48:22We had done our APC cohort analysis.
48:24We we know that age was
48:25driving a lot of this,
48:26so we said which you know no one
48:28had looked just for this specific
48:30disease before as we said.
48:31Does this make any sense?
48:33Should people be writing retrospective
48:36papers using things like the NCDB
48:39which doesn't have disease specific
48:41survival in it and writing you know how
48:43we should be managing a rare cancer?
48:46And the answer you know as you
48:47can see here nicely illustrated
48:49is we really shouldn't.
48:50So if one looks at by age
48:52if we break this down.
48:54Patients who are 64,
48:55which is young for Merkel cell up
48:58until about two years or so, right?
49:00Those patients and even up to three years.
49:02Those patients are actually
49:03dying from their Merkel cell.
49:04When we get to the more extremes of care,
49:07right?
49:09Your patients beginning at age 65 to 74,
49:12but particularly those about 75.
49:14Many of those patients, and again,
49:16we're talking about patients
49:17who are immunosuppressed.
49:19They're actually not dying from Merkel cell,
49:21so it just makes us pause and say,
49:25you know, we just need to be very,
49:26very careful,
49:27particularly on these retrospective data.
49:29How we're looking at it.
49:30So again,
49:31because we had our own cohort where
49:33we could look at recurrence disease,
49:36specific survival and overall survival.
49:41We said,
49:41well,
49:41let's take a look at that in our own
49:44cohort and what things that we saw that
49:46were associated with overall survival.
49:48Again,
49:48what you would expect age
49:51female sex was protective.
49:54If you are immunocompromised again,
49:56you know it makes sense that your
49:59mortality would be affected by that.
50:02It more advanced disease.
50:03If you've had in transit disease,
50:05but usually if it's really
50:07related to the disease.
50:08One of the things that your overall
50:10and then your your disease disease
50:13specific survival really should.
50:15Sorry guys,
50:16should really actually match
50:18up and hear the disease.
50:20Specific survival and those
50:22factors for overall survival
50:24are actually quite discordant.
50:26The things when we look at
50:28disease specific survival,
50:29the thing that stood out the most was
50:31actually patients who were active smokers.
50:33With the hazard ratio up to 14,
50:36which actually hadn't been
50:37previously described,
50:38but subsequently there's been one or two
50:40papers which have also echoed this finding.
50:42But really,
50:43some discrepancy and again,
50:45our our institutional cohort is limited
50:49because we don't have thousands of patients,
50:51we only have hundreds.
50:53But again,
50:54it really made us almost add an
50:57editorial to the paper itself,
51:00which then was published in the
51:02Annals of Surgical Oncology.
51:04So the overall conclusions are
51:06the surgical and the medical
51:07management continue to evolve
51:09with the utilization,
51:10particularly of immune therapy.
51:12For our paper. What we found was
51:15that there was little consistency
51:16between factors associated with
51:18overall and disease specific survival
51:20for Merkel cell carcinoma patients.
51:22And, as I mentioned,
51:23competing risk for mortality,
51:24particularly these older or
51:26immunosuppressed Merkel cell patients
51:28makes the use of overall survival 8
51:31poor surrogate for therapeutic outcomes,
51:32particularly these retrospective analysis.
51:34And there are hundreds of papers that I
51:38think that this statement applies to.
51:40So moving forward,
51:41I think that as a Community it would
51:44for these rare diseases we really
51:46need to get more work together
51:48for more prospective data.
51:53And then just finally and then I'll
51:55pause for questions I just wanted to
51:58just briefly highlight just one segue
52:00into some of the translational research.
52:02Again, that's been aided with
52:05the skin cancer score.
52:08So again, we have we talk about a similar
52:11disease with two separate ideologies,
52:14almost similar to some of what we
52:16see now with HPV related tumors.
52:18You can have squamous cell tumors
52:19of the head and neck,
52:20summer virally, associated summer,
52:21non virally associated in UV.
52:23So a lot of work that's been done in
52:25other fields and now seeing that there's
52:28response to immune therapy really allows you
52:30to look at things scientifically in a very,
52:33very interesting way where you can see
52:35viral associated non viral associated.
52:38And see what are the resistance
52:40patterns that can develop in both and.
52:43We had looked at this again.
52:44You know, again, immune therapy being used.
52:46But again when we're looking at resistance,
52:49there's work that's been headed by Jeffy,
52:51Shizuka and Jessica Way,
52:52and now Alex Frey,
52:53who's a surgical resident in Jeff's lab,
52:56is really looking at novel ways
52:58that we can take fresh tissue.
53:00Again,
53:00building upon our strengths in our
53:03Melanoma program with the score and really
53:06looking at these different conditions
53:08and then getting really great data,
53:11even unlimited samples,
53:12and.
53:12And this is work that that Jeff has
53:15has been doing with myself and others,
53:17and really pushing forward again.
53:19But all of our data is too preliminary
53:21to kind of show in a setting like this,
53:23but I'd like to say that maybe a year
53:26or two from now that we may have new
53:29targets or new ways that we could
53:31look at things ex vivo to make better
53:34targeted treatment for these patients.
53:38So again,
53:38thank you everyone for your time,
53:40and I'll pause for questions.
53:47Well, thank you Kelly.
53:49Very interesting.
53:50I'll start with a question.
53:51While people are gathering
53:53their own questions.
53:55Is there any prospect for a
53:56vaccine against Merkel cell virus?
53:58I know it's a relatively
53:59rare disease which is going
54:01to make that difficult,
54:02but with new technology,
54:03maybe not so crazy.
54:06So it's a great question.
54:08So for the polyoma virus itself,
54:11they're probably.
54:11It doesn't make sense to make a virus,
54:14but you know it sounds like
54:15you've been listening into Jeff
54:17and his research meetings.
54:18You know with some of the new
54:20technologies that we've seen with
54:22COVID vaccination and so forth,
54:24there may be a role for development
54:26because there are T cell antigens
54:28with this similar to something like
54:30HPV where there may be ways that you
54:33can do combination of a vaccination.
54:35Approach almost similar to wait Akiko
54:38Iwasawa's doing with the cervical cancer.
54:40So I think that that would be a great field.
54:43And if there's any experts that want to
54:45work with Jeff and I just give me an email.
54:49OK, great so there are some questions
54:51in the chat. Do you want to?
54:52Can you read them or do you
54:53want me to read them? Uhm?
54:56Insights into the differences in
54:59biology in the younger patients.
55:01So the patients I I worry about patients
55:05particularly who are less than 60 years old,
55:08and if those patients who
55:10are less than 40 years old,
55:11you almost want to double check
55:13that you have the right diagnosis.
55:15So as you're seeing from part of that
55:18analysis that we looked at between
55:20mortality and overall survival.
55:22Again, anecdotally,
55:22I think that the disease is
55:25more is more aggressive.
55:26I think we may see more metastatic disease.
55:29You don't have to re look at.
55:31Look at that specifically,
55:33but there's there's certain thing
55:35that's driving that in a different way.
55:37To have that earlier and again,
55:39these younger patients that we're
55:40seeing them in interesting,
55:41they're not immunocompromised.
55:45Just Clark has a question,
55:46is there a specific tissue
55:49or reservoir for the virus?
55:51Among many people who have it.
55:53It's just on the skin. It's good.
55:58There's some plot, and there may be
56:00some reservoir also in the GI tract,
56:01but usually it's a conventional skin flora.
56:07Brenda emails asked overtime.
56:08Is there a difference in the proportion
56:10of cases at a UV versus virus associated?
56:14So from our own cohort,
56:16unfortunately we're not able to
56:18answer that question we're creating,
56:20hopefully a TMI.
56:21We're trying to get that together
56:23because there wasn't a difference
56:25in how patients were treated.
56:27They historically at Yale.
56:28The immunohistochemistry stain for the
56:31polyoma virus in Merkel cells wasn't done,
56:33but we're very close to having
56:35all of that put together to
56:37start looking at that clinically.
56:38And like I said retrospectively,
56:40we're hoping to be able to look at that.
56:43And or HIV patients that
56:45increase risk. Of this tumor,
56:47not if they're well controlled,
56:49so more are CML patients.
56:53I worry about those, and then probably
56:56just general Immunosenescence is
56:58probably important post transplant.
57:02We don't see their their higher
57:04risk for Merkel, but you know.
57:06Again, it's a rare tumor,
57:08so we don't see this as much as we
57:12see horrible, poorly differentiated
57:14cutaneous squamous cells.
57:15You know, that's usually what we.
57:16We're worrying and battling
57:18more with these patients,
57:19but we do see it more often
57:21in the transplant patients.
57:22Perfect. Are there other questions?
57:28If not, I'll thank
57:29you very much. You're very interesting
57:31talk actually to both speakers,
57:32and we've learned a lot about
57:34neuroendocrine tumors today. Thank you.