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

Transcript

• 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.