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

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

January 12, 2022

Yale Cancer Center Grand Rounds | January 11, 2022

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

ID
7342

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.