Defining early-onset CRC and improving outcomes for MSI-H rectal cancer: Dr. Cercek (2022)

Manju George 00:00
Welcome to DocTalks. I’m really excited to have Dr. Andrea Cercek with us today. I am Manju George, the Scientific Director at Paltown, the nonprofit that supports Colontown. So a little bit about Dr. Cercek. She is an oncologist at Memorial Sloan Kettering, and she finished her MD from New York Medical College. She is also the Section Head of colorectal cancer and Co-Director of The Center for Young Onset Colorectal Cancer and Gastrointestinal Cancers. And her research focus is on the development of new therapies for patients, including molecular based therapies to improve outcomes for patients with metastatic disease. So we’re really excited to have you here with us. And thank you.

Dr. Andrea Cercek 00:44
Thank you so much for having me. It’s my pleasure to be here. So I thought I would talk a little bit about our Young Onset Colorectal Cancer Program and what we’ve done with our center, with our program, and then how we’re specifically looking at trials and trying to improve outcomes in all of our patients, including patients with early stage or locally advanced disease, in an effort to not only improve their outcome, but also minimize the morbidity of treatment that we have currently available, specifically in rectal cancer. I hope to leave a lot of time at the end for questions, but also feel free to interrupt me at any time. So the incidence of young onset or early onset colorectal cancer is rising. And that’s defined at the moment still as cancer under the age of 50. And that’s in sharp contrast to what we’re seeing in patients over the age of 50, which we attribute the improvement or the decrease in incidence in people over 50 to screening colonoscopies. But in people under the age of 50, it’s rising so much so and it has been this steady rise, that by the end of this decade, we actually project with computer modeling that the incidence is going to nearly double and that 1 in 10 of all patients with colon cancer and 1 in 4, so 25% of all patients with rectal cancer are going to be under the age of 50. And this rise is actually leading to a shift and a decrease in general in the incidence of colon cancer in the United States, and really what has prompted the current screening guidelines to be lowered to age 45. So although that’s good, I’ll kind of show you why we’re still not there yet, although that is a significant improvement still. We’re catching patients much earlier, with the decrease at 45. But the highest rise is actually in the 20 to 30 year olds who we really are not screening. So the cause is unknown. So there’s a lot of culprits. We’ve been eating more processed foods, junk food, foods high in sugar, we’re much more sedentary, as a group in general, sitting in our cars, sitting on our couches, staring at our devices, and then we’re ingesting different things than we used to. And this change, I should say, has really been going on since the mid 1990s. And so what are the some of the things? There’s definitely more drugs that have been available. Antibiotics are a primary suspect, because we’re definitely taking much more antibiotics than we used to decades ago.

Dr. Andrea Cercek 03:30
And then just a quick mention of racial disparities. So definitely within the United States, young onset colorectal cancer is rising in all groups, but it remains much more prevalent specifically in African Americans, high incidence in Asian Pacific Islanders, very high incidences in Hispanics, as well as in American Indians and Alaskan Natives. The shift is actually interesting in that, although in general, African Americans or blacks have a higher incidence of colon cancer and higher mortality, which has been reported and known for many years, and that applies to people under the age of 50, as well as people over the age of 50 for unknown reasons. Early onset colon cancer specifically is rising much more in non-Hispanic whites and has a higher tendency to be left sided, whereas cancer in blacks, including early onset cancer, tends to be more right sided. And this reason for location is really unknown. But there has been this general shift so that the mortality actually in non-Hispanic whites, in rectal cancer in particular, is approaching that of African Americans, which is something new that we’re not used to seeing. And obviously, all of this remains a huge problem in the United States, as well as globally, actually. So one of the main suspects, of course, is the microbiome and that’s the bacterial flora, sort of the normal gut microenvironment that exists in our intestinal tract that is meant to be part of our intestinal tract, we believe has shifted. We don’t have the evidence for this yet. There’s a lot of active research going on in this area. But we know that there are these good bacteria and bad bacteria. And when we have too much of the bad bacteria, actually, in mice models, we can see that they lead to these bad bacteria, what are called proinflammatory that cause more inflammation, can actually lead to polyp formation and lead to cancer formation. So that’s why this is one of the main suspects. And we know with things that we’re ingesting, foods, but especially things like medications, and especially things like antibiotics, we shift that flora. And we’ve seen lots of evidence of that, outside of this young onset population. And now we’re taking a deeper dive into our younger patients.

Dr. Andrea Cercek 05:56
This is just a nice graphic that I like that sort of looks at our bacteria that might influence the intestinal lining. What affects it in our diet? What are we ingesting from our environment? What have we been exposed to? Are we overweight? Are we exercising? Are we not exercising? Are we very sedentary. There has been data published that watching too much TV has been associated early onset colon cancer, not being outdoors enough, not having enough Vitamin D? Is there some sort of genetic or epigenetic predisposition that we don’t know about that might be leading to this? And then, of course, as I mentioned, exposure to certain medications and how that plays into this whole process of early onset colon cancer.

Dr. Andrea Cercek 05:56
And when we when we think about colon cancer and how it forms, if we believe that it develops the same way that we’re used to seeing in our 60, and 70 year olds, then this might start in really young people, like actually in infancy. So there might be some changes, perhaps that the mother while pregnant is ingesting some antibiotics, perhaps due to the way that the baby’s actually born. vaginal delivery exposes the infant to necessary bacteria that without that bacteria, if they’re born by C-section, maybe that offsets that. And maybe it’s even as early on as infancy or early childhood. So it’s a very sort of challenging area in terms of risk factor assessment, because it is quite extensive and also dates so far back. So it’s hard for people to say, oh, yeah, I took a lot of antibiotics as an infant, or this is what I was exposed to at birth or question things like were you breastfed, were you not breastfed, all of those are very important questions that come into play, but are very sort of hard to pinpoint down in this population. But there’s a big effort ongoing with that. And then the question is, though, there’s these changes in our microenvironment and then how do other factors come into play like our immunity, or things that affect our immunity adversely, something that we might be exposed to in the environment. Obesity, we ask patients, were you obese? Or when we meet them, they’re not obese, in fact, many of them are very fit, but were they obese as an infant or as a young child, those are all really important things that we need to take a look at. And then things such as diabetes, or what we call this metabolic syndrome, that affects our way of metabolizing certain things, and offsets that balance that perhaps might lead to early onset colorectal cancer. So all of these are very high suspects. So what we think is it’s this interplay, as I just described.

Dr. Andrea Cercek 07:51
But what we know, and what’s really actually very scary, is that this is a global phenomenon. So this is not unique to the east coast, where I am, of the US and it’s not unique to the United States. It’s really occurring all over the world, in developing countries, but also in developed countries and even in countries that are smaller countries. For example, my native country, Slovenia, very small country, very farm-to-table, very active in general as a population and yet we’re seeing this really significant rise. We’re seeing it in Asia. We’re seeing it in Australia. So it’s happening everywhere and so there must be some unifying factor behind this that we have not yet identified. So in an answer to this, actually, we opened our Center for Young Onset Colorectal Cancer. So it’s the center at Memorial Sloan Kettering dedicated to patients under the age of 50. We established it actually almost four years ago now. We were the first center in the world. And I’m happy to say that many other academic centers in the United States and now the world have actually followed suit, which is really fantastic and really important. And we helped them establish those centers. And the idea here was that we were seeing more and more young patients. The patients had different needs than what we were used to taking care of in our patients who were 60 and 70. And that’s not to say that treatment, you know, toxicity of treatment, financial toxicity, family dynamics are not important when you’re 60 or 70, but it is very different when you’re in your 20s, just starting your life or in your 40s, taking care of your young children, taking care of a potentially even aging parents having to deal with the burden of going through treatment. And so we really noted, actually with the help of many patient advocacy reports that were really influential, that patients really felt sort of at a loss after treatment, and that we felt that if we were able to offer early intervention, with ancillary support services like social work, everyone in our center meets our social worker at least once and many continue their care with her. Some are referred out to other support groups, some just don’t need such support and others, we refer to psychiatry and psychology, we have early fertility, which we noted is very critical for our patients. Others have since published this data that really even a conversation, even if they have advanced disease, at least a conversation and ability to decide whether or not they would want to have a child, even if it meant they weren’t going to live to meet that child was very critical for our patients. And so that’s something that’s offered early on. For our patients, sexual health is critical. It is very, very important in our patients with rectal cancer in particular, because of all the toxicity from treatment from the radiation and from surgery, but all of our patients in general, even men who undergo surgery. So we introduced sexual health or early on. Integrative medicine., many of our patients are interested in doing something for themselves in addition to the chemotherapy. Can I take vitamins? Can I do acupuncture? So we have a fantastic Integrative Medicine Department that offers those services that I find critical. And of course, the rest of the medical care remains as it would have been in terms of the referrals to medical oncology, surgery or our colleagues in radiation oncology. And then our second and equally I think as important objective of our center was to establish a clinical database. So a prospective database of all of our patients that come through the door enroll in our program. We have a biospecimen repository. So we collect things like stool for that microbiome analysis that I mentioned. We have a very lengthy, but important risk factor questionnaire, from infancy into early adulthood, in terms of potential things that they were exposed to. We collect blood as well, as well as tumor tissue for analysis.

Dr. Andrea Cercek 12:54
And just to give you an example, this is actually our team. Larry, on the left is our fantastic Project Manager without whom we would not exist and he meets the patients early on, introduces them with an email and an information session and helps us manage the database. Hadley is the second from the left. She is our social worker who I mentioned, meets all of our patients. That’s me in the middle and then my Co-Director, Dr. Mendelsohn is a gastroenterologist. And Asha is one of our Research Coordinators. And we’ve since expanded to other research coordinators and are hiring a nurse practitioner as well. So this is just an example of our patients treated. Unfortunately, we have no shortage of patients. We started out with 201 patients in 2018 and now we’re now up to 519. These are new patients under the age of 50 that walk through the door in this case. These are not existing patients that are part of our center. These are brand new people that we met in 2021, despite COVID. So really a large number of patients.

Dr. Andrea Cercek 13:58
And so just to give you a little bit of a sense of what early onset colorectal cancer is. One of our first questions and a really important research question is what are we exactly dealing with? Is this a totally new disease? Is this something that we’re not used to seeing? Or is this simply a disease that used to happen in people in their 60s and 70s that’s now shifting all over the world to happen younger and younger and younger. I had two 15 year olds this year. Pediatrics called me and said, This is not our disease, please help take care of these patients. So I treated them with the help of our Pediatrics Department, which is not something that we were used to seeing. And more and more of this is happening. So the crux of the question, I believe, was new disease? Something different? Or same disease and shifting? And how do we better treat it were the questions that came after that.

Dr. Andrea Cercek 14:52
So what do we know about this disease? So initially, the reports were really alarming. The large majority of these patients presented with late stage disease. And the thoughts were well, this is more aggressive. this is a different disease, this is something that we’re not used to seeing. But remember these are patients that are not being screened. And a lot of patients, not as many as there should be, but a lot of our patients over the age of 50, are thankfully detected and diagnosed with those screening colonoscopies. So they might have a stage I cancer or they might have stage II cancer that was caught early and that’s how they’re detected. These patients, many of them just don’t didn’t undergo screening because it was not recommended. But additionally, what we learned actually from the Colorectal Cancer Alliance, their analysis, their survey, is that a large majority of these patients saw at least two physicians prior to being diagnosed. They were kind of dismissed as Oh, this is hemorrhoids, this is nothing, just rectal bleeding, you’re fine. It didn’t occur to anyone to refer them for that screening colonoscopy. And then what we learned also was that many of our young patients actually themselves, deferred going to a doctor. They were busy, they had exams, they had a job, they had family to take care of so they didn’t undergo screening for six, seven months, or didn’t see a doctor rather, for many months, minimizing their symptoms, minimizing their rectal bleeding. So a really important thing that we want to spread to the general public is if you have persistent symptoms, go see a doctor, this could be happening, even if you’re in your 30s.

Dr. Andrea Cercek 16:33
And then what we looked at and others have looked at as well is, is this a hereditary cancer? Is this something that we’re used to seeing, you know, Lynch Syndrome, familial polyposis, adenomatous polyposis that we’re just seeing more of for whatever reason. And in fact, this is not the case. 60% or more of these were more random, or what we call sporadic where they don’t even have a family history. So their parents are in their 50s/60s, they’re completely fine with not even a polyp on their screening colonoscopies and here are these 30 year olds with colon cancer for completely unknown reasons, completely sporadic or random. So as I mentioned, our first question was really to take a good look at this. So we had a lot of patients, we had nearly 1,500 patients, half under the age of 50, half over the age of 50. And we wanted to look at their tumor biology. We know the molecular signature of colorectal cancer very well. We know that left sided tumors look different than right sided tumors. This has been reported. This is established. We actually treat them differently for all comers. And so our question was, if we can take a very good look at the molecular signature, but have complete clinical annotation, including not only the age of the patients, but the whole treatment history, the presenting symptoms, the location of their tumor, and then look at the molecular genetics, with that in mind, do we still see any differences because earlier reports were saying, Oh, it looks different, but they didn’t have the full clinical annotation and we know that if we take a group of 60 year olds, and we compare them, they may look different, because those that have a right sided tumor will look different than those with a left sided tumor. So that was really, really important to take a look at. So what we saw is that more patients that were younger, under the age of 50, had rectal tumors, and we were not the first to report this. This was known and we saw this as well. Why this is, we don’t know. But this was definitely the case for us. Because of that more young patients presented with rectal bleeding because of the tumor location, if it’s in the rectum patients bleed more, whereas if it’s on the right side, they tend to have more anemia. And that’s what we saw in our groups exactly. And then when we looked at the actual genetics, there was no difference. So left to left the tumors in even our very own cohort and our patients over the age of 50, even in their 70s and 80s, no differences when comparing left sided to left sided or right sided to the right sided. Suggesting really to us that in this population, these were predominantly stage IV metastatic tumors, when you truly compare and have a clean comparison, it really looks like the same disease. So there really was no difference. And although we all wanted to find something, we wanted to have this difference, we believe that this was really explained by this general shift in incidence, something is changing in our intestinal tract that’s just causing us to make the same tumors so much younger than we used to. And what kind of goes along with that, and I think makes matters even worse, is that this rise is not unique to colorectal cancer. We’re actually seeing this in other GI cancers as well throughout the intestinal tract. So young onset cancers are rising in pancreas, in appendix cancers, I see a lot of appendix cancers, many of them are under the age of 50, and this is rising in stomach cancers, and other neuroendocrine cancers as well. So something clearly is changing throughout our gut, it’s not unique to the colon. The colon is most common, obviously, it’s most common in general.

Dr. Andrea Cercek 20:20
And you could see here from the numbers, we roughly doubled our numbers when we look at all gastrointestinal cancers under the age of 50. But because of this rise, and because all of our young patients have the same clinical needs that our colorectal cancer patients have, we’ve actually expanded our center with all the services as well as the research focus, to all of GI, not just limited to colorectal cancer, with our numbers now approaching just under 1,000 patients a year under the age of 50 with GI tumors. So that’s been a really important piece of our center, this expansion with clinical support. And as I mentioned, we’re growing our clinical support team to better be able to take care of our patients. We have great established research efforts with our basic scientists, including applications for NIH funding, looking at things like microbiome, looking deeper into the tumor biology, epigenetics. Thankfully, and I’m very proud and very happy that with this we have great collaborations established with other centers in the United States, including Dana Farber. And we’ve helped established their center and are now collaborating with several analyses, including microbiome and risk factor questionnaire, which is fantastic, and super important. And then as well as internationally. As I mentioned, this is rising globally. So we really need to look beyond MSK, for sure, but beyond the East Coast, beyond the US, putting our heads together to try to figure out why this is happening. And then we have a number of clinical trials that are looking to address unmet needs and improve outcomes. So in terms of unmet needs, a big one that comes up for us all the time is fertility. As I mentioned, all of our patients need and deserve this conversation. But it’s challenging for us to sort of give them hard data to say, okay, you need surgery, and then you’re gonna get adjuvant chemotherapy with 5FU and oxaliplatin as we give our colon cancer patients, but I can’t quite quote you exactly what’s going to happen with fertility. We have a little bit of data based on a retrospective survey that we did, a little bit of data borrowing from the breast cancer data, but we don’t actually know from our own patients with our own chemotherapy, exactly what happens to their hormones when they regain their menstrual cycle. Can they have babies? Specifically in colon cancer in the curative setting in the adjuvant setting, but also in rectal cancer, where we use a lot of radiation and surgery, we don’t know the effect for example of radiation on testicular scatter. So we have a protocol now looking at patients with colon cancer and with rectal cancer in the curative setting, monitoring things like female hormones, LH/FSH. What happens to them on treatment? What happens to them off treatment and follow up into survivorship? What happens to sperm counts, sperm motility, the quality of the sperm during radiation and after radiation? And then in women as well, we’ve improved our radiation techniques for rectal cancer. We can move the ovaries outside of the field. We can do a lot of things. But we tell our young women that radiation to the surface renders it incapable of carrying a fetus due to the effects of the radiation and the scarring from the radiation on the blood vessels that supply the necessary blood to the uterus. But radiation techniques have improved. And so the study will also look at the blood supply to the uterus to see if perhaps that may not be the case, or what actually the effects are of the radiation on the blood supply specifically.

Dr. Andrea Cercek 24:11
And then today, I’ll talk a little bit about one of our trials looking to improve outcomes in locally advanced rectal cancer specifically. So this was a Phase II Study of Induction PD-1 Blockade in Patients with Locally Advanced Mismatch Repair Deficient Rectal Adenocarcinoma. It’s an ongoing study that we opened in December of 2019. So the rationale behind this was that we do well with total neoadjuvant therapy for locally advanced rectal cancer. So this is in all comers and remember, rectal cancer in particular is quite common in our young patients under the age of 50. That’s what’s really rising the most. And so what we do is in an early stage tumor, we give all of our therapy upfront before surgery, so that includes chemotherapy and radiation, then we restage them, and then we take them to surgery. And the idea of this approach is really to maximize response, decrease the chances of micrometastatic disease because we’re treating everything early and improve surgical outcomes. And in some patients, if they have a complete response, we’re able to actually defer surgery. It’s always with a discussion with the surgeon, but there’s been a lot of movement towards nonoperative management in this field. Specifically, because of the morbidity associated with rectal surgery. Many of our patients, up to a third, need a permanent colostomy. So we kind of were one of the first groups to establish sort of the benefit of total neoadjuvant therapy. There were earlier studies going on, but we really showed that when we give all this therapy upfront, which is called total neoadjuvant, therapy or TNT, you could see that our response rates are either tumor either being completely gone with surgery or completely gone with clinical evaluation, improved from 21% when we used to give chemoradiation alone and then surgery and then did chemotherapy, to 36% when we gave all of the treatment upfront. So that’s part of the NCCN Guidelines now and pretty established at most centers as the standard for locally advanced rectal cancer. So we do better. However, surgery as I mentioned, still has a lot of toxicities. Many patients experience urinary incontinence, many patients experience sexual dysfunction, men more so than women. It’s not talked about as much, but it’s true, and defacatory problems, up to a third, and a permanent colostomy in many of our patients that have very low tumors. And so these are not trivial. So although it is a curative procedure, and critically important for our patients, it does come with significant sequelae, which affect everybody but especially our young patients. Radiation also has its consequences. There’s short and long term toxicity of radiation. So negative impact on bowel function, bladder function, sexual function, which is critical for many of our young patients, reproductive function as well. Chemotherapy is important in downsizing but also has its own set of potential toxicities. So the idea behind chemotherapy is that we’re giving it for treatment for metastatic disease early. We’re giving it early to potentially have the opportunity of maybe not radiate or maybe not do surgery. And it can actually get rid of symptoms quite early, we found actually faster than radiation. And critical, I think here for us, is that actually it can give us a clue as to who those patients are that don’t respond to chemotherapy.

Dr. Andrea Cercek 28:12
So mismatch repair deficient locally advanced rectal cancer, or what’s known as MSI-high comprises about 5 to 10% of all locally advanced rectal cancer. So there’s about 40,000 of those a year. So about 5 to 10% of those, roughly maybe about 4,000 or so cases annually. The majority of these patients do have Lynch Syndrome. So they are part of our young onset patients, but these actually have a specific hereditary predisposition, not all. So some of them are still sporadic and are mismatch repair deficient. But about 84% of them do have Lynch Syndrome. And because they have Lynch Syndrome, many of them are very, very young because they’re diagnosed for the first time when they present with this cancer. We know that this particular subset of tumors don’t respond well in the colon to adjuvant chemotherapy, so to adjuvant 5FU alone. And what we noted because of our total neoadjuvant therapy approach in rectal cancer, we also saw this. We actually saw that nearly 30% of these patients when they got total neoadjuvant therapy, just chemotherapy, did not respond or progressed.

Dr. Andrea Cercek 29:25
And you could see that here. This was in huge contrast to our patients that have what’s called mismatch repair proficient or MSS tumors where everyone either responded or had stable disease here, nearly 30% of them actually were resistant to chemotherapy. So that was quite scary. And other studies have actually shown this as well.

Dr. Andrea Cercek 29:47
So this is the design of the study. The idea basically, is that we give six months of immunotherapy and then if they have a complete response, we assess them and they can be followed with nonoperative management. And they can omit radiation and omit surgery. If they don’t, then they undergo the standard schema. So the way that we designed the response criteria was based on published data where we were really strict about this, we needed our surgeons to look with an endoscopy as well as an MRI with our radiologist and they had to have complete disappearance of tumor visually, with digital exam, like a digital exam of the rectum, as well as by MRI. So very, very strict criteria for definition of complete response.

Dr. Andrea Cercek 29:47
This was a study called FOxTROT where they gave chemotherapy to patients with colon cancer that could have undergone surgery, but they gave preoperative chemotherapy and then kind of assessed response and they saw in their subset of patients that had mismatch repair deficient or MSI high tumors, that a large proportion of them did not respond, very different to their MSS tumors. It was kind of supporting the same things that these tumors are just not as sensitive to chemotherapy. But we know that this population does really well with immunotherapy. We have great data in the metastatic setting and we have a small study in the neoadjuvant setting or preoperative setting in early stage colon cancer where they gave it to a few patients with mismatch repair deficiency, and just a few cycles, and then took them to surgery and 60% of them had a pathologic complete response. So this was the idea behind the design of our study, where we thought, okay, this is the treatment paradigm, what if we swap out the chemotherapy, and instead of giving chemotherapy, we replace it with immunotherapy. And then we give immunotherapy for six months, and then assess the patients. And if they have a complete response, they can undergo observation, nonoperative management, they can even omit radiation. If they don’t have a complete response, they can get the standard of care chemoradiation and then if they have a complete response again, they can undergo observation. If they don’t, they can undergo surgery. So the beauty here was that we follow these patients very, very closely and if they had a complete clinical response to just immunotherapy, they can skip potentially both the radiation and the surgery. So this would be hugely beneficial, especially for our young patients, but for all of our patients, where they could omit the toxicity,potentially, of radiation as well as surgery.

Dr. Andrea Cercek 32:33
Okay, so this is the third study schema. I don’t think it’s anything other than what we mentioned, just to show you that we’re doing very specific, thorough sort of assessments and careful watching of the patients on immunotherapy with the baseline exam six weeks, three months and six months. This is the study design. And this was the response criteria.

Dr. Andrea Cercek 32:59
And here’s the summary of the patients enrolled. So the total number of patients enrolled is 16 patients so far. 11 of them have completed all six months of therapy. So it’s the 11 that that we’re presenting as evaluable. And what’s important here is that all of the patients had very big, advanced bulky tumors, 94% of them had lymph node involvement. So that suggests like a later stage tumor, not a very small tumor where we would potentially just be able to do surgery or not need to do chemotherapy or not need to do radiation. These were patients that by standard treatment, we would have offered chemotherapy and chemoradiation and then very likely also surgery. We assessed 14 patients, and out of the 14, 57% had Lynch Syndrome, which is kind of what we expected to see.

Dr. Andrea Cercek 33:57
And then these are the patient responses. So the most important thing here is that out of the 11 patients who completed therapy, all 11 of them had the tumor disappear with just immunotherapy alone, none of them needed radiation, and none of them have needed surgery. So this was really, really, really exciting data for us, obviously, in terms of 100% response rate, which has never been seen. But then more importantly, I think for our patients, you could see in the age range, the youngest is 26, oldest is 77. But all of them, none of them needed radiation. We have several young women who want to have babies of whom that was critically important. We had several patients with very low tumors who would have needed a permanent colostomy, who have not needed surgery. We’re following them very closely. Four of them have crossed the one year mark so are already, kind of statistically speaking, in a very good place in terms of the very, very low chances of this tumor growing back. But it has been really exciting data so far and really nothing better than then happy, happy tears from patients and happy messages in terms of how well they’ve done and how well they feel after completion of treatment. So it’s been really incredibly rewarding and fantastic and very promising so far. So that’s the patients. I’ll say that patient number 13 is still on treatment. He was assessed here just at three months, but already had no tumor. So it was very, very exciting that he’s already kind of reached that group as well. But we’re not including them in the report because he hasn’t completed the full six months of therapy.

Dr. Andrea Cercek 35:48
And this is a little bit graphic, but I just want to show you because I think a picture really speaks 1000 words. So this is one of our patients. 30 year old woman, newly diagnosed Lynch Syndrome, presented with rectal bleeding, as most of them did, some rectal pain, diagnosed with this rectal tumor and enrolled on our trial because she was mismatch repair deficient. And then we did a genetics workup and found out that she does have MSH2 pathogenic mutation and does in fact, have Lynch Syndrome. And this is her endoscopy. So the top of theslide is the start of Dostarlimab treatment. So all the way on the left, you can’t really miss it, is a visual of her tumor with an endoscopy. So this is a rectal tumor. So the endoscopist in this case here, our surgeon, looks in with the scope, through the anus, into the beginning of the rectum from the anus, into the rectum. And you almost don’t see what’s called the lumen or the hole that leads to the rest of the bowel up into the colon. This is all tumor. This is all very abnormal. This is treatment on Dostarlimab. Beautiful response very early on. This is just four months of treatment, nearly no tumor, and this is just the beautiful perfect lining that we would expect anyone to have that does not have cancer, so completely gone, it was already gone here. This is when they biopsied. We see a little bit of blood. So that’s why this picture was just taken after the biopsy, but you could see very rapid, phenomenal, just fantastic response. And there, they marked the scar, which I would not have appreciated. But that’s just the little scar and that’s what we see on MRI as well. And this was a year out and this patient remains disease free now over two years out from completion of therapy just nearly two years out. So really fantastic, beautiful response. And again, sorry that it’s graphic, but I really think it really illustrates how well this response, how quickly the response, and obviously you can see from this, our patients feel better really very quickly. And so no radiation, no surgery, this is just immunotherapy alone.

Dr. Andrea Cercek 38:26
So in conclusion, with this trial, we’re seeing 100% response rate so far in our patients who have completed six months of therapy. This is critically important for our patients as it may allow them to avoid chemoradiation and surgery. We of course need to continue follow up. We need to really establish the durability of this response. And we have ongoing very close surveillance of our patients. In the schema, its every four months they undergo surveillance with MRI and visual surveillance with endoscopy. And this represents a potential new treatment paradigm based on such robust responses. And our hope is, more broadly, as part of The Young Onset Center for all of our patients, it’s part of our research focus, to do this, but for other patients as well, not just our patients with MSI high tumors, but to really try to focus on improving outcomes while minimizing morbidity in all of our patients but particularly our young patients with early advanced disease, as well as with metastatic disease. And then I think the greater goal of The Young Onset Center is to identify the patients that are at risk. We don’t know how to find them. We can’t screen everybody. We can’t do surveillance colonoscopies, as I mentioned in the 15 year olds that I’m seeing, but our goal is to find risk factors, and find those people that are at risk for whatever reason and screen them and prevent this cancer from happening in the first place. And thank you so much for your attention. I really appreciate your time and welcome any questions.

Participant Question 40:16
From August 20 to February 21, do they continue to have Keytruda?

Dr. Andrea Cercek 40:25
No. Thank you for asking that. That’s a great question. Do you see the blue line on top? The drug is called Dostarlimab. But it’s a PD-inhibitor just like Keytruda, but it’s a different drug. But we finish here. Thank you for asking this. It’s only six months of therapy. That’s it. So this woman finished here in May, and then did not receive any therapy. All of this, including to now, it’s just observation. So we actually weren’t sure how long to do the treatment for. Based on some of the earlier data and the fact that this was locally advanced, we decided to do six months of therapy, and it really looks like that is sufficient for response. Many of our patients, we see it quite early on. But everyone gets just six months of therapy.

Manju George 41:21
Okay, thank you for that. I think there was another question.

Participant Question 41:25
Yes. Hi. Frst of all, thank you very much for this wonderful and very exciting work. And thank you for your presentation. My question is, out of those 11 patients that you had with this wonderful response, were any with mucinous tumors?

Dr. Andrea Cercek 41:43
Great question. Yes, we had two patients with mucinous tumors. So those are quite tricky. We biopsy the patients frequently each time that they’re assessed, so at each of these, they get a biopsy, as I mentioned. So we saw disappearance of the tumor very early. With mucin on the MRIs, we discuss them with our tumor board and if the agreement was that they were mucinous tumors based on assessment, based on MRI, we agree to watch them. We have a lot of experience with mucinous tumors and know that often these take a long time to regress. So two of those patients did have mucinous tumors, and then by MRI, there’s still something there, but we know that it’s mucin. But it is definitely trickier with mucinous tumors.

Participant Question 42:40
So when you said you had complete pathologic response, what you said that for mucinous tumors, the tumors didn’t actually disappear, but the biopsy didn’t show anything?

Dr. Andrea Cercek 42:50
Correct. So yeah, not that we take the Biopsy with a grain of salt, I don’t put too much weight into it, because they just kept the superficial area, but all of those biopsies were negative in all the patients, but since we didn’t take any of them to surgery, we don’t call it pathologic, but yeah, the tumor was completely gone in all the the mucinous patients as well.

Manju George 43:17
Dr. Cercek, do you want to talk a little bit about the presence of mucin against the finding tumor cells in it like with the mucinous tumors?

Dr. Andrea Cercek 43:29
Yeah. So, we don’t know to be honest, I think from the metastatic setting in some of these MSI tumors, there is a concern that if it sits there, it can eventually grow, we don’t know, or if the mucin is just dead tissue. I think that’s why observation in these patients is going to be so important. I can tell you, prior to the study, sort of my inspiration for this study, were several patients that I treated that had these ugly progressive tumors on chemotherapy, and then I treated them with immunotherapy and they had beautiful responses. And I have a few that have mucinous tumors that I’ve watched now for years. And they just kind of sit there or they’re just slowly regressing over time. So it’s still up for debate. I know that we’ve had cases certainly discussed at tumor board where it looks like tumor in the metastatic setting and they have a rectal primary, they undergo resection and then there’s absolutely nothing but mucin and everybody regrets having put these people through surgery. So I think mucin gives everybody pause, we pay close attention to it, we’re doing that anyway on trial. So I don’t think we’re missing anything or compromising the care of those patients. Because we’ve seen so much so that they undergo surgery for no reason sometimes. So, it’s the best we can do, I think.

Manju George 44:58
Okay, so what you’re basically saying Is that from your clinical experience, even when you have found mucin, but no cancer, the patients seem to have good prognosis. And based on that, you’re saying that this is likely to be the case here also.

Dr. Andrea Cercek 45:11
Exactly, exactly.

Manju George 45:14
Thank you very much. And I had one question. Have you guys looked at the link between microplastics in diet? I think that we’re all eating microplastics whether we know it or not.

Dr. Andrea Cercek 45:25
Yes. I love that question Manju because I have looked at it myself a lot. I think, you know, it’s they are everywhere, right? I’ve read a lot of papers and sort of tried to find kind of preclinical things that we could look at. It’s definitely a plan of mine. We don’t have anything established yet. But actually, when you really start thinking about it, you realize that they are in absolutely everything. They’re in every Starbucks cup that we drink and in every cup that kids drink, like everything, everything. So baby bottles, I mean, you know, everywhere. So the only thing I’ll say for that, and I’ve thought about it a lot also because of where the tumors are located and how they happen, the only thing is we’ve looked at polyps in these patients and survivors, and they do make polyps. So part of me thought, well, if it’s microplastics, maybe it’s kind of a one and done, you know, something happens, the plastic gets embedded and causes trouble and then a cancer develops. They do make polyps, but it doesn’t seem exactly at the same frequency that colon cancer survivors in their 60s and 70s do but they do make them. They make them much more than we would expect someone in their 30s and 40s. So there’s probably something more but whether there’s a global change, or maybe the estrogens in the microplastics. I don’t want to spread false rumors. It’s not linked to estrogens at all. But maybe there’s some changes that happened that we just don’t know about. So yeah, to your point, I think yes, that’s one of them. And like they’re all over the sea, right?? They are in everything we ingest.

Manju George 47:10
It’s even in breastmilk?

Dr. Andrea Cercek 47:13
Right. Yeah.

Participant Question 47:14
I was wondering, I know, it’s not quite a fair question. But, in your medical opinion, if you compare Dostalimab this Pembro, how do they compare? Is one a little more effective than the other? Are they very similar? What do you think?

Dr. Andrea Cercek 47:30
I think they should be very similar. They should be the same. I don’t have any data to suggest otherwise. I can tell you, you know, this trial is with Dostalimab, so I think it’s fantastic. It’s working really well. But we’ve had great success in the metastatic setting and in the anecdotal patients that I mentioned with Pembrolizumab and so they should be the same. They are both PD-1 inhibitors. But I don’t have data to tell you. There’s no like head-to-head comparison. And there won’t be, I don’t think.

Manju George 48:05
Okay. And is it that for this trial, when you were designing it, this was the drug that was available and that’s why you went with it?

Dr. Andrea Cercek 48:11
Yeah, exactly.

Manju George 48:13
Okay.

Dr. Andrea Cercek 48:13
Exactly. Yeah. It was an investigator initiated study.

Manju George 48:18
Okay. You had to go with what was offered?

Dr. Andrea Cercek 48:20
Yeah.

Manju George 48:21
And then one question I had was that in MSI-high recal cancer, you’re seeing a lot of Lynch Syndrome, right? Is that already known? Or is there a reason why?

Dr. Andrea Cercek 48:34
We don’t know. It’s a little bit different patterns too in terms of MSH6, MSH2, being the predominant finding mutations, We don’t know why. It’s been published. We saw it in our cohort. We’re seeing it now in this trial, though, it’s early. And it’s been published by others as well. But we don’t know why that is. There’s no good explanation. It’s just a bit more than what we’re used to seeing in colon where they tend to be more sporadic.

Manju George 49:04
Okay. And then I kind of want to tell you that in Colontwon, we have a Colontown Junior Group, which is for pediatric colorectal cancer, and like you were mentioning, you have two 15 year olds. The idea is that these polyps and things take like 15 years to grow.

Dr. Andrea Cercek 49:21
Right, I know. I mean, it really makes you wonder if it’s something in utero. These two that I mentioned, were like, literally, their parents are, you know, 40 and don’t even have polyps,

Manju George 49:33
Okay, Like completely sporadic?

Dr. Andrea Cercek 49:36
Completely.

Manju George 49:37
Yeah. Okay. And then, you talked about a study, like where they had a couple of cycles of IO, and then 60% of them had pathCR, so when you compare your study with Dr. Ciombor’s study, where she’s using ipi-Nivo and a couple of cycles of radiation, right? How does it compare? Yours, the trial schema is six months of Dostarlim, right?

Dr. Andrea Cercek 49:37
Right.

Manju George 49:39
And do you see any side effects? Is a kind of comparable to Pembro’s profile of side effects?

Dr. Andrea Cercek 49:48
Yes. I think to the single agent. yes. To the combination, which is what Dr. Ciombbor is doing and also what was done in the colon study, I think we do see more toxicity with dual checkpoint blockade. So that was a concern for me, and now that I see that we have this data, for me, it wouldn’t make sense to do two drugs because we’re already seeing 100% response rate with just a single drug. I do think duration plays a role here and in my study design, in particular, my goal really was to see how we can maximize immunotherapy alone to decrease the morbidity of radiation and surgery, because we know in this disease, radiation works. I mentioned our data because the way that we sequenced it was chemotherapy first, then we did chemoradiation. So when you’re taking care of these patients, we saw that the tumors were growing on the chemotherapy, which was not what we were used to seeing, but when we gave chemoradiation, they were salvaged and the disease responded, and they got to surgery and they were cured. But then they had to have radiation. So the idea of with this study, and I think what distinguishes it really is that so far we’ve not had to radiate anybody, we’ve just been doing immunotherapy alone and having a 100% response rate. And so we’re really optimizing the therapy and omitting both radiation and surgery.

Manju George 51:53
Okay. Are you collecting ctDNA and other markers?

Dr. Andrea Cercek 51:58
Yes, yes, we are. Yeah, we’re in the process of analyzing that. I think the ctDNA will be interesting, because we’ll see how it correlates with response and how quickly people clear it. It may or may not be helpful to guide us in terms of like the tumor being completely gone or not. I think that correlation with MRI will be really interesting. So we collected it at every point that we had endoscopic evaluation and biopsy and imaging.

Manju George 52:28
Okay, okay.

Participant Question 52:29
Well, I was wondering, why was it chosen to do immunotherapy for six months initially? Why six months? Because I know that the studies for stage IV, immunotherapy, I believe, was for a year, initially. So why was the duration of six months expected to have such an advanced response? Why not a longer time?

Manju George 52:53
Okay. Thank you. One question. So with the bulky MSI-high tumors, the response is a little bit delayed, right? Like usually you don’t see regression right away on the scans, right? Do you want to make some general comments about your experience dealing with these kinds of bulky large MSI-high tumors?

Dr. Andrea Cercek 52:53
That’s a great question. So I thought about this a lot, as you can imagine, because obviously, the goal was still to cure so we didn’t want to compromise duration. I was very conscious to make sure that the patients had the opportunity to undergo radiation if they needed it and that we weren’t going to give them something that’s going to compromise their chance of cure and a two year mark in a curative setting just seemed really long. And when you look at the metastatic data in patients, at the time, it was just in patients who were refractory. So in the MSI high metastatic patients who got chemo, two, three, four lines of chemo and then had immunotherapy. That was first published by Dr. Lee, the maximal response, the time to response there, was around eight or nine months. So we figured from that number, that naive tumors, early stage, that weren’t metastatic, that didn’t see any chemo before, didn’t have a chance to become a little bit more resistant to the microenvironment would respond better. And then also having seen some of the earlier data in the neoadjuvant setting in the colon cancer with 60%, after just two cycles, six months kind of seemed like a fair compromise to do. But it is a great question, In certain patients, should we have done more? Could we have done less? We assess them at three months, many do have endoscopic regression of the tumor. Not all though. So I think in the end, it was it was a good choice, but that was kind of the thinking with sort of extrapolating from a bunch of different data points. And then importantly, for me, to allow them to be followed closely, and then to get that standard of care if they needed it for cure.

Dr. Andrea Cercek 55:18
Yeah, so that’s another great point. So that was another thing that and why we did such close assessment because we thought, Oh, if they have pseudoprogression, or if these tumors obstruct, but in fact, they respond.

Dr. Andrea Cercek 55:30
You can see from this picture, the response is really quick. But they tell us- they stop bleeding very quickly, after the first or second dose. They feel better, it doesn’t hurt, they stop bleeding, they have normal bowels. So it’s different. It’s actually different and much more powerful. I think the response is faster and more powerful it seems.

Manju George 55:56
Okay. So do you feel that there’s a difference when you use neooadjuvant in the early setting?

Dr. Andrea Cercek 56:03
I do. I do. I think it’s key. I do. I really do. Yeah.

Manju George 56:08
Okay, thank you so much. We are past the time and thank you so much for your time and the great presentation.

Dr. Andrea Cercek 56:14
Absolutely. It’s my pleasure.