Updates on the Study of Appendix Cancer - JP Shen, MD - MD Anderson Cancer Center

0:16 Looks like people are popping in. We had a little over 200 registrations. looks like I'm going to give it a couple more minutes to let people get in. That's interesting.

0:50 So, I'll go ahead and introduce myself. I'm Amanda Moore. founder of Appendicure and I am a caregiver to my husband David who was diagnosed with appendix cancer in 20 January of 24. we we found Dr. Shin after he had a major surgery with a with an appendix cancer specialist. the recommendation after the surgery once the pathology came back it was it was six months of folox every two weeks and it was a 50/50 chance of recurrence and you know the explanation was really they treat it like col colon cancer. this was 24 you know that didn't sit well with us so we went and got more opinions and actually about five more opinions and Dr. Shin was one of them and he was the only person who could produce data that said with our particular type of cancer the stage the the pathology results that it just did not make sense for our situation. So, so you know, David is Ned today and and hopefully we'll stay that way. but, you know, I feel that that we definitely dodged a bullet with six months of of chemo that actually would not have helped either way in regards to a recurrence.

2:25 so we are forever in debt to Dr. Shin and thank you so much for joining us. please introduce yourself and and and I'll stay silent until we get to the question and answer point. >> All right. Yeah. Well, thanks for the introduction. so I'm Dr. JP now assistant professor at University of Texas and in the cancer center. you know, it's been 7 years since I've been here and I guess really nine years since I' I've kind of begun specializing in appendix cancer going back to my training at at UC San Diego. so, you know, appendix cancer is relatively uncommon. it's, you know, often called a rare tumor, but the the incidence is increasing. there's probably not more than 5,000 new diagnoses a year in the United States.

3:20 and it's been well documented that the rate of in which you know people are getting a petting cancer is much higher which is unfortunate. you know previously there wasn't really a whole lot known about it mostly because people hadn't really taken the time to study it and so that's really kind of been the the focus of our lab. you know we we let's say our lab we we so you know I a physician a medical oncologist by training you know so I I kind of see patients and evaluate if they need chemotherapy and if so what what is the best chemotherapy I've also kind of now got into designing next clinical trials but most of my time is really spend as a scientist. so we run a full wet lab.

4:13 So we take tumors from patients and grow them in mice grow them in organoids so we can test out new potential therapies. and then we also have a computational division. So we have you know people trained as computer scientists that help us analyze tumor genomic data. So what genes are expressed in the tumor, what genes are mutated because it turns out that that's really important in predicting you know what drugs are going to work for each individual patient. So we're actually now it's exciting times here in 2026 where we've now are kicking off a big effort to start using machine learning to help us do this to help aggregate data. and so I think that you know the pace of drug development has been very slow in appendix cancer. You know there's not any FDA approved drugs in appendix cancer currently but we think that we're starting to to to speed that up. so you know for for a long time there was this kind of now I think outdated and debunked idea that appendix cancers are the same as colon cancer and should be treated the same. you know for a long time the NCCN guidelines had the statement there that that's crossed out on the slides that you should you know consider systemic therapy for colon cancer for appendix cancer. that's no longer the case now. Although unfortunately the the current version which is like the first draft of the national guidelines for appendix cancer really just kind of copied the colon cancer guidelines without a lot of thought which is unfortunate. and so the the really the you know rather than directing people to the NCCN which is kind of the the standard for most tumor types really the the surgeons have been leading the the treatment of appendix cancer you know kind of since its inception. And so these guidelines that are endorsed by the society of surgical oncology you can see the references there which is called the consensus guidelines for the management of appendicil tumors that that's really the place you should look for guidance and you know to direct your physician to read these guidelines not necessarily the the ances it's called consensus because it was a group of like I think like somewhere between like 120 to 140 physicians all of whom see a lot of appendic cancer patients. and it went through multiple rounds of voting until the you know basically guidelines were agreed upon by everyone. So that's why it's called consensus.

6:33 you know the the people on this call probably know that you know relative to colon cancer appendix cancer is much you know much more indolent disease course. you can see that with with well differentiated also called grade one tumors. you know many patients are alive at 10 years. In fact, majority of patients are alive at 10 years. It's you know very different story for the grade three or poorly differentiated patients. you know because the hisytologology basically what the tumor looks like under the microscope is so critical we encourage everyone to u if possible get a expert pathologist to review their pathology.

7:13 Unfortunately, a lot of times when, whenever we see a new patient, every Anderson, we have our pathologists review the the basic, the slides from wherever you had your surgery get sent to us and we have a group of pathologists review that. And, you know, maybe as much as a third of the time the diagnosis changed in in a meaningful way. So, it's it's very important to have someone who who does this frequently evaluate the the heogen under the microscope because, you know, it it changes not only what to expect in terms of how long you're going to live, but it also changes whether or not we think you're going to benefit from chemotherrapeutics.

7:53 don't want to get too much into the the weeds of the molecular differences, but you know the reason that we think that appendix cancer needs different treatments than colon cancer if you look at you know the mutations the kind of the underlying genetic abnormalities that lead to cancer appendix cancer is completely different than colon cancer. you essentially anywhere you look whether you look at the DNA level the genes that are mutated are different if you look at the RNA level the genes that are expressed is different if you look at the micro environment like how the fibroblast immune cells and other non-tumor cells respond to tumor cells is different we did a big study where we looked at circulating tumor DNA that's kind of the middle panel so you know most of the time you're not going to be able to detect any circulating tumor DNA and appendix cancer is very different than colon cancer You can see that it's on a log scale, but you can see there's less than 10 times as much tumor DNA detectable in the blood in pennies cancer versus colon cancer.

8:54 there were some questions that advance about goblet cell. We'll talk a little bit about this. goblet cell is a really interesting tumor type, a subtype of 10 to 15% of appendix tumors are going to be called goblet cell and that's based on how they look like under the microscope. I don't have a a picture of the of the goblet cell, but essentially the goblet cell is the cell that you normally have in your intestine. And what they're supposed to do is they receive signals from your brain to release hormones to the other cells around them. So it's in a way kind of like a neuroendocrine cell.

9:26 So a cell that receives information from the brain, secretes hormones, but it's also kind of like an intestinal cell that forms a barrier. So these these goblet cell tumors are kind of a hybrid of a endocrine tumor and a traditional epithelial intestinal tumor. but under the like at at the molecular level they're very different. And so we we we discovered this in collaboration with the company who who generated the the sequencing data that this gene called ZFP36L2 which is a zincfinger binding protein is is the most commonly mutated gene in goblet cell. and we've now in the lab used crisper to knock that gene out and you can see that basically it makes the the tumor cells grow faster and so we're the next step will be to you know now that we've established these organoids we'll start treating them with drugs so we'll be able to see when we see this CFP36L2 mutation what are the best drugs to use in in that situation so that's you know in progress but but not quite ready for prime time prime time meaning treating patients and so you know it's relatively hard to do clinical trials in appendix cancer but not impossible and that's so we we've really started doing this you know as of now I think there's only eight prospective clinical trials in appendix cancer that have been run ever four of those were done at Anderson I guess like I said completed and published so in the published literature there's really just eight this is one of eight and so you know anecdotally we had seen a lot of patients with low-grade mucinous tumors get chemotherapy and not respond. And so we didn't think it was helping them and so we wanted to do a trial to kind of prove that point. And and so basically this was what's called a crossover design if you can see on the the right side of the slide. Meaning people either got six months of chemo then they crossed over and they got six months of you know just observation no treatment or they got observation first and then they crossed over and they got six months of chemo. So everybody got 6 months of chemo, 6 months observation.

11:33 The randomization was whether you started treatment first or not. And so the question was, you know, can you safely delay treatment and and you know still achieve the same outcome. And so and and so what we found is so not a single patient achieved a actual response. So to be called response you have to be below 30% like size of tumor. so you know there were not a single not a single objective response and if you look you know kind of a timeline here you can see this is the size of the tumor you know during the observation periods is basically flat and during the treatment periods is also basically flat and so there's really no differ there was no difference in the rate of tumor growth whether you're getting you know five based chemotherapy or or nothing and and so just to so so you know fortunately This didn't make it into the new NCCN guidelines, but you know, the time to give someone with a low gradede mucinous tumor 5FU is is basically never. you know, if if you think if this was a developmental drug, if you did a phase one study and you had a response rate of zero, that drug would never be tried again in, you know, those patients ever because, you know, the chance of it actually working is is basically zero. And so you know based on this we're now looking for other therapies because we know that again this is specific for low-grade patients lowrade mucinous tumors that that five is in effect. so what one thing we looked at was a class of drugs called taxes. you know pletaxyl, dosataxel, capacit these are all FDA approved taxes. abraane is a kind of special formulation of pletaxyl which which we've also used.

13:20 these drugs work in esophageal cancer, gastric cancer, small bowel cancer not in colon cancer but you know we think colon cancer is really kind of outlier in the intestinal tract. And so you know again because you know because drugs like Paxel were tested and didn't work in colon cancer. people had not tried them previously in appendix cancer, but that didn't make a lot of sense to us given that appendix cancer is is, you know, arguably more similar to gastric cancer than it is to colon cancer. and so this was just a very small study of the first 13 patients that we treated with appendix cancer with taxes. you know these people these patients had you know many prior lines of chemotherapy and despite that we still saw 30% response rate which is pretty good for patients who have had three and four lines of priory and so based on this we routinely incorporate pletaxel combinations in treatment of appendix cancer so I a lot of times we'll go with carroplatin pletaxel but there the other other combinations that we use the you know moving on this this is kind of relative to the case that Amanda mentioned you know for early so just like patient a lot of physicians were using 5U treatment for appendix cancer because it worked in colon cancer. after people had surgery to remove an early stage so it would be like a stage one, stage two or stage three appendix cancer a lot of physicians were recommending chemotherapy that's called agivate chemotherapy. that didn't seem to make a lot of sense to us just because anecdotally we couldn't think of that many patients who had early stage appendix cancer who actually relapsed.

15:09 and so it didn't really seem like the chemotherapy was doing. So we to study that we we we now have a database where basically all of the you know every time a patient sees us at M Anderson their data gets you know moved from our electronic health record into a database and we we can now search that database and so we were able to find you know roughly 200 patients who had their surgery Anderson you know people with stage one two or three appendix cancer and and only 19 of those had relapsed. So the overall chance that your tumor would come back any appendix cancer stage 1 through three is is less than 10%. you know so that right there means that you know if you treat all these people with chemotherapy 90% of them their tumor wasn't going to come back anyway. you know so so the you know either either the chemotherapy is really really good or the risk of the tumor coming back is just pretty low.

16:02 And it turn it turns out that for the most part the chance of relapse for most early stage pendicil tumors is pretty low. you can see you know goblet cells especially low only 3% you know gets up to 17 well sign ring cell being the one exception where you know the 30% of sign ring cell tumors recur. That's the you know one of the few times I would recommend using chemotherapy agently in appendix cancer. and then we kind of look to see you know is the chemotherapy helping everyone and so again this is retrospective meaning looking backwards but you can see that if anything the people that got adgiant chemotherapy did worse than the people that that didn't get agent chemotherapy we don't think the agent chemotherapy is hurting people. This is just you know higher higher risk people were getting chemo and the chemo wasn't really doing anything. And so if we look only at the stage two patients, you can see that, you know, absolutely no difference. You know, basically if you have a stage two tumor and you get chemo, you're going to do great. If you got a stage two tumor and you don't have chemo, you're going to do great. You know, like 95% of these people are still alive at six years or five years, regardless of whether you get chemotherapy. So for for this reason you know except in very very rare circumstances like a signate ring tumor or a really large number of positive lymph nodes or you know we think that the tumor really is metastatic and it just wasn't seen on surgery you know would not recommend agitate chemotherapy for for early stage patients and so this we we sent this poster at ASCOGI just earlier this month in San Francisco and the manuscript is u in review and it'll it'll soon be posted to the pre-print pre-print repository called metarch. So by by next week hopefully you'll be able to sue us on >> you know one of you know there's a lot of challenging problems in in the appendix cancer one of which is that it's hard to have a quantitative measurement of the size of the tumor on imaging and this is because in the peritinal space the tumors tend to you know latch onto surfaces they'll coat the surface they intestine they'll coat the surface of the liver And so if you're looking at it, it's very obvious that there's tumor there. But it's hard to measure on a CT scan. And you know, measurement on a CT scan is the primary way in which we assess if drugs work.

18:24 You know, you need to call it a response. We have them get 30% smaller on a CT scan. And so, we wanted to see if we could use blood measurements, to help us, you know, track tumors and and predict. And it turns out that the you know some appendicil tumors will express CA some CA199 some CA125 you know some none of them but most most of the appendicial tumors will express one of these three tumor markers and it turns out that it is strongly prognostic that if you've got you know no elevation in any of the tumor markers your your chance of being alive at 10 years is is very good. Whereas if you have elevation, it's it's much less. And if you have if you're in the very high highly elevated, which is the light blue line, you know, the survival is is much worse. And that that's true for both low grade and high grade tumors. So we we use we use tumor markers quite a bit in terms of assessing how well chemos work because the you know you know CT you know there's not one perfect way to measure appendix cancer. CT scans are important but the blood work is also important.

19:30 and so I kind of mentioned this earlier when I talked about the the goblet cell, but you know, because it's challenging to do clinical trials in appendix cancer, like we're still doing them. but it is challenging. we're trying to learn as much as we can from all the patients who are not treated on trial. we're now up to just over 4,000 patients in our database. as institution, we see upwards of 300 patients a year. and so aggregating this we now we're getting a large enough cohort of patients to to really be able to study. And so this is why we can tell you that you know you know pennies cancer happens to to you know significantly younger people versus colon cancer. you know 37% of the pennis cancer patients that we see are diagnosed under the age of 50. and the you know unfortunately if you look at over time that that's actually moving moving young.

20:23 you know one of the things that we can get from these retrospective data is what is the best chem you know amongst the chemotherapy regimens that we're using which one is best. and it it does look like there is clear benefit to adding the vef antibbody bevicism to frontline chemotherapy. you know my I was taught by the faculty at UC San Diego that you know mucinous tumors are more likely to respond to arotican and so I usually use fulfurior bevicismab as the front line but we now have some data to suggest that that you know you know fulfury plus bevicismab does do a little bit better than fulfox plus bez bevvisismab in the front line you know this is not a huge number of patients it's only like 160 patients where we're trying to the reason it's only 160 patients is this is you know most of the patients that we see at MD Anderson live not in Houston, Texas but you know in you know Mississippi, Alabama, Georgia you know all people come from all over and a lot of times we'll get the recommendation you know you should get you know full plus in the front line but they they go back to to home to get that and so we're in the current standpoint we don't capture that data very well but we're working on on doing that we're actually using large language models to extract this information into a structured format. So we we hope to be able to do this analysis on on you know all 4,000 patients or nearly all 4,000 patients in the future to kind of give us more more granularity about you know which are the patients that would do better with fulfism or just a subset. So those those are all questions that we're trying to answer.

22:04 this is one area that we've been really excited about. So just want to highlight this was not work that we did but was done led by Andy Lowey who is very well-known surgeon for appendicial also pancreatic cancer and then Shumato who's an old friend from UC San Diego who is a medical oncologist and so based on a couple anecdotal cases of patients with gen mutant appendix cancer who responded well to the drug paly they did a whole case series 16 patients. you you can read the the paper to get more details but but a very encouraging response rate and so you know given what we showed you about 5FU does not work in low-grade patients. So gene tumors tend to be lowrade mucinous tumors. if I see a low-grade mucinous tumors, my my frontline therapy is either this the palocyc or a similar molecule there's there's also a drug called a bemic which is very similar e either one of those two would be our my kind of first choice or potential immune therapy. the again highlighting the fact that the pathology review is critical because you know this data is in low grade patients. It's unclear if it would also apply to high-grade patients. I also think that that these drugs the CDK46 inhibitors will be active in some gen type tumors as long as they're p-52 wild type also. and and we're working with Dr. Way and others to to to really test that hypothesis.

23:40 Okay. yeah. So this is the attestion. So the other I think very exciting development in you know especially low gradede tumors is this immune combination. So this was a study that we did here at MB Anderson and was sponsored by Genitech. so Tesla is a PDL1 inhibitor. PDL1 is a negative signal on the T- cell. So if you block the if you block the break of the T- cell, the T- cells should be more active. More active T- cell should recognize a tumor and kill it.

24:09 bevvisismab should change the micro environment. normalize the vasculature and and we think act on the fiberblast to hope hopefully get those activated tea cells closer to the tumor. and this combination worked very well in again this was this study was mostly lowrade patients. You can see eight well differentiated grade one seven moderately differentiated that's grade two only one poorly differentiated grade three tumor. this was not randomized, but we compared it to historic control. And so, you know, not surprisingly, these patients who all got 5FU chemo, which we know doesn't work, didn't do very well, but the the ones on the trial did significantly better.

24:46 and so this is our go-to really for most of our lower grade patients. we'd love to try combinations like higher higher order combinations. For example, there's no reason from a safety standpoint that you couldn't do the the Pala plus the Tesv. it's really just kind of an insurance limitation, but we're trying to test that in pre-clinical models so that we can kind of test that in in patients and and ideally get get a sponsorship for a clinical trial. I don't generally use the Tesla Bev in high-grade tumors just unfortunately they seem to grow a little bit too fast because this is a slow acting regimen. but we'd be excited about trying the combination of chemo plus the immune therapy which which is kind of how gastric cancer is treated or is how gastric cancer is is treated right now.

25:32 in we are currently in negotiation with with pharmaceut to sponsor a trial like that. Okay. definitely time for questions and unfortunately I've got a hard stop at at six but you know immune therapy is there's a reason that the oncology community is really excited about immune therapy because when it works it can work really well. you know, with traditional chemotherapy, it's not a question of if the tumor is going to become resistant. It's they will all become resistant.

26:02 It's just a question of when. you know, it's maybe one in like maybe one in 10,000 tumors will be cured with just traditional chemo when when it's metastatic. and so this is actually data from colon cancer. and I know I spent most of my time telling you that colon cancer and appendic cancer are not the same, but we we just presented this again at the same meeting in San Francisco that if you take two. So on the left here you have colon cancer tumors that have liver metastasis.

26:31 On the right you have colon cancer tumors without liver metastasis. And you can see that on the left you if you have liver metastasis whether you get an immune regimen or just standard treat it's no difference and you know outcomes are poor you know maybe 10% of patients are alive long term. on the right now this is colon cancer patients without liver metastasis. And the reason that's relevant to appendix cancer is that liver metastasis is very rare in appendix cancer.

26:59 less than 10% maybe only 5% of patients with appendix cancer will get liver metastasis. So in most cases you know the right curve is is is more like what appendix cancer is like and so this gave us a lot more encouragement that we think that the tumor in the paritinium or in the lungs you know most of the time appendix cancer stays in the paritinium sometimes it will get into the lungs almost never into the liver.

27:24 those tumors tend to respond those kind of anatomic sites have more immune surveillance and are more likely to respond to immune therapy. So if you know colon cancer which is not traditionally thought to be a immune responsive tumor we're seeing you know that the the survival is meaningfully longer in patients who are getting immune therapy versus standard therapy and you know importantly you can see that you know almost 25% of the people are getting immune regimen are alive three years later. This is what people with metastatic you know this is this is from the time of the third like so this is people have already gotten full fox in progress fulfury and progress and now this is the third wine treatment and even three years from now 25% of them are alive which is pretty good and so with this like you know this is an appendix cancer talk but I've changed my based on these data I've changed my practice of colon cancer that so if I see a colon cancer patient without liver metastases or without liver metastases in the third line I I'm now using the accommodations whatever and for the most of the most of the time we're getting insurance approval I would say maybe 80% of the time this is approved by insurance and so we're we're using this we're using this regular graph nuplex if nebo in a lot of colon cancer patients and I'm actually because the tes didn't necessarily work so well in in high grade appendix cancer highra appendix cancer being more similar to colon cancer I'm using the regular abnola map in in Patty's cancer was gone. okay moving along and so you know you know this slide here I mean so you know imunotherapy when it works is great the big problem is that it's really hard to predict who is who's going to be the person that it works for and who is a person that it does nothing.

29:13 you know right now most of the time there's really not a good biioarker for that. In lung cancer and head and neck cancer, you can look at this PD1 expression or PDL1 expression. but that's not very useful in colon cancer. We haven't looked that much in appendix cancer because we don't have enough data, but I don't think it's going to be very useful in appendix cancer either. the one thing that we are using now is the what's called a tumor micro environmental profile. And so this is data from a company called Boston Gene.

29:43 but there are other companies that are starting to generate this now. you know the two the appetic cancer tumor actually most of the cells in that tumor are not tumor cells. You have a lot you have a lot of macrofasages, you have a lot of fiberblast. sometimes you have a lot of immune cells, sometimes you don't. but by doing the by doing RNA sequencing you can actually get a profile of how is the body responding to the tumor cells. And you know, we haven't proven this yet, but we think that when we see that there's more B and T cells, so so T- cells are the cells that are the kind of most critical part of the immune system. But when the T- cells are active, they usually recruit B cells as well. When we see more of these and together, those are called lymphosytes.

30:30 When we see more of these lymphosytes, we think that these are the tumors that are more likely to respond to immune therapy. And so we we haven't we haven't proven that yet. but you know we we when I you know when we see tumors that have a large number of lymphosytes present and have a an immune environment like this is kind of this fibroic immune environment usually has low immune cells if we see an immuneenriched immune environment we think that those patients are more likely to respond to immune therapy and you know more likely to to use it.

31:02 but this is also kind of we think going to help us predict likely the patients that respond well to the angioenesis inhibitors like like those. So you can see like relative to colon cancer penicellin. So this in this plot here we're comparing appendix cancer patients to colon cancer patients. You can see that appendix tumors have a much lower proliferation rate relative to colon cancer. but they're much more likely to to upregulate angioenesis factors. which is part of why we think that the the the bevicismab which is a ve inhibitor is is an important part of of cancer treatment. You can also see here that the more fibroic the tumor is the less lymphoid cells you have there's an inverse relationship between the fraction of fibroblast and the member of the lymphosytes and so we you know the big question is how do we change that? How can we kind of change the fiberblast so that they're not keeping the lymph lymphoid cells out of the the tumor? And this is something that would work yeah so you know looking at retrospective data is very useful but it will only really tell you about drugs that are commonly used. Like if you want to develop new drugs and kind of introduce new drugs into the treatment landscape you need to get data from from somewhere. And so usually that's pre-clinical models. you know before seven years ago there really were not there was virtually no there were a couple of models of appendix cancer but not but not very many and they weren't very widely distributed. And so that's that's one of the major undertakings that we did was we wanted to make mouse models of appendix cancer so that we could use the mice to test new drugs.

32:37 And so we did that and that's how we we we demonstrated that this drug plet which is a taxane drug like we talked about earlier if you inject it directly into the peritineal space which is you know directly into the abdomen which is where appendix cancer lives that that is highly active and so based on these data we now have a a clinical trial open actually we just finished the phase one phase and are actively enrolling in the phase two phase. the main eligibility criteria is that you have to be possible to do a diagnostic laposcopy. So if you've had right now we're excluding patients with prior CRS hipek. So this is only patients with denovo metastatic disease who've not had a prior CRS hypek at the moment but you know hopefully after this initial trial we will you know be able to expand our our eligibility criteria because I think that I think there's a lot of promise to the interparitinial therapy and so that kind of there were you know brings us to to pipe a lot of questions about pipec I say you know so we actually don't do pipek at m Anderson you know pipec is a surgical procedure because you have to do a diagnostic laparoscopy where you kind of insiflate or you know fill the abdomen with pressurized air and then in that pressurized setting the aerosolized chemotherapy is is added. That's why it's called pipec pressurized intraarital aerosolized chemotherapy.

34:03 you know the there are many trials of this going. So this is available already off trial in many centers. but there are now a lot of trials that are open or being open. Dr. Wagner at the University of Pittsburgh or sorry Eligi Health in Pittsburgh has a trial and Mustafa Roof is I don't know if his trial is open at City of Hope, but it will be open very shortly or or two. But there there are many other sites like New York City, Miami, Dallas that that are that are doing this.

34:37 it you know it I I I think it's it's definitely promising the early there's data presented at the this conference called Soji which is perishal surface oncology group international last October that that looked very positive. but there's you know there still have not been a huge number of patients treated and so this is one of Dr. R's papers you can see that you know in 12 patients the you know response rate was roughly 50/50 which is not it's not bad because these are you know again these are all patients who've either relapsed after surgery or have had multiple chemotherapy regimens. So 50% response rate is not bad you know in in this patient population. but you know we really need to kind of treat more patients ideally on trial to learn what are the tumors that are likely to respond. And the other the other important thing to remember is that you know PIPAC just refers to how you're getting the chemo. a lot of these studies have been done with oxy platin like so this one was with oxy platin but the you know Dr. wider study at Algate Health is going to use mito and Dr. roof's neck study may also be my so this so whether you use you know mitocinx platin pletaxel you know the results could could very well be different and so also many of these trials are combining the pipac part with systemic chemotherapy in the off weeks usually you can only do the pipek about once every six weeks because you have to surgically access the abdomen so you know I think there's a lot of promise a lot of promise to pipe but you know what's the idea ideal drug, what's the ideal timing, should it be combined with systemic therapy? And these are all kind of questions that are that are that are needing to be answered. But I think that it is you know in in the right patient population I think it is is generally safe and you know it's going to take work from from our surgical colleagues to identify what is the best combination and and who's the best patient you know to to respond to these different drugs. and we're we're almost done kind of my part and we'll move on to the question. So, so you know, very excited about immune therapy, but but I think more than anything else, the thing that I'm most excited about in terms of appendix cancer treatment is this Krass inhibitors. And so, this is our own data that we presented at ESMO I guess two years ago now or a year and a half ago.

37:12 so, again, this is not highlighting the differences between mucinus and colonic type, which are pretty similar to each other and goblet cell tumor. You can see that you know pancreas cancer is the prototypical kass mutant tumor. You know like 90 plus percent of pancreas tumors have kass mutation. but you can see mucinus appendix cancer almost as high. and that that tells you that you know kass is a critically important gene to mucinus appendix cancer and you can see that colonic type is also there and you know both of these significantly more you know significantly more tumors are kass mutant and appendix cancer relative to colon cancer or lung cancer.

37:49 goblet cancer goblet cell var is very much outlier. So there are some cares meet with goblet cell tumors but but they are pretty unknown. why is this important? there's a huge effort in the pharmaceutical industry at least 10 maybe maybe 12 or more than that pharmaceutical pharmaceutical companies are making krass inhibitors. this drug RFC6236 is likely to get FDA approved in 2026 from Revolution Medicine. this drug is not likely to go on in development but there are other similar drugs that are moving on.

38:26 This was from Rody who was bought out by BMS Bristol. the these two drugs. So so the MRTX is a G12D specific inhibitor meaning it only inhibits the G12D mutation. RMC 6236 will inhibit any of the G12 actually inhibit you know it will be active in any of those tumors. we tested both of them in organoids and then in mice and you can see that you know you don't I'll let you take my word for it but there's a lot less tumor cells after you hit the the mouse with the drug versus control. You can see that KI67 is a measure of proliferation. You can see that it goes way down. the you know after we treat we did some single cell sequencing and after you treat with the the drug there's you know very few tumor cells left and so we're very excited about using kass inhibitors and appendix cancer we are trying to get a industry sponsored study of you know any kass inhibitor specifically in appendix cancer and we're in negotiation for that so we think that that will happen within 2026. And then on top of that, we are we at MD Anderson, we have lots of early phase studies that are tumor agnostic, you know, basically any solid tumor patient. And so whenever possible, we try to put appendix cancer patients onto Kass inhibitor studies. and this okay, this is B. So we've had six patients total so far, six appendix cancer patients treated with KAS inhibitors. And so so far we've seen you know biochemical response in every patient. this is kind of one example of with one of my patients you can see see you know seventh leg so the said six prior different treatments before the krass inhibitor you can see now that the CA is dropping dramatically the one of the things that we're working on is that the this is again why I think the tumor markers are so important is that the size of the tumor on CT doesn't always correlate well with how well the drug is working if the tumor is very mucinous and so you know by you know some of these patients where they clearly had a benefit and their tumor marks are going way down. If you just went off the scans it may not you know would appear just maybe stable.

40:50 So we're we're working on better ways to you know perform and interpret the CT scans but also alternative ways to measure the the response using tumor markers and and you know in some cases CTD. Okay, I think that was my last slide. So, so, so first you know, you know, a lot of our research is is for the patients, but would not be possible without the patients. So, that that's our our first thanks, but also thanks to the members of our lab.

41:16 in particular, this guy does all of our mouse work. hugely talented scientist and the computational read is the man on the far right. has done essentially all of our RNA sequencing analysis. yeah, and with that, we'll I'll turn the mic over to Amanda. And think you got you got your own slides, correct? >> Yeah. Okay. And so that took slightly longer than anticipated, but I think we got >> Sorry, I switched I switched the slide off of your team and I apologize for that. I Yeah, but I I got it there now.

41:50 >> Anyway, that was a lot of information. >> Thank you so much. I think I I really understood probably about 40% of it. But the good news is is that I will go through it with a fine tooth comb with you and and your wonderful assistant and the others that she has referred me to and and and dissect it for those of us that are challenged with medical terminology. so let's get into the questions and let me just preface this. we had a lot of questions asked beforehand and some of them were repeat so I tried to combine them and I've tried to put them in categories cancer appendix cancer type and other other questions outside of that you're a asking questions in the Q&A and I'm sorry I should have not said called it chat I should have said Q&A but I know I see them coming in and I'm hoping that we can get to some of them but if we don't I promise you I will post the answers to those questions in the very very near future hopefully tomorrow with Dr.

43:02 Shen's help. So first lowgrade appendicil neoplasms lamb and or PMP so Dr. For patients diagnosed with early stage lamb such as PTI, especially when the original pathology was done at a local hospital, how do you help patients understand their true level of risk and decide on the right followup or surve surveillance plan? >> Oh, great. Yeah. So, it's a great question. you know, lamb it's kind of an odd thing in that you know the the so the reason it's called so lamb stands for low gradede appendicus neoplasm.

43:38 and so it's importantly it is not a carcinoma which means it's a precancer. so it's not technically a cancer. What what's kind of unusual about it is that you know the risk of that coming back as a cancer is low but it's not zero. so so monitoring is important. you know I would say more often we would see things kind of overcalled like we see like you know something was called adnocarcinoma that our team would would call a lamine. So it I I think most of them are actually let so like if something's called a laminate it's probably a lamine. but it would be important to review that. But I would generally we do like at least I would want to I would probably recommend imaging for at least like on a yearly interval for at least the first couple years and then and timmer marker measurement. So but it's it's really important that you know so so lamin is a diagnosis not a stage. so you need to also assess like if there is like presence of extra perariteneal or if there's presence of peritinal mucin that increases risk or if there is you know cellular containing deposits already outside of the appendix then then the risk is much higher and so we just actually published a paper on this with Ashley Sumage the fellow and Beth Helmic faculty kind of describing risk of relaxing and and landing. so I would I would refer to that. and then you know so what what lamog so we I honestly in MD we don't really like to use the term PMP you know PMP is a syndrome. It's not a diagnosis. You can have PMP from ovarian cancer or colon cancer or gastric cancer or appendix cancer. and how you should manage it is is different. I mean there are some times that you'll have you'll see PMP and it's not clear what the origin was but most of the time you can't figure it out and it's usually beneficial to do that. so we we don't you know there are some cases where you won't know where it started but usually usually you do and usually it's beneficial. you know what low grad disease traditionally does not respond very well to chemotherapy and so that's why usually surgery is a treatment where you know I showed you in the slides that we've seen activity with the CDK46 inhibitors we've seen activity with immune therapy we've seen activity with kass inhibitors so I think in the future we may move into a new advent treatment and then resection modality but you know that's kind of we're kind of not quite there yet. the yeah so that's so that's why a low gradede disease is primarily treated with surgery is that traditional chemo hasn't been that effective. but the you know whereas high high grade tumors generally are more effective and if generally it's better to treat if you're going to do chemotherapy or systemic therapy is generally better to do it neoagiant than adgivant and that's for one you're more likely to get the treatment because you know the complication rate after a CRS hip is is is significant and so you might be many months before you could do chemotherapy afterwards Especially with immune therapy, there's a lot of data from lung cancer melanoma that new agent immune therapy when the tumor is still present with more and the ant and antigen are still present, it's more effective than adgiant. and likely that that is true for you know traditional chemotherapy as well. So our our general practice is that we give people you know if you think you need systemic therapy, we we do all of that before surgery and then usually finish the surgery with high peek and then that would be then obscure.

47:30 Okay. Surveillance after CRS surveillance. Yeah. So surveillance. So okay. So surveillance is directly kind of linked to the risk of relapse. And so I didn't include that in or it was in the slides but I didn't really talk about it. you know for mucinus and colonic tumors the risk of relapse is highest in the first two years. and so the the interval scanning is most frequent in the first years. Then we space it out. gobblet cell tumors oddly enough can relapse quite late. And so goblet cell were kind of moving towards less frequent scanning but for longer just because they you know we we it's not uncommon for goblet cell tumors to relapse five six seven years after seven years maybe a little bit longer but five years is not unusual for a goblet cell tumor whereas it would be pretty unusual for lucisence >> and the recurrence rate statistics for PMP with right hemi no hypo really so it depends on what PMP from what type of tumor. So like you like it's not really like >> you can assume that every Yeah. everyone here but we don't know if it's ham or lamb lammon. Hammond or lammon, >> right?

48:43 >> Yeah. So I said but they really you can't like you you really can't answer that question without having an accurate path of diagnosis. >> Yep. Got it. okay so let's move on to high-grade timing of chemotherapy around surgery. Yeah. So, like I said, you know, I you know, we don't have there'll probably never be a study that looks, you know, that randomizes people and does a head-to-head comparison of chemo first versus aduant. But, you know, for the reasons that we mentioned, we like our practice is generally to do chemo first, then surgery. you know sometimes like if there's risk of obstruction or you know patients are very symptomatic you know sometimes you have to go to surgery first. but you know except for those kind of rare instances we generally we generally do chemo first. but for this reason you know we generally discuss all of our patients at a multi-disiplinary conference where you have you know medical oncologist surgeons radiologist pathologist to make that decision.

49:44 But unless there's a compelling reason to do surgery first, our standard practice for high grade is to go with chemo version. >> Yeah. And this is a question I think it's a loaded question because I don't think you know until you start, but like cycles of chemo like like how do you know how do you decide when it's >> Yeah. So that's a good yes, we don't again you without prospective data, it's hard to say. I usually go with just six. I don't this you know reasons for that you know in col again this is a colon cancer extrapolation which is maybe not accurate to penny's cancer but you know except for very rare cases six cycles of folox was equivalent to 12 in terms of relapse rate in adgivant setting you know if anything I think appendical tumors become resistant to chemotherapy faster than colon cancer because they they're they're more plastic from the transcriptional state. I I can't think of a single time where you know after three months of chemo we saw additional response in the next three months.

50:52 yeah honestly I can't I can't think of a single one because normally like any tumor marker drop or imaging response we get is in the first three months and then you know we'll be stable after that but you know before surgery you know you're trying to get shrink tumor you know to facilitate a better surgery if if three months of treatment doesn't do that you just six cycles I think it's very unlikely that adding more to that is going to get you So so that that's why I you know our practice is to invest two three months. Again we don't we don't have prospective data behind that but that's that's what we do.

51:29 >> Got you. so and in this next question the the the side effects I mean like instead of asking it this way let's ask it like your patients that that are struggling on fallox when do you tell them like let's try something different and and then are there repercuss repercussions? >> Yeah. Well, you you know you know folox is great for coloc I I usually go with fulfury first for my own patients with the exception of goblet cell tumors where I I tend to do full fox first you know but if people are having neuropathy I would stop it right away like if you're getting neuropathy from oxaloplatin it's not gonna you know it's very likely be permanent so I I would stop it >> yeah quickly I okay got it all right let's go to low grade. Wait, wait.

52:21 Somehow Oh gosh, I'm going the wrong direction. Sorry. >> Okay. Goblet cell. CTDNA reliability and goblet cell. >> yes. So, you know, for reli so if the CTA is positive, it's almost certainly a true positive. I mean, we've seen a couple of positive cases that have kind of resolved on their own, but I think that's, you know, sometimes your immune system can kind of eliminate residual disease. I don't I don't think I've ever seen a clear false positive. The problem is is the false negative. And so, a lot of tumors if they stay in the abdominal space, the peritinal space may not cross into the blood. there's this thing called the blood paritinal border. some tumors kind of infiltrate across that and so the tumor gen can get into the blood but some don't.

53:18 and that's true for you know goblet cell are slightly more likely to be detectable in the blood but that's partially because goblet cell tumors are almost all high grade like vanishingly few grade one goblet tumors. The goblet cell tumors are almost all grade two or grade three. and the the chance that you can detect tumor in the blood is is higher in higher grade. the other thing we found is that tumors with p-53 mutation, it's more likely that you could detect turmeric in the blood and got goblet. So tumors tend to have more p-53 mutation relative to non-gobblet. but you know like so a positive test is reliable generally but a negative test is not always it's not always unfortunate. So we're working on >> do you have a do you have a percentage of what what a neg what what negatives are false?

54:12 >> but so so the the the negative predictive value depends on the population core. So like if if you like the rate of false negative is going to depend on what the true positive rate is and so it depends on what patient population you're looking at. So if you're extending out like shortening the time between you know scans and such with goblet and but you're extending the time out longer years more than 10 I'm assuming.

54:46 are you catching these things seven years later with CTDNA testing? >> goblet cell more on imaging. we haven't like we haven't the terror testing's only been around for like maybe three years. So we don't have any long-term like we haven't done CTA testing five six years out really anymore because the the the testing's only been routine for the last it's only really been routine for the last three years and I guess we >> for the patients where we kind of haven't been doing CTA testing we haven't necessarily been starting it you know several years later I suppose we could do that but we we haven't for the most part We kind of start it after surgery and continue it. But we for the historical patients that had like surgery like 2021, 2022, we haven't necessarily been been adding it.

55:45 >> Okay, I'm going to go to the next question in one second, but I have to say this because I just noticed it. My mother-in-law, my mom, and my sister-in-law are in this call. and so I have to give them a shout out. Love you guys. we've got a great support system. Okay. So, we've got some smart cookies here in the appendix cancer community. They want your data. Where is it? >> Well, yeah. So, yeah. So, you know, in general, we're happy to to share our data, you know, with any any cancer researcher. the I, you know, I'm imagine I know you're going to talk about Nord, Mike. I'm not super familiar with Nord. and I don't know if there's like a way for us to, you know, submit data to them. you know the this Sierra stands for the something epidemiology some I should know that so like all of our MD Anderson cancer data like goes into SEIR the problem is that like SEIR is I mean SER is okay I mean it's collects data on lots of cancers and so it has a huge number of patients but the other than kind of like this is an appendix cancer diagnosis it doesn't capture a lot of the other important information like what is the hisystologology, what is the grade, what is the st like it roughly captures stage but like to to really kind of make the like but for example it does not capture what chemotherapy people got.

57:15 it doesn't capture details about their surgical history necessarily. and it's I I you know I think you have to take that data with a grain of salt just because every institution kind of submits the data on their own and we like we've seen in the data like so we like basically each cancer center has a tumor registry and then that tumor registry data gets submitted to SEIR like when we've compared our chart extractions to our tumor registry like we found like a lot of issues honestly and so that makes me question an aggregate of lots of people's tumor registries just because un like unfortunately that most tumor registries it's a human like looks at the chart and fills out you know who a human who is not a physician >> looks at a chart and fills out information and we we've seen a lot of >> and so to toain explain this in like layman's terms like every hospital records this stuff differently and and so they don't have like a like you know MD Anderson does it their way MSK does it their way Mercy does it their way and so on and and so it's it's difficult to to garnish all the information.

58:24 >> Yeah. And a lot of it is incomplete. So that's that's the problem with sears. I mean it's they're definitely you know >> Yeah. >> It's better than nothing but but it's but there are limits and that that's why we really been focused on >> and so I must I must ask you because if you don't ask you will not receive who is the best point of contact at MD Anderson if patients and and caregivers won't. So >> that's still that's that's me. Yeah.

58:47 Unfortunately, we don't have you know, in a >> in a perfect world, we would have someone else that that would do that, but but unfortunately, that's me. If you message me and I don't reply, please >> how to get in touch with him. So, >> please respond again. we, you know, I try to not miss emails, but it happens. so, so again, we're happy to to share these data. We we put an we presented an abstract on this year and a half ago, and we're we're in the process of writing a manuscript. once the manuscript is out, we can publish with that the sub the you know take all the identifying information out and and publish the the outcomes data so that people can can can work with it.

59:28 we're a little bit limited by MD Anderson in terms of how we can't just like put the data out on the web until it's published. but >> don't get me I just had this conversation earlier today. I don't want to interrupt you, but we have one minute. And and so guys, fortunately, we're not going to get to even all the questions that were pre-ased. very quickly, I want to say that ACPMP, which is the most amazing organization on the planet. In fact, they were the ones who told me about Dr. Shim's study and and had, you know, that's the reason I reached out to him in regards to my husband. they have com you know partnered with Nord and they have it's a very technical thing a patient registry for appendix specifically for for appendix cancer it's going to launch soon I know the date but they won't let me tell it but I promise you I will let everyone know and I I encourage you to upload all of your your data there and and I can help you if if you need to like you know the pathology your your medical records.

60:38 they've developed a system that will that will put it all in the same format, something that research scientists like Der Shin can can use for research and and and innovations in the treatment and cures of appendix cancer. I wish that we could continue but we cannot. and I will work to get the rest of these questions and the ones that are in the chat the Q&A as well. I'm so sorry you guys. I wish we had more time, but Dr. Shen has promised he will come back and do this again with us on a regular basis. so I'm shooting for at least a quarter, but I'm really hoping for six every six weeks.

61:23 Thank you, Dr. Shen. >> Yeah, you're welcome. I'm sorry we didn't get through all the questions. I can I can if you kind of consolidate that we can >> absolutely you can count and send post responses. >> Absolutely. >> Awesome. Well, I hope this was informative for people. >> So informative >> a lot of lot of information and sorry we kind of went through it quickly but we are yeah like I said we try you know we learn more about appendix cancer every day and we're trying to translate that knowledge into better treatments and better outcomes you know as fast as we can.

61:55 >> Thank you so much. Nice.