Dr. John Paul Shen, MD Anderson Cancer Center - Appendix Cancer Quarterly Update

0:07 Looks like we've got people filing in. Just going to give it a few minutes to let people come in before we get started.

0:38 As people are coming in, Dr. Shin, you're in Switzerland. What are you doing in Switzerland? >> so I'm here at a conference with a Swiss company called Artidis. they make a atomic force microscopy assay, which we it's being used in other tumor types now to assess the mechanical strength of the tumor. and we think that this may be useful in appendiceal cancer to kind of help us predict risk of relapse, response to therapy, that that sort of thing. So the the project is is kind of in the pilot phase now, but we should be able to start testing tissue you know, in the next couple of months.

1:18 >> Oh, that's exciting. Yes, and you'll you'll share all of that information with us once the data is available, I'm assuming. Yes. Okay, well, let's go ahead and get started. I think people will continue to file in, but thank you so much for joining joining us. for those of you don't who don't know, Dr. John Paul Shin is an assistant professor at MD Anderson and one of the most, you know, experts in the appendiceal cancer as well. they really have the only appendiceal lab in the country in the United States.

1:59 but thanks everyone for joining. Dr. Shen is in Switzerland, so he's going to have to drop off at about 10:00 till. but he's going to go through kind of the the updates, the landscape of appendix cancer, and then we'll we'll take questions, those that have been submitted pre pre-event and those that will come in the Q&A. so Dr. Shen, I will turn it right over to you. >> Okay.

2:32 all right. So, you guys are the shared the slides there slides are >> Yep. I got >> Okay. we'll welcome everyone. Thanks for for tuning in. just have a few slides to kind of give a brief overview. you know, I assuming this audience will be reasonably familiar and then that way we can kind of get right into the the question and answer. Here we go. yeah, so obviously based on, you know, now decades of research from our lab and and many other collaborators, it's very clear that appendix cancer is is not the same as colon cancer, which is why our lab is really focused on developing new treatments so that we we can avoid going back to the colon cancer type chemotherapy, which, you know, in in some patients is helpful, but in a lot of cases this is really not that helpful.

3:25 the you know, one of the the big issues is that, you know, most appendiceal tumors are mucinous, and, you know, one of the the key features that's not always appreciated at centers that are not you know, high-volume centers that don't necessarily have a lot of experience in treating appendix cancer is that the histologic appearance, which we call the grade, it's sometimes called the differentiation, well, moderate, or poorly differentiated is is same as grade 1, 2, or 3, is is really strongly predictive of how long people will live, and also it's it's really important in terms of how likely chemotherapy is to work. And so, we approach a a well-differentiated or a grade 1 tumor completely differently than we approach a grade 3 or a poorly differentiated tumor.

4:16 This is now, I guess, 3 or 4 years old. but, you know, again, this is hi- goes back to the kind of importance of grade in low-grade mucinous tumors, 5-FU-based chemotherapy, which is kind of the standard colon cancer chemotherapy, really doesn't work at all. this is kind of showing you that this study was set up so that every person got 6 months of chemo and 6 months you know, no no treatment, just observation, and the rate of tumor growth during the chemotherapy period versus the observation period was was exactly the same. And so, that really in my mind, and I think in most people, has kind of you know, it kind of settled the question that, you know, 5-FU-based treatment doesn't work in in low-grade tumors. Again, that's not necessarily true for high-grade tumors, but for low-grade tumors, it doesn't work. And so, we we try not to use them in under living from the treatment.

5:11 one thing that we talked about in in in the last session, you know, this is more relevant to high-grade tumors, but we've seen some activity with with drugs like paclitaxel or Abraxane. This paper will finally come out, hopefully, in the next 2 weeks. but, in, you know, the subset of patients where the tumor is caught in stage 2 or stage 3, where it's just localized to the appendix, you know, the outcome is very good with just surgery alone, and doing ad- you know, colon cancer-style adjuvant chemo afterwards doesn't doesn't help.

5:52 we've harped on this a lot is that you know, the you know, it's hard to one of the challenging things about appendix cancer is the normal imaging, whether it be a CT scan or MRI, is is challenging to really assess how much tumor is there and how it's changing. and so having the blood-based tumor markers can be very helpful. you know, they're not elevated in every single person's tumor, but if they're elevated, you know, in your tumor, tracking them over time is is is a really helpful way to you know, know how well the chemo is working or you know, to to monitor if the tumor is is progressing.

6:37 Let's go over that. yeah, and so you know, some of the the the promising things in in low-grade tumors especially GNAS mutant tumors, this is work from Andy Lowy's lab who who's one of our collaborators. we've seen a lot of success with drugs like palbociclib, also called Ibrance, or abemaciclib. I forget the trade name of that one. we are actively working to get this added to the NCCN guidelines, which will help a lot with reimbursement issues.

7:10 unfortunately, it's a battle every time we try to prescribe this for someone. most of the time we're winning that battle with the insurance companies, but hopefully we'll we'll put but we've got working with a couple of other groups who've also been treating patients with palbociclib. we're trying to pull our our data so we can have another publication, which hopefully will put this in the guidelines cuz it's it's definitely more effective than colon cancer chemotherapy for these patients.

7:39 we're also very excited about exploring immunotherapy. We did the study with Genentech a few years ago now. there's some new data that maybe atezolizumab is not the best immunotherapy. However, because we did this is the trial we did we're getting insurance authorization with this combo atezolizumab and bevacizumab. you know, but you know, potentially we would even see more benefit from a better immune drug.

8:13 and so some we this paper is also about to be published hopefully in the next 2 weeks. in colon cancer again not the same as appendix cancer but we've seen activity with the different immune combination nivolumab which is a PD-1 inhibitor kind of like atezolizumab, ipilimumab which is a CTLA-4 inhibitor so it's a different type of immune stimulating drug it all it activates T-cells but in a slightly different way than nivolumab and then regorafenib is a vegf vascular endothelial growth factor receptor so it's kind of like kind of like the Avastin also called bevacizumab but it's an oral drug small molecule. and so that combination because we're seeing activity in colon cancer we have some ability to get insurance authorization in this whole cancer and so we've been using this in some you know, higher grade of penicillin patients as well.

9:19 you know, one of the the big things moving forward is that the immunotherapy is kind of high risk high reward in some cases high risk in that it sometimes has a really big benefit and and a sustained benefit but for some tumors it does nothing. you know, the side effect risk is is reasonably low. you know, higher in in younger people, but usually, you know, less than 5% of patients will get a serious side effect from immunotherapy, but the big the big risk with immunotherapy is that it's just not going to work for your tumor.

9:51 we're trying to better understand how how we can predict which tumors are going to respond to immunotherapy and which ones are not. I in my clinic use the Boston Gene assay quite a bit. you know, there's data in other tumor types that suggest that you know, more T cells at baseline, more activated T cells at baseline, less fibroblast kind of predicts more likely to respond to immunotherapy, but we're still trying to to get to get better at this.

10:26 We skip that. in terms of clinical trials, we do have this trial open now where we're we're using intraperitoneal delivery of the old drug paclitaxel. we are we have four slots left before that trial will close. so the trial's looking positive in that we're seeing activity. you know, the the side effects seem manageable you know, relative to traditional chemotherapy given intravenously.

10:57 you know, we we haven't cured anyone with this, but we are excited about this kind of as a platform and the the next version is going to be paclitaxel plus a immune drug called evenisimab. Evo is a it's one drug, but it targets both VEGF and PD-1, so it's kind of like doing the atezo and bev together in one molecule. this drug has looked good in lung cancer and it's also being tried in in colon cancer, cervical cancers, and so some of the therapeutics was was generous enough to to donate the drug to us for the study and so we'll be hopefully opening that before the end of the calendar year.

11:43 this is kind of a picture of what what, you know, the before treatment, you can see the the white stuff there is all tumor. and then, you know, you can see there's less of it afterwards. that you can get also kind of imagine like why this is not easy to see on a CT scan because, you know, the tumor is just kind of stuck to the This is the abdominal wall. you can say that's right where the port came in, you know, the that's going to look just like like a few little ditzels on a CT scan, but if you're looking at it with the the camera in the OR, you know, you can see obviously that that that's tumor.

12:20 so this is why it's necessary a lot of times to do that diagnostic laparoscopy surgery in order to kind of assess how much how much tumor is present. Well, so I'm not in any means an expert in PIPAC, but just wanted to you know, mention it just because there is some promising data coming out of multiple centers including City of Hope and Allegheny Health in Pittsburgh and and others. Mustafa Roof is is this is his work here, but Peter Wagner also is is doing this at Allegheny Health. you know, very early days, but but I think definitely an option to consider.

13:00 we're very excited about KRAS inhibitors. this has been accepted and hopefully will be online in the next 2 weeks. this is kind of showing the preclinical data. but we'll kind of jump around to the the clinical data and so the in a mix of phase one clinical trials and some standard of care therapy with G12C Keras inhibitors, which are FDA There's two G12C Keras inhibitors that are already FDA approved. we've seen at least kind of stabilization at least stabilization of disease in almost everyone and some pretty nice biochemical response, meaning like the CAs dropping. these are a couple of my patients who you know, showing their their biochemical response who've been treated with a lot of prior treatments and then you know, went on to the Keras inhibitors and had had really profound drop in in the in this case CA19-9.

14:07 the and this slide is just kind of showing that if you just, you know, the traditional way that clinical trials judge how well a drug works is that they you do a scan at the beginning and that's your baseline and then you do another CT scan and then you measure the difference. that does not work really well with pancreatic cancer. You can see like if you did, you know, the top row is if you just do the the traditional CT scan way to measure the tumor.

14:36 whereas we're now trying to promote using measuring the tumor markers, whether it be CA, CA19-9 or CA125. you you can see that we can see you know, you know, pretty profound drop, which we think will equate to some, you know, patients living longer. Cool. So, that's you know, that was just kind of an overview. I I wanted to do that relatively quickly just to kind of save time for questions. And so, Amanda, do you want to to who I think you are >> Yes.

15:13 yep, so so now guys, if you want to ask questions, go ahead and start submitting them to the Q&A portion. If you don't know where that is, in the bottom of your screen it should say more or there might just be a Q&A button in the attendee view. but either way, it's there, so Q&A, more, Q&A, either way. let me go to the pre-submitted questions. we'll just start down the the line until we get live questions, so your genomic profiling found the most frequent mutations in KRAS, TP53, SMAD4, GNAS for patients in this audience.

15:57 What does it actually mean when they see one of those those names in their own pathology or genomic report? >> That's Okay, so so great question. the Knowing the mutations in the tumor is important for several reasons. the most importantly is that it there there there there'll be different treatment options based on the mutation status. you know, so so you know, KRAS inhibitors are not available yet, but they should be you know, reasonably shortly, like hopefully within the next year.

16:35 the first KRAS drug will probably get FDA approval either really in the next couple of months. that So so knowing the the knowing the KRAS status is is important. the and then within that there's different versions different mutant versions of KRAS. so depending on which mutant allele, like G12C, G12D, G12V are the most common ones. the you know, the the options for drugs are different. For example, like like if you know, if you have a G12C mutation, you could start on a KRAS inhibitor basically right right now.

17:13 the P53 and SMAD4 we don't have drugs that target those, but it's important to know that because both of those mutations are associated with more aggressive behavior. more likely to just the tumor generally more more aggressive and we see them more in high-grade tumors and then so we would be In cases there's a there's a question coming up about how to handle grade two tumors.

17:47 you know, if you have kind of intermediate tumors, but you also have P53 and SMAD4 mutation, you know, in the setting of the rest of the information, sometimes that would make you more likely to go with the traditional chemotherapy. you know, GNAS mutation is more common in low-grade tumors. the the data from the Lowy group you know, has shown that the CDK4/6 drugs like palbociclib, also called Ibrance, is active in that population. And so the the you know, certain mutations knowing the mutations is important for picking the best drug for that tumor as well as kind of just knowing more about the overall risk of relapse and and aggressiveness of the tumor.

18:29 >> Okay. now kind of a a finding that was it was grade two mucinous looked more like grade one than grade three in both survival and genomics. Why does that matter? You know, like how does it get graded, treated, and should grade two patients be be you know, asking different questions? >> Yeah, so this is this is a paper that I've been involved with working with with Tempus. so it's it's it's their data.

19:03 it You know, traditionally we would treat a grade two or moderately differentiated tumor with more like a grade three tumor and then would get kind of the same cytotoxic chemotherapy. you know, we're potentially moving away from that. it you know, I would say the the data from Tempest I would say is more kind of hypothesis generating meaning like we I wouldn't necessarily stop treating grade two tumors with chemotherapy based on that data.

19:48 you know, I think it definitely highlights that it's important to to to to use a a three-tier system and not just a the the two-tier system. >> Yeah, because if it bumps it is high grade, right? >> Yeah, so I think it the the grade grade two tumors are challenging because some you know, there's a there's a you know, some of them behave more aggressively and some of them are less aggressive. It's harder to it's hard to know. I mean, I think that you know, if you have a grade two tumor that's not responding well to therapy, I I would you know, be more likely to to switch you know, I think than in a grade three tumor.

20:31 you know, definitely would want to do molecular profiling to to look for potential target options and you know, it you know, a good I would you know, generally I would be more likely to consider an immune therapy approach in a grade two tumor versus a grade three tumor. but if you know, we're we're trying to trying to generate more data on alternative treatments for the grade two tumors to kind of know how that works. So, it's it's unfortunately not we don't know >> Well, I guess we're still we're still we're still learning. I think Probably what people also want to know is like, you know, how do they know if their tumor was not graded under the tier three and then and then what do they do do about it, right? I mean like What what >> I mean So I mean I think I think that's probably the best solution to that.

21:29 You know, I think you know having a you know, if possible like, you know, being seen at a a center that has, you know, expertise in appendiceal cancer is is worthwhile to have like an appendiceal true appendiceal expert review the pathology. It You know, I it if if it was not kind of done that way initially at your institution, probably they're they may not be capable of doing that. So I I I think that is You know, right now we don't have a great way to kind of do that in an online, you know, theoretically it would be possible to do that online. We don't necessarily have a way, we don't have an apparatus to do that yet, although it's something that we would like to kind of build forward in the future. We're we're kind of at early stage of this, but trying to use AI to interpret the the images and that that would it would be easier that way to kind of disseminate the the grading to community places versus having the patients come to the to the you know, expert centers. So I think in in 2026 probably the best way to do that is to, you know, to to get a referral to a you know, one of the major appendiceal cancer centers, but hopefully in the future we'll have a a better way to to address that that, you know >> Okay. Let me >> They take some pictures of the patients.

22:57 So >> So let me jump into some of the live questions. Melinda, yes, this is being re-recorded and answered this afterwards. Mary Joe is asking, are you using photon count counting CT scanner for appendix cancer? and or know of centers that are using it. >> I To be honest, I I am not super familiar the with that technology. you >> I asked you that a while back. Yeah, so. >> Yeah, I don't I don't believe that we're doing that at MD Anderson at least in this I mean, you know, MD Anderson is a big place, so it's possible that it is being done, but I'm not aware of it. but I don't believe it's been used for, appendix cancer. So, I apologize that I don't I don't know more about that.

23:41 >> Yeah, I know a few. If someone wants to reach out to me, I I did some Googling on that, so I can share that. does Okay, this is Josephine. Does low grade only refer to grade one? What about colorectal, chemotherapy treatment for grade two mucinous? >> so that you know, it's a great question. you know, different people I think will mean different things when they say low grade, so it's important to, you know, this is like when we when you go to publish these things, it's really important to be specific about how the grading is done.

24:17 you know, we like at at MD Anderson, like we have our pathologists review the the the you know, we get the slides or the blocks up from wherever the surgery happened, so our people can review it. you know, cuz we don't kind of just trust everyone else's grade. there's actually a study that was done at UC San Diego where they showed that, you know, the the diagnosis could change up to a third of the time when it was reviewed by a by an expert. so, when I say low grade, I usually mean like grade one or the other the challenging thing about grading is that with, you know, not every tumor fits neatly into the one, two, or three category.

24:55 you know, sometimes are and then also if you've got tumor in multiple areas, they're not always the same. Like you could have some that are you know, more differentiated well, you know, like well differentiated and some that are less differentiated within the same it's in the same patient. which is challenging. But so when I say low grade, I usually mean well differentiated with grade one or sometimes our pathologist will say well to moderate, which is kind of like 1.5 like, you know, one to two. that that's what I would call low grade and then two or higher would be high grade.

25:30 the and then you know, I think it's reasonable to try the colorectal chemotherapy for grade two tumors. but you know, if it's not working well, I would be much faster to switch off of that to a you know, potential immune therapy or you know, say CDK4/6 inhibitor potentially versus a a grade three. so a a grade two mucinous, I mean, I would also go with their irinotecan combo more so than oxaliplatin.

26:07 but yeah, we're we're trying to really find the best the best treatment for grade two. so the the >> >> you know, the we think that the three tiers important because you you can see that they really are kind of three groups in terms of how well people do. But if the question is like, do you get you know, when we only had colorectal cancer chemotherapy available, the question was like kind of do you do chemo yes or no?

26:31 Like, you know, you know, to grade two and higher was yes and less than grade two was no. you know, hopefully we're now kind of moving into having more treatment options. so we can kind of you know, have a more nuanced picture. >> Okay. Thank you. anonymous is saying pet pet scan has been better at picking up activity versus a regular CT. Thoughts on this her he Anonymous the CEA has been under five since surgery but has had multiple active nodules.

27:06 >> You know you know generally we don't we don't generally run pet scan on our appendix cancer patients but you you know every case is unique and you know if it's working for you I would continue to to do that. You know our again I'm a medical oncologist on the chemotherapy guy not the the imaging person our radiologist and surgeons really like the the CT scans and that's why we use that the most other places are more you know kind of more standardly use MRI.

27:41 You know in my experience I've had some cases where we could see things much better on MRI than we could on CT scan but it really it's really different on each patient. The one thing about pet is that you need generally like the tumor has to be like at least 1 cm the solid mass has to be at least 1 cm generally for it to reliably light up and so if you have cases where the tumor is like just kind of coating the surface and not forming a discrete mass that the pet's not always that that helpful.

28:10 >> So for moderate grade GCA without SRC is a right hemi sufficient if the tumor was restricted restricted to the appendix and the say say say some say come. >> cecum Yeah okay that's like the British spelling of cecum. Yeah so again I mean I don't want to I don't want to give a specific advice because I don't without having full information but you know generally my data suggests that a grade two so moderately differentiated grade two goblet cell tumor the risk of that coming back is is quite low. like I think maybe like 5% and so yeah, just right right hemi colectomy should be sufficient. obviously in the right hemi colectomy it's important that the surgeon kind of do a an exploration just to make sure that there's not tumor you know, in the operating room just because you could have, you know, small amounts of tumor could be missed on a CT scan. So when they're going in to do the right hemi colectomy it's important that there is a surgical inspection of the the peritoneal space. But assuming that's clean, then yeah, right hemi colectomy >> when David had his right hemi colectomy, we were told that the surgery would come to a stop if they saw any spread and it would not continue. So that's something kind of important to know and which is also why you should go somewhere that recognizes what spread looks like because a lot of people that do right hemis, you know, don't do a lot of appendix cancer so they don't recognize it.

29:43 >> Yeah, so the reason that you would stop the surgery is that you would start with chemotherapy in that case and then and then you know, come back and do a a more complete surgery. >> Yeah, I just remember being in that waiting room like on pins and needles thinking he was going to come back any second and I'll realize that they had to abort but that did not happen. so where does MD Anderson stand with the Bromac trial?

30:08 >> That is a great question. I need to follow up with my contact with from the cult thermo. it so the issue had been like supply like the the the so so the Bromac like Bromelain is like a natural product extract from pineapple. So it's like an enzyme that naturally is produced in pineapples and I guess the way that they were making it is they just like start with a huge number of pineapples and >> Crazy.

30:37 >> it it's smash it up and extract the the protein. The the problem is that the the batch-to-batch consistency wasn't like up to like I guess Australian or FDA standards. And so so we just haven't been able to get the the drug like physically shipped to us. I I've heard from someone else that that is maybe now getting fixed or has been fixed cuz this has been a while since I've talked to them. To be me honestly, we have a huge list of patients that we think will be really helped by bromac.

31:15 I've only I think there've only been maybe two people treated with it at MD Anderson, but it it it seems to work well. we tested it in our lab and it you know does dissolve the the mucin pretty well. so hope it so I thank you for the question. reminds me to follow up with them just to to just to see, but we really think that it's going to be helpful for for the especially, you know, well-differentiated or grade one mucinous tumors.

31:43 >> Yeah, that's that's good good to hear. I I wrote something about that a few months back. Remember thinking pineapples? so direct I'm I know I cannot pronounce this. >> This one's a direct direct on ras it. >> Yeah, is it going to be an option for KRAS mutation tumors, Julie asks. >> Yeah, I I I I I I think so. our you know, the data that we have so far looks very promising. we that you know, we tested that drug in our mouse model and it worked.

32:15 and patients who have been treated with other we don't we haven't treated anyone directly with rax and ras it, but we treated people with very similar drugs and and they worked. you know, logistically, like how once it gets FDA approved, theoretically you know, your physician prescribe it for you, but I'm not sure how that's going to work from like an insurance standpoint, but you know, I think we are working on kind of clinical development of of RAS inhibitors in appendix cancer.

32:55 you know, right now the best way to get on a KRAS drug if with appendix cancer is to go on to a clinical trial. but you know, the the the you know, with the exception of the G12 C mutations where there's FDA approved drugs, you know, everyone that we've treated with the KRAS inhibitors been on a clinical trial. So, we know that that's not an option for everyone, which is why we're trying to you know, get these you know, get these available as standard of care, but you know, just the the reality is that it it it's going to take a little bit of time, I think before that happens. but you know, we're very of all the things in appendix cancer, I'm most excited about the the KRAS drugs.

33:33 >> Well, where there's a will, there's a way. so Beth, high-grade mucinous, how can we get more information in the clinical trial with Pax- Paxlisib Lisel? she was in RIOT3 clinical trial with Dr. Wagner at AHN in I guess in November and has sub- sub- subsequently been on I'm going to butcher this Regorafenib. >> Regorafenib and Nivolumab, yeah. Yes, that's one of the the things you mentioned in the slide. So, that's the VEGF oral VEGF inhibitor and Nivolumab.

34:12 so but how can you get more information on the Pax- you can you can message me. you can let's see. It did did you know, honestly it is listed on clinicaltrials.gov and like the the the trial number is going to be and it's in the slide deck that Amanda's going to share. the But if if you're interested in potentially enrolling it, honestly the best thing is to contact either myself or Dr. Helmig.

34:50 and we can we can kind of go over more of the logistical stuff. >> Yeah. And your email is in the the deck as well, right? >> I think it's Yeah. Yeah. So yeah, I I honestly just email me. It's fine. if you I don't mind if you email me, please email me again. Amanda knows this that I have not I I I Honestly, I need to get a better AI agent to like help me organize my email.

35:16 >> for you to help you with that, Dr. Shin. >> Yeah. So we we need to to I got I I need to be more organized in that regard, but >> accept. You should accept. Okay. Are there any treatments to attack mucin? If not, are there upcoming treatments? >> Yeah. So so the the the the the bromac looks really promising there. that basically kind of dissolves the the mucin like to make make it more liquidy so you can like suck it out.

35:45 that I that's looking very promising. we think I I I think maybe to some extent the KRAS inhibitors may help with that. they're also we know that in tumors that have both KRAS and GNAS mutations, we know that the GNAS mutation contributes to the mucin and so this is something that we've worked on very early stages trying to make drugs to block GNAS, but there may be some other drugs like farther along that kind of block the GNAS pathway.

36:17 but you know Yeah, again, I really need to follow up with the bromac team, but that you know, cuz you know, bromac's has tested in multiple phase one studies already and and is kind of shown to work really well. So, it's just a question of getting access to it. I think that's really the best the best thing out there right now for for reason. >> Okay. Any studies with semaglutide? tide? >> You know, not that I'm aware of. That's So, yeah, no, you know, it's it's it's something that we could certainly It shouldn't, but you know, it's not not the not that I'm aware.

36:59 >> All right, this is an important question. so, your study said that there was no survival advantage to to chemo in stage two patients and that they shouldn't be offered it. So, that's obviously a big departure. so so >> Go. Go. >> Yeah, so so so like I guess the question the real question is is is when patients doctors are saying chemo, right? I mean, same thing with David. Chemo chemo chemo. you you said no chemo. And so so like what should people say to their doctors when they still recommend chemo and they can't make make a trip to to Houston to be a patient?

37:41 >> Well, I think it's it's it's good to ask like why, you know, you know, why they want to do you know, why the physician's recommending it, like kind of what data and you know, what they think like what's going to be the outcome. You know what I mean? Like you know, what what what's the like in the case of like the adjuvant, you know, like our data kind of shows clearly that risk of it coming back is low and you know, doing using chemo is not going to change that risk.

38:12 The you know, in what metastatic setting is is is is going to be different, but Yeah, it I'm trying to think the best way it to address that. Yeah, I mean I think I you know asking the question is good. You know what you know what what is the expected what's going to happen if I do chemo what's going to happen if I don't do chemo is is I think a good question and if if they don't say have a good answer for that you know then maybe it would be time to you know get a second opinion.

38:50 >> And and going talking specifically about goblet cell like can you walk us through why this this subtype behaves so differently a lot of a lot of appendiceal members have that specific subtype. >> So you know why questions are hard but I mean so we know that like in a molecular like the mutations that you find in a goblet cell tumor are very very different than the mutations you see in a mucinous or a colloid type tumor.

39:19 so fundamentally it's you know the it's different also in addition to the mutations being different like the cell of origin is different like the you know goblet cell tumors we call them goblet cell because we think that they came from the goblet cells of the intestine so like in the normal intestine the goblet cell is a cell that basically takes information from your brain and then like secretes hormones into the gut. So it has both a what we call like an intestinal type phenotype but also has a like neuroendocrine type phenotype.

40:01 and so and so it's a the to be called a goblet tumor you have to kind of see features of both neuroendocrine cells as well as intestinal cells. And so it's just a you know it's fundamentally a different disease than mucinous appendix cancer. And so, why is the risk of a grade two or stage two goblet tumor coming back lower than mucinous? you know, hard to say why, but they're just you know, it's just intrinsically different.

40:33 and you Right now, we are working on kind of generating data on chemotherapy response specifically in medicine metastatic goblet cancers. you know, right now the best thing we have is still primarily the colon cancer treatments, but you know, we're working on kind of new new things in that regard. you know, so one thing you know, we've seen pretty good response from the taxanes in goblet cell tumors. some of our better responders and we intraperitoneal paclitaxel were with goblet cell tumors.

41:09 So, that's that's one kind of consideration, but we're we are actively working on this, you know, to try to develop new new treatments specifically for the metastatic goblet cell subset. >> Okay. this is a question that I've kind of always has confused me, too. So, like can patients like a conclusion drawn from retrospective records rather than prospective trials? Like like if I guess can can retrospective trials studies be trusted and is it even possible for appendix cancer to have, you know, prospective Yeah.

41:49 >> Yeah, great question. So, I think, you know, can a retrospective study be trusted? I think absolutely yes. The you know, unfortunately, we don't have a huge amount of data in appendix cancer. So, any you know, I I to me, I look at, you know, having any data is better than no data. you know, if you have both prospective data and retrospective data, generally the prospective is more trustable because you know, the problem with retrospective data is that it can be biased by it can be biased. Like like for example, the the advantage of prospective is that you kind of have set criteria.

42:36 and you But but honestly, the prospective So it can also be biased. you know, depending on you know, how patients were enrolled and also like the other important thing about a prospective study is like, you know, the prospective study, if the patients on that study aren't necessarily similar to you, then the results of that study aren't necessarily going to apply to you. and so, the the one advantage of retrospective studies usually has more patients. You know, you can look at, you know, hundreds or thousands of patients and see what's happened. you know, a prospective study is going to be smaller. So, both you know, knowledge about what is going to be the best drug is helpful kind of wherever it comes from, in my in my opinion.

43:24 >> And and I'm going to butcher this. Are antibody drug con- conjugate chemotherapy studies underway for appendix cancer? >> so, I think it's is that what you're promising? we have not I don't know of a study specifically for appendix cancer. I you know, it'll be interesting. We have like a separate group that does a lot of phase one trials called investigational cancer therapeutics and I send a lot of my appendiceal cancer there patients there for trials. and we've seen some pretty seen some pretty decent results with antibody conjugates. Usually, the entry criteria for there is that you have to test the tumor to make sure that the target is expressed. For example, like if you have a HER2 antibody drug conjugate, you need to make sure that the tumor expresses a high level of HER2.

44:20 other other ADCs that are in development are against like MET or claudin. you know, those So, you know, I think that if if there's high nectin is another one. if there's high expression of the target of the ADC in your tumor, I think it's definitely a a reasonable option. sometimes you could get that off label cuz there's several FDA-approved drugs. or or potentially through a through a clinical trial.

44:52 >> And what are they showing So, I think what are they showing What are they showing for treatment response? >> I mean, it was you know, a small number of people said it only, but we've seen you know, you know, reasonable response, and I think it's it's going to be I haven't seen, you know, like anyone getting cured with ADC, but you know, it definitely active and and I think prolonging people's lives. >> Okay. >> and then for the for the most part, they seem to be more side effect-wise seems to be better tolerated than the traditional chemo.

45:27 you know, for the for the most part. >> Thank you. So, your lab works at the intersection of experimental molecular biology, computational biology, and clinical oncology. how important is it for patients to to make sure that their data counts? Like, I'm going to put you on the hook here. like, how important are data registries to to continue and advance the research of appendiceal cancer.

46:04 >> Yeah, with we need support just because you know there's not you know, a lot of the questions that are you know in the chat like you know, how well do these things work? You know, the way that we can address that is we need to collect information you know, from you know, from people have been treated and that way we can you know, aggregate you know, how well it works. And so with enough if we have enough patients where we have their you know, like pathology information molecular information, treatment information how well it works. That will allow you know, scientists like myself and others to you know, basically learn you know, when we see mutation X, Y and Z, this drug is going to work better versus you know, this this other drug. You know, I mean right now the amount of drugs we have is is kind of limited but as we start to get more drugs available in in appendiceal cancer which which is which is coming. I mean I'll say it's I I know it's never fast enough but we're we got more stuff coming.

47:11 having more of this data is going to be important to kind of help understand like you know, which appendiceal cancer patients are going to benefit. And so because because you know, patient to patient appendiceal cancer is so different. You know, grade one tumors and grade three tumors are essentially different diseases. But you know, being able to collect this information will kind of help us sort this out. For example, like the question about you know, how best to deal with grade two tumors. Like we really need to we can see the molecular information but we also need to like pair that with the outcomes to know, you know, is is chemotherapy really helping these people or not? You know, like are they living better than grade three because they're getting chemotherapy or would they live better than grade three even if they didn't get chemotherapy? You don't we we you know, answer might be different for different people but You what I mean? These are you know, the more data we have, the more patients can of contribute their data to to registries like like the one Amanda is doing will help us to kind of you know, have better answers for these questions.

48:07 >> How do you think AI is going to expedite this process, if at all? >> well, no. AI is definitely helping. I mean, we honestly, every process in our lab, we trying to optimize more with AI. we actually including my email inbox. need to to put that on the list. But you know, the AI is helping us because it used to be like to get you know, information put into a registry like in a format that you could analyze it you would have to basically have usually it's like a medical student or a fellow like read it and type it in like an Excel.

48:46 And that is like super tedious and you can't do that on thousands of patients. So, now we basically have AI that can read the note and extract like you know, this is a stage four B tumor, you know, treatment first line was Fulfox, then Folfiri, then you know, and so we can basically extract that all into our database and then we can merge that with the the molecular data and outcomes data and kind of see, you know, what what mutations are important in terms of predicting response.

49:14 that that sort of thing. where I mean, so right now we're using primarily we're using the AI to help us extract data, but we're also trying to help it understand the molecular data like you know, we a lot of times we're doing whole exome sequencing and so you know, that's a huge amount of it. It's more data than a human can really understand. And so we're trying to now help have the AI help us. So, the next thing that we were going to kick off very shortly is having AI help us understand the the histology like the you know, what the tumor looks like under the slide under microscope. you know, right now we need an expert pathologist to interpret that for us, but hopefully we could get AI to you know, working with our expert pathologist and AI, hopefully we could have something where, you know, a person could just kind of scan, you know, send in the scanned image of their slide, and then we could say this is, you know, likely what the grade is, such a thing.

50:07 So, I think that's all very doable. we just have to to kind of implement it. >> Yeah, I understand. That's great news though. Dr. Chen, I it we're right down time. I can't believe it. Thank you so much. Have a great trip in Switzerland. Find all the cures for our rare cancer while you're there, and thank you very much. >> >> I know you're getting virtual claps all around. >> All right, well, I did. Thanks everyone for for your attention and and to me.

50:35 >> Yeah. Oh, look, I see all the hearts rising up. That's great. >> >> All right. Bye, guys. Thank you so much. I'll send out the recording shortly.