Educated Patient® Webinar: Stomach Cancer 101 Series: Part II – Treatment

Dr. Janjigian: Good afternoon everyone. My name is Dr. Yelena Janjigian and I'm a medical oncologist and Chief of GI Oncology Service at Memorial Sloan Kettering. My research and clinical practice are dedicated to helping patients with esophagus and stomach cancer. Today I'm joined with - by my colleagues and other experts in the field of this research and treatment, and today, I am going to introduce my speakers while Ryan is working on his technical issues. So I'll go starting with Dr. Manish Shah. Manish, say hello. [00:03:00] Dr. Shah is a medical oncologist and head of Solid Tumor Oncology at Cornell Medical Center in New York City, and he is joined - joining us. And today is also Dr. Zev Wainberg, he is a medical oncologist and a leader in the field of upper GI research from Southern California.

Dr. Wainberg: Hi.

Dr. Janjigian: And we have - hey Zev, thanks for joining. And then Dr. Richard Kim is joining us from Florida. Richard, say Hello.

Dr. Kim: How are you?

Dr. Janjigian: Great. I guess I'll keep going with the introductions, let me just open this. So treatment options is the first portion of this discussion. We'll talk about gastrectomy, chemotherapy, immunotherapy and targeted therapies as options for treatment of stomach cancer. Before we go into more details about the treatment options that are available for stomach cancer and their benefits of each, we will talk about how - briefly how each treatment is selected, and explain what treatment options are available for patients with stomach cancer and highlight the benefit of each of them. How big of a role does convent - combining therapies play in the treatment of stomach cancer, what are some of - some of the more important things patients should be aware of, and then when it comes down to how to understand and how to choose which treatments may or may not work. So let's start with treatment, particularly with surgery and chemotherapy. Dr. Shah, perhaps you can kick us off?

Dr. Shah: Sure. So welcome everybody, and thanks for inviting me. What a great panel to talk about this. So maybe I'll start off with - it's obviously very scary when you're diagnosed with stomach cancer, a cancer that is between the esophagus and the intestines. The stomach is important in digestion and absorption of food, and maybe I'll start with maybe symptoms. So people may have weight loss, nausea, some abdominal pain. It's not uncommon that an endoscopy may identify some gastritis or something like that, but maybe not identify the cancer, and another endoscopy is needed to be done. I think if you have symptoms for any of these types of things, be persistent, follow up with your doctor. I've had patients sometimes get three, four endoscopies, particularly for a type of stomach cancer called Diffuse Stomach Cancer where their tumor doesn't grow as a mass for an ulcer, but grows sideways within the wall of the stomach. So [00:06:00] that's a key aspect of it, and I think once you're diagnosed with stomach cancer, you would probably most likely get something called a CAT scan. That's a scan that actually looks inside your body in a two-dimensional way to see where the cancer might be, and hopefully the cancer is localized to the stomach and hasn't spread anywhere else. And if that's the case, then we would think about surgery and - and treatment around surgery. We can certainly talk about this further, but maybe Yelena or Zev -

Dr. Janjigian: That's a great summary, Manish. Zev, many patients ask me when they come to see me, "Doc, how long do you think I've had this for?" They come in with mild symptoms or relatively well, maybe five to ten-pound weight loss, and some of it thought to be maybe intentional with diet and modification of their exercise routine. In your experience, how long do you think this tumor ran? What do - maybe you can discuss the data. What does it suggest?

Dr. Shah: It's always one of the toughest questions we have to answer, I think. And - because the truth is, we don't usually know in the bulk of patients, how long something has been there for. It's - there are certain patients where we - that they're screened, and we all see these patients who either have a history of Barrett's Esophagus, or some element of screening has been done for some other reason in which we can see a detectable lesion that may be premalignant. And then that gives us some intelligent way to assess how long things have been there for. But by and large, I struggle with that answer as well, because it's not a simple question to answer. I generally tell patients that the truth is, we don't know for certain, but usually at the onset of symptoms, it's been there for some months before. Certainly any onset of symptoms would have materialized. It is a tough question to answer that I think is unsatisfying to most patients, because most patients come to us and they ask us how long, and they want an answer and we struggle with that.

Dr. Janjigian: Well so, in my experience and what I saw some data to suggest, that many of the tumors that we see in the West are rapidly growing. In other words if a year ago, for example a year prior to the diagnosis the patient would have had an endoscopy, often that endoscopy is negative or non-diagnostic. And then that year between the two tests, often the - then cancer can develop and present stage two even stage three disease. So it's - that's why screening, particularly in the western population is so tough that the cancer can go from nothing to a pretty advanced tumor [00:09:00] within a span of eight months or less. Richard, and in your experience, do these patients - are they seen by the surgeon first in patients with no obvious spread - cancer spread, or do they come to see you first? And how - what should the patient ask for? What type of doctor should they see?

Dr. Kim: Sure. I think as Dr. Wainberg mentioned, most of the patients present with some form of symptoms. So stomach pain, dyspepsia, weight loss, and usually they would see a primary care doctor first. They - he or she would assess the current ongoing symptoms. Then we'll refer to usually a gastroenterologist, where they would scope the patient. They would - they will do an endoscopy to look inside, to see what's going on in the esophagus or stomach. Now once they look in the esophagus and if they see anything that's suspicious, obviously or that's a concern for tumor, they will do a biopsy of it. Once the biopsy comes back as let's say, proto deficiency adenocarcinoma, or some form of cancer, that's typically when they get referred to either a medical oncologist or a surgeon at that time to do the full workup. Now obviously, depending on the stage of the workup, I think obviously the treatment will be different. But I do think one key point here is that the treatment and the management of stomach cancer really requires a multi-tiered approach. It's not just me seeing the patient, you really need your colleagues, surgeons, endoscopers, radiation oncologists, surgeons, pathologists, they all need to get involved in your care and management. So I think the key point is that, yes, most of times the primary care gastro oncologists, they will see the patient first, they'll give the diagnosis, then they'll get referred to either myself, a medical oncologist or a surgeon to do further workup.

Dr. Janjigian: And what if the surgeon sees the patient first and recommends surgery immediately? And what - what would you advise your patients or your family member for example, who's diagnosed with stomach cancer to do?

Dr. Kim: So I think that's the - sort of a key difference I guess here, is that we - that's why we - you really need a multi-tiered approach. If you're diagnosed with a cancer, most of the times, you need some form of peer rapid therapy, unless it's a very early stage. And if you see a surgeon first especially in the community, I would say they would take the patient to surgery first, without doing any further assessment. So I would be very cautious of that. And if any family member is diagnosed with a stomach cancer, I would strongly recommend that you go to a tertiary center where you have everybody on board to come up with a final plan, and not to be too quick on doing a surgery right away.

Dr. Janjigian: And you bring up an excellent point about a multidisciplinary approach. And what we mean about that is, when we have multiple types of doctors in the room together talking about how best to cure a patient. And one thing that's important to notice, when, when you're first diagnosed with cancer, there's [00:12:00] this emotional need to have the cancer out of your body. And you think the faster you do an operation, the better. But that's often not the case, particularly for most cancers in the US, even if they're non-metastatic, an earlier stage, doing potentially treatment before going to surgery is an important consideration, particularly as newer types of drugs are available. And one of the things we brought up during the outline is the combination treatments, and how we best cure patients in a setting of early stage disease. Manish, I know you you've been very interested in this topic, particularly with combination of immunotherapy and emerging data. Perhaps you can talk about the types of combination treatments that are possible and how best to find these types of treatments when you're perhaps not at a tertiary cancer center.

Dr. Shah: Great. So I think - so I think that the challenge for gastric cancer is that 80, 90% of patients diagnosed in the United States are actually not managed at a tertiary Cancer Center, it's actually patients who are seen in the community or other centers that are not specializing in G I cancers or gastric cancer. So it is challenging I think too, for many patients to find super-specialized care. And I think it's probably on us to sort of try to educate patients as best as possible, so again, this is a great forum for that. I think that what Dr. Kim was saying is - in terms of this stage, what we're what we're trying to say is that if the tumor is just in the stomach wall and barely involving the stomach wall or into any lymph nodes, maybe surgery is the right thing to do right up front. But if the tumor is a little bit more advanced, if it's going deeper into the wall or involving lymph nodes, then a combined approach with chemotherapy and surgery might be a better - might offer a better option. So I think asking these questions will at least get the ball rolling in terms of how advanced is the tumor, what's the best option, and then getting to a combination therapy. It's - it is clear that multiple agents when you combine that together, you can have a higher response rate with treatment. And recently - a year, year and a half ago, there was some data that if you combine three drugs together for patients who had locally advanced tumors, the tumors that went through the wall or into lymph nodes, if you combine three chemotherapy drugs together, you may have a little more side effects, toxicity. But you can have significant activity as well with response rates, major response rates or even having a complete response, much better than having one [00:15:00] or two drugs alone. So giving that chemotherapy, we call that the FLOT regimen, before and after surgery has become - become a standard in patients who have locally advanced disease.

Dr. Janjigian: Great. Zev, could you tell us a little bit and what is your sort of quick recap of biomarker testing and genetic testing in your clinic? Particularly for localized tumors, and a bit about MSI tumors maybe, and the most common hereditary syndromes that the patients need to be aware of and to ask their doctors if it was tested for?

Dr. Wainberg: Yes. Sure. So this is an emerging area. Most biomarker work has been done in, we know in advanced stages, but certainly, some basic biomarker information I think, is helpful even in localized disease. And you touched on MSI, which can - reflects the three or 4% of gastric cancer, maybe more depending on what ethnicity and what background, that is called microsatellite instability in gastric cancer, or in any cancer for that matter. This makes one very sensitive to these drugs that we're gonna talk about in a moment referred to as immunotherapy drugs, or checkpoint inhibitors. And it also perhaps, is important for us for prognostic reasons as well. So it helps us guide our patients into some decision-making, whether now or for the future. So we do here, and I think most big centers do routinely test for MSI tests. And even in localized gastric cancer, there are a number of other biomarker tests that I think are, to be fair, dependent on where you are and where you're treated and what academic center that are either a part of the routine panel to be tested or they're applied individually, on a case by case basis. We also - and I think most academic centers do, certainly in the majority of patients now, recommend some full detailed family history and genetic testing be done to inform whether there's a hereditary predisposition for that person's cancer, particularly obviously if they come - if it comes at a younger age.

Dr. Janjigian: And Richard, what are some of these syndromes that we need to be aware of? Or Manish, for either one of you, if you want to jump in? So if a patient comes in and a genetic testing or referral's recommended, what is the more typical [INAUDIBLE]? And how did [INAUDIBLE] practice?

Dr. Kim: So I think - I'm sure that Dr. Shaw will explain this as well. But one of the most common is the one - if you have a mutation in the CDH1 [00:18:00] gene. That's the one that predisposes you to get early gastric cancer and lobular breast cancer as well. And at least at our place, there is a high-risk clinic, I'm saying that sort of see those patients and screens them accordingly. Some of them will need a prophylactic gastrectomy and-or a mastectomy, as they're at very high risk of developing those types of cancer. And so I don't know if Dr. Shaw, you want to add more to it, but that's the one I'm looking.

Dr. Shaw: Thank you. So Hereditary Diffuse Gastric Cancer is I think, one of the main predisposition syndromes that we think about, particularly in someone as Zev said, if you're diagnosed with Diffuse Gastric Cancer below the age of 50, or if you have a first-degree family member with Signet Ring Cell or Diffuse Gastric Cancer, or a person or relative with Lobular Breast Cancer or a Signet-Ring Cell Colon Cancer, all of these are features of this hereditary Diffuse Gastric Cancer Syndrome. And it turns out that if you identify a family that carries this gene mutation, unaffected individuals, people who don't have cancer, they're at risk of developing gastric cancer at about 1% per year starting in their 20s. So the recommendation is to have a prophylactic gastrectomy. We call that a risk-reducing surgery to remove the stomach and reduce their risk of getting subsequent stomach cancer. So the recommendation is a prophylactic gastrectomy, amongst people who don't have the disease, but who carry the gene mutation. And there's a lot of work, I think we'll talk about this further, but in the last five or six years, a lot of work has been done on defining molecular subtypes of gastric cancer. Dr. Janjigian led the field here for this, and one of the subtypes is, as I mentioned, Diffuse Stomach Cancer or genomically stable, and this subtype has actually a few mutations. But one of the mutations that it does have is a CDH1 mutation, which is what we're talking about here for the Hereditary Diffuse subtype. The other hereditary type of gastric cancer is actually from Lynch Syndrome. A lot of people think of Lynch Syndrome as primarily for colon cancer, but you also have a tenfold risk higher - higher risk of getting stomach cancer as well. And patients with Lynch syndrome have a mismatch repair deficiency. And these patients may benefit from the checkpoint inhibitor, but I think it's one thing to think about from a family history standpoint. And then finally - finally, FAP is the third category for gastric cancer risk.

Dr. Janjigian: This is what we're trying to impart on you - and again, if you remember ten percent of what we said today, it's great. This is all recorded as well, is if you have [00:21:00] gastric cancer at a younger age, or if you have cancer that runs in your family, a lot of this in-depth analysis of the tumor that we do to understand how best to treat your cancer also gives us a look at your germline analysis or the DNA analysis of your normal cells and things you can pass on to your children. And you have to ask your doctor, “Hey, was biomarker testing done on my tumor? Is there anything about my genetics that need to - that I need to be aware of?” The field of stomach cancer research has really exploded this year and there's been transformative changes. And one of the important parts of this puzzle for early-stage cancers that we need to know if this tumor, the MSI high tumors occur because those tumors need to likely be treated completely different with surgery and potentially immunotherapy. We hear a lot about this buzzword, immunotherapy, and it's a class of drugs that uses the body's own immune system to activate - and activates the immune system to fight the cancer. There's been two separate or two or three, several important trials this year that demonstrated it in metastatic disease; these treatments work. And the FDA approved immunotherapy for use in metastatic disease, but also early-stage esophagus and GE junction tumors. Zev, maybe you can tell us about the CheckMate 577 data a little bit, and the immunotherapy highlights in general.

Dr. Wainberg: Sure. We've all been fortunate and Yelena, Manish, Richard and myself, all have been fortunate to be a part of this field that is changing rapidly and providing us as oncologists, new tools, and immunotherapy drugs. And as Dr. Janjigian said, immunotherapy, this class refers to agents that help the immune system fight the cancer, and that can be categorized into many different groups. But on a superficial level really refers to antibodies that are given intravenously to patients about once a month or once every three weeks and help your own immune system attack cancer. And in the last year, we've seen these drugs getting approved for stomach cancer and esophageal cancer in various settings. And so, my distinguished colleagues on this call have really led this effort. The CheckMate 577 study was the first study to look at it in a really big way in patients after having had esophagectomy. After they've had primarily esophageal cancer, not stomach cancer, but mostly in the esophagus and having had surgery. And then patients were randomized to receive either nivolumab, which is an immunotherapy drug, a [00:24:00] PD-1 inhibitor, or placebo. And it showed a dramatic improvement in the group of patients who got nivolumab and that allowed the FDA to approve it in that context in patients after having had an esophageal cancer surgery. A lot of the patients enrolled have to - to be fair, have gastroesophageal tumors as well. So, there is often as we all know a blurring of the lines here between stomach and esophageal cancer, but generally, by and large, that study was designed for esophageal patients and really changed the way I think we treat patients now after esophageal cancer surgery.

Dr. Janjigian: Great. Thank you for that. Richard, do you use immunotherapy in standard practice in your clinic? How do people tolerate it? What are the common side effects? What do you usually tell your patients about these class of drugs?

Dr. Kim: Sure. As our panelists mentioned here, the immunotherapy has been evolving, not only stomach or esophageal tumor, but other GI tumor as well. Right now, the use of immunotherapy in gastric is you either could use it in combination with chemo, or you could use it as a single agent. And some of the side effects that we're talking about that's caused by immunotherapy, one is to understand immunotherapy is not chemotherapy, right? It is totally different. The mechanism was clearly explained. It works differently. But however, since it allows the immune system to attack the cancer cells, if you do it too much what happens is that you get autoimmune phenomena, right? Your T cells get overactive. And instead of attacking the cancers, it attracts your own body. And those are the side effects that you see with immunotherapy, especially if you start combining two immunotherapy together that rate was much higher, but some of it was common autoimmune phenomena, you could see are probably autoimmune colitis. You could get autoimmune hepatitis. I think the most common is rash. Probably you see that that's pretty manageable, or you could get issue with the hormone issue with a thyroid, pituitary. Those are the side effects that comes with the territory. Granted as a single agent, most of those side effects are probably less than 10%. So, it's not very high. Once again, if it's like combining immunotherapy with immunotherapy, that rate gets higher. But overall, it's very well tolerated. Patients like this much better than chemotherapy because it's just not chemo and you don't get the typical side effect you get from chemo.

Dr. Janjigian: That's right. And for patients with metastatic disease, most of the time, the chemotherapy and immunotherapy are combined together and now are done in the beginning of treatment before cancer progresses, so in first-line therapy. Manish, what are some of the trials you're excited about? Tell us about how do these trials come about? What does this idea of randomization and [00:27:00] how do patients find the trials that suit them the best, please?

Dr. Shah: Yeah. Terrific. Maybe taking a step back just a minute and maybe really emphasize how immunotherapy has transformed what we've done. And I think my colleagues, Dr. Kim, and Zev, Dr. Wainberg, you already mentioned this, but I think it's just really, really important. For 40 years when we've been giving treatment for gastric cancer, we've been giving drugs that actually killed dividing cells. And by killing dividing cells, we can treat the cancer, but in the process, we can kill also normal cells that are dividing. Cells in the GI tract or cells in the bone marrow. And these is - this is what causes some of the side effects from chemotherapy. About 10 years ago, we started using a drug called Herceptin or trastuzumab for tumors that over-express a protein called HER-2. And HER-2 is a protein that's on the surface of cells. And when it's overexpressed, it can drive the tumor growth. And by blocking that signal, you can have activity. That was the first targeted agent that was approved in this disease. But recently in the last three or four years, as was mentioned, immunotherapy was a whole new way of how we target this drug or this treatment, the cancer. And then what it does is it activates your own immune system against the cancer. And by doing that, we're teaching or educating your immune system to fight the disease. And actually, in a trial that Dr. Janjigian lead, she demonstrated that patients who received chemotherapy plus immunotherapy have a far better outcome than patients who receive chemotherapy alone. And that was done based on a randomized study. At the beginning of the trial, patients were assigned to either receive chemotherapy alone or chemotherapy with immunotherapy or in this trial, immunotherapy without chemotherapy option. And by doing that, what we can learn is which of the arms worked better? A lot of patients prefer not to get randomized, but honestly, we perform randomized trials when we as clinical investigators, we don't really know which way is better. We call that equipoise where we say you could get treatment one or treatment two, I'm not sure which one is better. I think that treatment two might be better but treatment one is probably still really good. I just don't know which one is better. We're going to treat 500 people, half will get treatment one, half will get treatment two and we'll [00:30:00] figure it out. And that's how advances are made, not only in oncology but all through medical care. And the first randomized trials were done in cardiology. That's how we know that statins work for you to prevent heart disease. And this is part of clinical research. It's how we advance care. And by doing that, our patients are living longer now than they were five years ago. I think it's really important to think about that.

Dr. Janjigian: And equipoise is such a great word and concept to learn about because most of these studies are carefully designed by panels of experts in the field. At a minimum, the control arm or the second arm has what you would be getting in clinical practice and the standard of care. And what these randomized human trials offer you is an ability to get something cutting edge, maybe five or six years before everyone getting it. For example, some of the trials that led to the FDA approval in immunotherapy this past year, our patients enrolled in them in 2016. So, it really is important to put trust and to read carefully - trust, but double-check all the information and learn a lot about the options. And the next topic for us to discuss. And I'd love to hear our attendee’s questions about this is how do you select the best trial? How do you know what trial is best for you? And right now, really the important part of the puzzle that we need to figure out is we already learned about important biomarkers and how to use immunotherapy in later stage of cancer, in stage four, when the cancer is metastasized to other organs and surgery is not feasible. And one of the most satisfying parts of my career so far has been seeing patients live with that and live despite metastatic disease. And in some cases, are cured despite of metastatic disease in patients with the HER-2 positive tumors and some of the MSI tumors and other subsets of cancers that respond very well to immunotherapy. And so, the next push really on our agenda is to cure more patients in earlier stage disease, patients who are undergoing surgery. And so, the trials that are out there right now in the US are focused on looking at the combination of chemotherapy that Dr. Shah discussed. The FLOT regimen and other regimens with immunotherapy before surgery’s done, and sometimes after the surgery as well. And so, perhaps we can go around and just talk about some of the trials we're most excited about that folks should watch out for, and as always, you can reach out [00:33:00] to our teams, but use your physician. And if the team that you're working with as your starting point, because those doctors know that you're the best, but Zev, on the west coast, what are some of the trials that you're most excited for in early stages [CROSSTALK]

Dr. Wainberg: Thanks, Yelena. I think, first of all, as a patient, I always find my patients get very overwhelmed because if you Google clinical trial in stomach cancer, you'll see possibly hundreds, if not thousands of entries related to stuff that is relevant to your case, perhaps, but relevant not; completely different stories. So, it's really important before seeking out your own trial is to talk to wherever you are treated. Talk to your trusted oncology provider and say “Do you have a trial that fits my needs, or is there anywhere nearby?” Maybe not quite in your center, but that has something really exciting that may fit my needs. And so, I really think as a patient, it's very overwhelming doing the clinical trial search and on your own, because quite frankly, clinical trials open and close all the time and are now increasingly focused on certain subsets. And what excites me in stomach cancer is beyond immunotherapy, which I think has been a sea change in how we treat patients, and in combination with chemotherapy is also trying to focus on targeted approaches. Dr. Shah alluded to HER-2 positive, which is one biomarker, but we already know that there are many other biomarkers out there discrete from HER-2, that themselves are subject of new drugs, new antibodies, either being combined with chemotherapy or being combined with immunotherapy. And all of us who participate in his field are really excited to see whether we can find some new targets that themselves could be affected by these new drugs. I think we're hopeful that in the next five years or few years we're going to see some new targets be validated beyond the ones already mentioned.

Dr. Janjigian: Richard, perhaps [INAUDIBLE]

Dr. Kim: Yeah. I would say that if I could take one step back and I think the key point here is that everybody who's diagnosed with at least advanced disease should get their tissue profile, your tumor profile. I think that's a key point. We've talked biomarkers but there are trials going on right now that they're purely biomarker-driven, meaning that if you have certain mutations, certain overexpression, certain proteins, you may qualify for some of the trials. I think the first thing as a patient is once you're - at least when you're diagnosed with advanced disease, you should consider asking your doctor to profile your whole tumor [00:36:00] so that you know what you're dealing with. I think that's a key point here, which could lead to some of the trials that we talk about or some of the earlier study that targets maybe not specific to the gastric per se, but all solid tumor types. I think that's the key - one of the key messages here. The one thing the trial that I would say that I'm interested in is - I think this trial is being conducted in Europe is as Dr. Janjigian had mentioned when you're trying to cure somebody after chemo at the beginning that you under surgery, the afterward, we don't know if getting more chemo is better, staying chemo or changing up to the immunotherapy. There's a trial going on right now in Europe, where after surgery is done after you get chemotherapy, then you go into surgery, then you're randomized to the immunotherapy versus chemotherapy because we don't know if one's better than the other. That's one of the trials ongoing right now. But there are a lot of exciting trials in gastric cancers that targeting certain overexpression mutation that's going on such as FGFR2 B amplification or overexpression. There are trials ongoing now targeting claudin 18.2. I think that there are a lot of - something going on in gastric cancer, so I think there are plenty of trails available for patients to go on, hopefully, but I do think that it's very important to get your tissue profile and talk to your oncologist to see what's best for you.

Dr. Janjigian: Manish?

Dr. Shah: Yeah. Another concept to think about and this is also emerging technology is, we are developing the tool to identify DNA presumably from the tumor in the blood. It's more established in colon cancer, but it's being developed in upper GI cancers as well. And ideally what it is, is that a blood test can - if you have evidence of circulating tumor DNA in the blood, it indicates that you might have microscopic disease that's still there. And our efforts to try to use that technology to see if we can maybe treat people before the cancer actually develops into a mass that we can see on a scan to see if we can clear that circulating tumor DNA. And that may be a way to really - I think be a game-changer as well. And then I think other - Our technology is advancing quite a bit. Another very exciting area is where you can grow someone's tumor and outside of the body, like in what we call it as tumor organoid, and you can test that tumor for different drugs to see if you can identify if that tumor is sensitive to certain things. There are trials expanding that as well. [00:39:00] I think in addition to the targeted therapies that Dr. Kim mentioned, and combinations, which are likely to really make major advances, I think these other two technology-driven advances will change practice as well over time.

Dr. Janjigian: All great points. OK. Maybe we can spend the last 20 minutes or so answering some of the questions. There was a question in the chat about a patient with signaling cells futures with again, the genetic possible treatment, or the genetic screening of a patient who was age 58 at the time of passing, what would be the screening implications or recommendations for the son of the patient? Manish, do want to take this one?

Dr. Shah: Yeah. Honestly, we don't have great data here. In colon cancer, they recommend starting colonoscopies 20 years before a parent or a brother or sister was diagnosed with colon cancer. Let's say your mom was diagnosed at the age of 60, then you should get your colonoscopy at the age of 40. For gastric cancer, we don't really do screening for that. I think what - unless there's a hereditary predisposition syndrome. So, you make sure that you have a good family history, you see your oncologist or clinical geneticist, and you make sure that you don't have one of the syndromes that we talked about. And if you don't, then we don't really have any screening recommendations for gastric cancer. We don't recommend endoscopy at a certain age or anything like that. But what I advise my patients is you just stay diligent. If you have any heartburn that doesn't go away, any weight loss, any pain, then don't sit on it, see a doctor and see - and tell them about your family history. And that will likely lead to an endoscopy and evaluation.

Dr. Janjigian: All excellent points. Deborah, if I may add, the likelihood that your husband had genetic predisposed stomach cancer, that then passed onto your child, and when your husband was diagnosed age 58 is very low. So, that's in some ways reassuring. It's very scary he was still diagnosed with stomach cancer, but it's unlikely that it's one of this hereditary diffuse gastric cancer syndrome. Cancer has given his young - his relatively older age. That being said, as Manish mentioned, the colorectal cancer risk is on the rise. So, the time to first colonoscopy is actually has been moved up. And so, in some people, it's as young as age 45 or even younger. Again, there's no clear data to support this, but[00:42:00] if there are any symptoms of reflux or if the patient is anxious as the kids of patients with the cancer diagnosis are, it would be reasonable to do an endoscopy at the time of first colonoscopy. Again, because the colonoscopy is done, this is something he could discuss with his gastroenterologist. The other topic we were going to discuss is, depending on the stage of the disease, how should a patient approach their care team to discuss the topic of what is the goal of treatment? Question is, is it curative and intent treatment? The important factor to remember is this, the patient is always there with the goal of treatment regardless if the disease is cured of an intense therapy or it's chronic treatment. Richard, how do you frame these discussions with your patients? How do you approach this sometimes difficult topic of chronic treatment and the goals of treatment?

Dr. Kim: Yes. I think this is a very important question. Obviously, the goal depends on the stage of your tumor. Many cancers that we see. Typically, once again speaking, if you have stage four, which means that your tumor has metastasized outside the primary organ site, the goal becomes palliative. When I talk to my patients that I'm going to give chemotherapy, immunotherapy, or targeted therapy, I do mention that my goal is not curative. Even though there are some patients that live very, very long time, that's outside the box and not the norm. I tell them that it's a long war so there are a couple of battles that we have to go through in first-line, second-line, third-line, depending on their biomarkers. We do the profiling of tumors to see what other weapons we could use. In a patient with stage four that's how I approach a patient, but I do make it clear that my goal is not to cure because I don't want to give false hope. But understanding that, like I said, with the immunotherapy, with targeted therapy combination, some of those patients have a very dramatic response that we have not seen in a couple of years ago. I have a patient with stage four gastric cancer, who's four years up, five years up, past five years. You know what I'm saying? There are patients like that but once again, that is not the norm. Now, for stage one, two, and three patients, obviously, the goal is to cure here. And depending on the stage, we give the chemotherapy before and after. But I do tell them that- obviously, if you have a lot of lymph nodes, now, I do tell them that the chance of recurrence is very high. I try to be realistic as well, "Even though I'm going for a cure, I'm going to use chemo, whatever, after surgery-"

Dr. Janjigian: Richard, I think that's a very important point you bring up because the patients, the first visit that they see the surgeon or myself they wonder what stage they are or their risk of cancer recurrence. But the critical piece of this is after the surgery [00:43:00], when the tumor is microscopically dissected and each lymph node is examined, is that's when we really know the stage and risk of recurrence based on each individual lymph node and whether or not it's involved.

Dr. Kim: Yes, I agree. Before surgery, you have a general idea what stage it is because you do go on endoscopic ultrasound, CT scan could tell you basically what staging we have. But like you mentioned the key prognostic is after some form of chemotherapy, how you're responding to it and what comes out of it will ultimately determine the overall prognosis. And I try to be realistic about that to our patients as well. You know what I'm saying? If you have a lot of nodes involved, chances are it's going to come back, and so we go from there.

Dr. Janjigian: Worldwide H. pylori is an important class one carcinogen, right? A lot of gastric cancers historically were associated with H. pylori infection. How different is H. pylori-related gastric cancer from other types of stomach cancer, and do you routinely treat H pylori in a stomach cancer patient if it happens that the biopsy came back positive?

Dr. Wainberg: No, it's a good question. We know that stomach cancer is a very common cancer outside of the United States. In fact, in Southeast Asia, it's the most common cancer. If you go to Japan, Korea, Taiwan, China, this is the most common cancer out there, stomach cancer. Or one of them certainly. And they're leading into H. pylori. H. pylori is a worldwide bacteria. It's endemic. Usually, it doesn't cause cancer. The large majority of patients who have H. pylori are not going to get cancer and even very few of them will actually get ulcer disease. But it is certainly a predisposing factor, as you indicated, for some gastric cancer. Patients in whom they have H. pylori we usually recommend eradication. The gastroenterologist are usually the ones who are going to deal with that, not so much the oncologists because we usually have the patients by the time they're diagnosed with cancer.

Dr. Janjigian: Well, it's interesting because some data suggest that H. pylori and this whole idea of microbiome and things belong in your body for a reason, that if it's in there and it's asymptomatic that you shouldn't even screen, test, or treat for sure, because it may actually increase certain types of reflux and other inflammatory diseases. But stage four stage, it doesn't seem to be that H. pylori is a common factor, at least in the US, that most of our tumors are actually GE junction tumors. And it does not appear to be an independent prognostic factor. What about other biomarkers? I think Naomi is asking if stage four tumor, non-MSI, HER-2 negative, [00:46:00] do you test routinely for PD-L1, EBV? What are some of the other biomarkers that you think are important to review on the homework list for the oncologist and to remind them to do?

Dr. Shah: Sure. I think it's great that HER-2 and MSI were tested, Naomi. But I think other things to think about, the PD-L1 CPS, I think is important, although immunotherapy can be used no matter what your CPS score is. I think all of us believe that the higher the score, the more likely there is to benefit from immunotherapy. The EBV or E-Barr test is helpful as well because there were some studies that, as Richard has said, if you are HIPA positive, you have a high likely of benefiting from immunotherapy. And then there are some rare mutations that should be checked for as well because they have their own approvals, like an NTRK fusion for NTRK inhibitors. It's about one and 300 in gastric cancer. And then also TMB, tumor mutation burden. Tumors that have a high mutation rate, so 10 mutations per 50 megabase pairs or more, they would be eligible for immunotherapy pembrolizumab as well. I think that there are other potential mutations for clinical trials like Claudin 18.2 as Dr. Kim mentioned as well as an FGFR mutation as well. But the first ones I mentioned are the ones that you could use for off-the-shelf treatments.

Dr. Janjigian: Very great points. Last but not least is nutrition. It's probably the most important part of being able to stay on chemo is remaining nutritionally strong, trying not to lose weight. One of the most important prognostic factors is, what percent of your body weight have you lost? Often our patients present with cancer in the abdominal cavity or the peritoneum, which is a potential space where the stomach, the liver, and the intestines all exist and live. Having cancer in that space really makes you more nutritionally compromised and so nutrition is such a critical part of it. That being said, using fresh ingredients, using your common sense, not cutting out too much out of your diet. I've seen people go on all raw diets. Eliminating sugar completely out of your diet is often detrimental to your own nutritional status because you could then continue to lose weight and become so weak that you're no longer able to tolerate the intense regiments that we're prescribing to you with chemotherapy, immunotherapy, and often surgery, and so on. Although the nutritional piece is critical, I think [00:49:00] doing it with common sense, using a balanced diet, eating small frequent meals, five or six meals a day, and trying to not lose weight, is the way to go. Some of these nutritional supplements - cancer patients are extremely vulnerable because we all want to live a healthier life and a good life and so be aware of internet cures. There's no easy cure for this disease without a professional in the picture. We do think that there's some utility to Western medicine in conjunction to Eastern medicine and other alternative options and so what I recommend typically is a referral to integrate a specialist to balance out these ingredients. A lot of these supplements are not FDA controlled and so you really don't know what goes into it. We see these alerts often for these supplements especially in New York area. They see admissions to the ER with certain toxicities. Often it's related to some supplement that patients take. But I'm just curious, Manish, Richard, and Zev, how do you educate your patients on this topic? It's an important topic but it's hard to do a lot of clinical trials in it.

Dr. Kim: Go ahead.

Dr. Shah: Oh, well, I was just going to just touch on something you had said, Yelena. That we don't know how the supplement may interfere or interact with the treatment that we're giving. Years ago, we were studying a mushroom extract from China and we figured out that the active ingredient was berberine. It turns out that this drug actually can interfere with Taxanes in the lab. I don't think that any one of us knows if a certain supplement is actually going to be effective or not going to be effective but I think that there is a real potential that it could interfere with your current treatment, so that's something to consider if you're thinking about taking supplements. Otherwise, I would echo wholeheartedly what was said earlier about trying to maintain a balanced diet, maintaining exercise, hydration. If you're overall healthy that way then you're likely to tolerate more treatment and that's likely to be beneficial to you.

Dr. Kim: Yes. The only thing I would add that once again I'd mentioned at the beginning is that this is a multi-tier approach. We do have a nutritionist in our campus as part of our team as well so if you have any patients that are losing weight, that cannot maintain the calorie intake, I do make a referral to him or her to go over each daily [00:52:00] routine the patient goes through. I could point out all the herbal stuff that patients bring in, we don't know how it interacts with the chemo. It may enhance the efficacy or it may decrease the efficacy, or it has toxicity as well. Something that we just don't know. I generally tell the patients to avoid all the herbal stuff if possible. That wasn't me. Anyway.

Dr. Janjigian: Zev, what do you tell our patients or your patients about dumping syndrome in the postgastrectomy, how common it is and how to avoid it, or what to anticipate?

Yes. I think it's hard. Postgastrectomy is a real tough challenge, especially the first few months. We're on this panel, a bunch of medical oncologists, but sometimes the mixed messaging that comes from surgeons versus oncologists is a big part of our struggle. I agree with Dr. Kim, who just said, having a nutritionist as part of the team- a nutritionist or dietician depending on which institution, is a good idea because I think that this is not an easy thing to get used to. A postgastrectomy life requires adjustments, it requires realistic expectations, but it also requires working with professionals who can give you good candid advice about how to deal with things like dumping syndrome or maintaining weight, as you alluded to in the beginning, Yelena. Small frequent meals, we all have known for a long time, is a lot better for you than trying to maintain three large meals a day. Having realistic, tangible goals about making sure your weight is being maintained, and not suffering from trying to do too much is always an important thing that our nutritionists and dieticians try to instill in all of our patients.

Dr. Shah: I might add that for dumping syndrome, for example, dietary changes can make a big impact. If you cut down on carbohydrates, cut down on sugar, you can actually impact dumping syndrome quite a bit. This is a syndrome after surgery where people maybe feel flush and have diarrhea after a meal. Frequent small meals, dietary changes, these seem to make big impacts on your overall health and quality of life.

Dr. Janjigian: Absolutely. No oatmeal and banana for breakfast, have a scrambled egg with a little cheese, maybe. OK. There's a question about ranitidine, and should they consult physicians about the risk? With Zantac, there's been a lot of literature and popular press about risk of gastric cancer [00:55:00]. I guess, since we're a bunch of oncologists here it's a little bit of an off-topic question but we can try to answer it. In our clinic everything's cancer so of course, the answer is, "Get an endoscopy". But consult your doctor, because we're again, very highly specialist group of gastric cancer doctors. I don't know if others have other thoughts about this.

Dr. Shah: I would say that the vast, vast majority of people who've taken ranitidine do not have stomach cancer. Talk to your doctor about the risks specifically unique to you. Weight loss, nausea, pain, other things like that, would be larger red flags for me.

Dr. Janjigian: Yes. All right. A general question, "About how long will I have to be on treatment?" What are some things that you tell your patients when they ask that question? And then we can close up after this. Go ahead, Manish. You can take that one.

Dr. Shah: Oh, sorry. I was just going to say for patients with metastatic disease where the cancer has spread past the stomach, what I tell them is that it's hard to know how long we'll be on treatment, it depends a lot on how well we tolerate the treatment and how well the treatment works. What I encourage people to think about is they try to make treatment part of their life, not a window of three months or six months and then stopping it. Because I think we have data that the more treatment we can give people, the better their outcomes are.

Dr. Janjigian: That's exactly right. If we can just finish up with little parting thoughts. This was a great discussion. What I would like everyone to remember is that there's a lot of hope and discovering this disease, and all of this has been largely because of the trust that our patients and their caregivers put in the medical professionals and the research. And we thank you for that. Please continue to seek out specialty care. This is an orphan disease in the US and we are really working hard to understand different subsets of it because each patient needs to be treated with personalized care and treatment plan that sometimes involves surgery at the beginning, sometimes in the middle, or after many cycles of chemotherapy. This is an important factor to consider using both immunotherapy and targeted agents and chemotherapy. Both standard and experimental [INAUDIBLE] would give you the most options. And there are a lot of options so there's a lot of hope. Zev, maybe you can give us your parting thoughts [00:58:00].

Dr. Wainberg: I support everything you just said. We really are optimistic that the future will continue to show new improvements as we've seen in the last few years. Every year we see new improvements and we're looking forward to working with our patients and their caregivers on further improvements in the years to come. Thanks all for being part of this journey and also thanks to Debbie's Dream for helping put together this great symposium.

Dr. Janjigian: Manish.

Dr. Shah: Yes. As was said by you and others, I think that it's really important to recognize that there has been progress made. I think that you're part of the community that cares for you, ask questions and you'll get answers. There are many treatment options, there are new treatments available to you, and our ability to take care of people now is better than it's ever been before. I think with that there's hope that we can even do better.

Dr. Kim: Yes. I'll just echo the points. Once again, key point is that this, as Dr. Janjigian mentioned, it's an orphan disease so if you do get diagnosed somewhere in a community hospital I do really recommend that you guys seek out to do a tertiary cancer center where they have more experience of taking care of this. I do think that there's hope, once again, there's a lot of development of immunotherapy, chemotherapy, targeted therapy, better surgical options, so I do think that we're doing a better job of taking care of this patient. And hopefully, in the future we'll do a better job in terms of extending overall survival.

Dr. Janjigian: Excellent point. Really tremendous seminar, I enjoyed hearing everyone's input. If you'd like to watch this webinar again it will be available on the webinars on-demand page of curetoday.com within the coming days so please tune in and check that out. I want to thank our panelists and the audience for attending and participating in today's event. I also would love to thank Cure and our partner Debbie's Dream Foundation, as well as our sponsors Bristol Myers Squibb, I'd like to thank you, and Merck for making today's educational webcast possible. Please check out in your email tomorrow the survey that will be linked to the gift card. If you answer all the questions you'll get a gift card. To win a gift card. Thanks to all of you for joining. We'll see you next time [01:01:00]. It's a pleasure. Have a great rest of your summer and take care of things.

Dr. Wainberg: Take care. Bye.

Dr. Kim: Bye. Thank you.

Dr. Shah: Bye-bye. Thank you.