Episode 189: Canine Cancer from a Breeder's Perspective

Breeders hold the blueprint of their dogs’ future in their hands. Understanding the hereditary links and the role of selective breeding is vital to reducing cancer prevalence. Being proactive, rather than reactive, is important. Every decision a breeder makes shapes the next generation of dogs. Hear from Victor Stora DVM, DACT to learn what you can do to improve your breeding outcomes.

Watch the video version of this presentation here.

Transcript:

Nicole Engelman  00:04

Welcome to the Good Dog Pod. Join us every other Wednesday when we discuss all things dogs, from health and veterinary care to training and behavior science, as well as the ins and outs of Good Dog and how our platform can help you successfully run your breeding program. Follow us and join Good Dog’s mission to build a better world for our dogs and the people who love them. 

So hi everyone. I am Nicole, Good Dog’s Community Lead, for those of you who don't know me. Today we have a really exciting presentation for everyone: canine cancer from a breeder's perspective, with our guest, Dr. Victor J. Stora, we haven't really been able to dive into this topic too much in the past, so we're really excited that he's here today to help us cover it. So just a quick overview of what we're going to focus on: Breeders hold the blueprint of their dogs’ futures in their hands, and together, we're going to learn why understanding the hereditary links and the role of selective breeding is vital to reducing cancer prevalence. Being proactive rather than reactive is important, so we're going to discuss what that actually means. And every decision a breeder makes shapes the next generation of dogs. I know we say that a lot at these webinars but I think today it's going to be really relevant and of the utmost importance when we're thinking about how we can reduce canine cancer in the future, and hopefully have a future where there is no more canine cancer. 

So before we dive into all of that, I just want to thank our partner, Purina Pro Plan, for helping us bring you this webinar, as always. Again, this was a topic that was really requested by everyone here, and like I mentioned, something we haven't been able to dive too deeply into yet. So thank you all for continuing to let us know what you want to see more of, and you can always share those ideas for future webinars or podcasts or articles with us at breederteam@gooddog.com, because we love hearing what you want to see more of. And I want to also mention, I know I said this last time, but we've hosted a ton of webinars already this year. I think this might be somewhere past number 12, maybe even 15, maybe more—but whatever the number is, there have been a ton of webinars. So I just want to remind everyone where you can always find all of the recordings in our Good Breeder Center, so you can watch those whenever you have time. Maybe you missed a few, maybe you had a litter on the ground and you were really busy for a few months. So those recordings of all past webinars from not only this year, but every webinar we've ever done is all there. So I just want to make sure everyone has that, especially as summer kicks off, maybe you have some free time, maybe you don't and you can play these in the background while you're caring for your litters, whatever it may be. I just want everyone to know where you can always find those recordings. As always, we got a lot of questions in advance of this presentation, and I want to just share a little more about Good Dog for anyone who is new here and unfamiliar with who we are: Good Dog is on a mission to build a better world for our dogs and the people who love them by advocating for breeders like yourselves, educating the public and promoting canine health and responsible dog ownership. We are an online community that is created just for responsible dog breeders to connect with serious quality applicants from all across the country and find forever homes for your puppies. We do that by giving breeders the power of technology to level up their programs, providing them with tools to run their programs seamlessly from start to finish, so everything from getting your litters listed really beautifully online to connecting with buyers that we bring you from all across the US to our best-in-class software to manage everything that happens in between your litters being born and going off to their new homes. And we also have a number of free educational resources just like this, and health related discounts to help your breeding programs thrive in other ways as well. So if you're not yet a member of our community, we invite you to learn more about our mission and apply to join at GoodDog.com/join and before I let Dr. Stora take it away, I want to share a little bit more about him and his background in canine health, since this is the first time we've been able to have him here, so we're so excited to welcome him to his first good breeder webinar. Dr. Stora graduated from LSU School of Veterinary Medicine and then completed an internship in small animal medicine at Virginia, Maryland College of Veterinary Medicine. He went on to a residency in reproduction, medical genetics and pediatrics at Ryan Veterinary Hospital at the University of Pennsylvania that was sponsored by the American Kennel Club, AKC Canine Health Foundation and the Theriogenology Foundation. He specializes in canine genetic counseling and andrology, and has special interests in canine and feline internal medicine, critical care, dermatology, and behavior. He currently works at GoodVets in downtown Brooklyn. Dr. Stora is a diplomat of the American College of Theriogenology and a member of the American Veterinary Medical Association Society for Theriogenology and American Society for Andrology. And he is a longtime breeder of Shetland Sheepdogs, one of my personal favorite breeds under House Astori (kennel name) so Dr. Stora, with that, I want to pass things over to you to get our presentation started.

Dr. Victor Stora DVM, DACT  05:10

Okay, I'm sorry everybody; I’m a little sick, but I was able to kind of get this together. This is a topic that is close to me and that I kind of got into a little bit later on, after my residency, but during it, and we'll go through everything. It's a very large topic. It's difficult to cover everything. So if you have questions, you know, I'll be available for emails and stuff like that, but this is part of my specialty. I do have a personal clinic where I treat oncology patients because of the genetic impact it has. So I'll start now. We already had an introduction to my background. So I work at GoodVets in Brooklyn, and I also have my own private practice at my house, which is only for specialty work, such as reproduction and genetic cancers in general, but genetic markers of cancers is kind of where I like to stay. But I'm also a breeder, so I breed Shelties. I've been doing that for a while now. I started in 2007 with the first and then they just blew up from there, and I've been active ever since. There was a brief remission where I didn't really do anything, and I'll talk about that, but we're kind of back into the breeding and showing game. It helps me tell what I think is important or what I look for. When I ask myself what I look for with my dogs and what I want from them, this is the perspective that I would take or I would look at basically. So during the talk, I want to talk about what breeding traditions there are which tend to decrease the genetic variance, meaning that the first generation, or the generation that is breeding is not 100% or better than that its ancestors, meaning that we're kind of narrowing the genetic amount of alleles or markers you have, or the genetic variation per animal. So limiting that kind of also then starts to bottleneck you into different disorders, and cancer is one of them. However, cancer is probably the most difficult one to actually test for or talk about, because there are other things that go with it, which we'll talk about. So, you know, I want to just dive into a little bit about what breeding traditions can increase your chances in a kennel that decrease invariance and homozygosity, we call it. I also want to talk about, then, genetic diseases and traits, the patterns that you see, because that's how we recognize that there's a problem, right? There's first the pattern, and then we kind of see the pattern, and then we break it apart to see if we can understand why it's happening. And then the last thing is just the implications of probably the part that everyone wants to know about, which, unfortunately, we know, like the least about, but it's understanding the implications of breeding and cancer genetics itself. So this is just a schematic of basically how cells work and how organisms are alive and how they stay alive. So there are genes that are encoded in DNA, which we all know from high school bio, and genes make proteins. It's very simple, but it becomes extremely complex. But on the simplest scale, you can think of it like this. So if there's a problem with the makeup or the blueprint, the protein that is made is abnormal and it can no longer function—whether that is a regulation, whether that is something that is required for producing a certain product, either one of those will eventually fail if there's a mutation that causes a non-structural protein to be made. And then also, when we breed dogs, it's artificial selection. This would not happen if you threw a bunch of dogs, or, you know, animals into an area and then let them go by themselves. Because we are choosing right? We choose who and what to breed. We exclude what to breed, too. I don't think people think about that on the other side too. You know, we both choose to keep in and we choose to keep out. So when you are breeding dogs or you're playing with biologic organisms, there's always a risk, and you can never make it go away. That's just because of how life works and how everything goes on. But there is always some level of risk when we're dealing with these selections. The weight of the risk, the potential and the benefits should always be better than if you did not do that. So that's kind of what I asked myself, like, will my next generation be better off if I choose these two and mate them and then keep litters from them? Or do I choose someone else? Do I need something else in my kennel? And it's hard to say what exactly everyone should be doing, because it's very varied. You know, everyone thinks, “Oh, the geneticist is bad.” I'm not bad. I'm the easy one. Actually, I'll tell you to keep more than you would probably want to keep, just because every time we exclude, we exclude variation, and we have to keep these animals within our kennels or with us. So you have to choose ones that are particularly good. But you should always look at maybe it's not 100% as close to the standard as you want, but it's enough. And it's enough because it will give you genetic variance based on what you've tested, how you look at the dog, all of that, all of that, should factor in. So going for perfection is exclusively breeding towards an extreme. Perfection is not something that exists. In biology, that will never happen—that there can be something perfect. So you have to always, again, weigh the risks and benefits of things, because before that, if there's testing that you can do, or if there's even stuff that you know by keeping lineages because we have very long pedigrees, then that's something you should go by. So, you know, I wanted to talk a little bit about why there is an increase in hereditary disorders of pure red animals, dogs and cats, and others alike. There's a decrease in the variance, meaning that, again, we keep breeding towards an extreme; we may exclude stuff or genes that would be necessary to keep our kennels healthy, because it's not exactly what we like to see or want. But also we need to kind of consider both extremes, like health, we have to consider—and then we also have to consider, “Is this prospect actually appropriate for the standard, or is it enough?” That's not perfect, but is it enough? Because when you put too much selection pressure, you may actually be selecting for diseases unintentionally, but you may be actually selecting to put those diseases into a breed, and that's what happens when you go to the extremes of either side. There are certain genetic phenomenon that actually will restrict the variance. Probably the most important one to think about is popular sire effect. So you're in a breed, a male wins Westminster or you’re National; everyone wants a piece of that. So you limit the variation, because we are all going for that one male that won that. I’m not saying you shouldn't use him in your kennel, but it can't be 100%. There has to be some level where that's not actually integrated into your kennel, because if you just make it uniform, and you keep selecting and selecting and selecting for using that male or using that sire multiple times, everyone else is doing it, too. So because everyone else is doing it, you're selecting for what that sire has that you can't see. So everybody walks around—animals and the organisms—walks around with hundreds of deleterious mutations that would kill us, but we're varied enough where we have two sides of DNA, maternal and paternal, which genes are selected, or if the maternal line fails, the paternal line still has the ability to make that protein that you need, or make that substance or break something down without it affecting you, because there's a variation in it. If you take that dog and he has heart disease, and your breed club breeds him over and over again, you would never see heart disease in your breed unless you did that or another dog that has heart disease, because that heart disease gene is never supposed to find itself again. And basically what happens with inheritance is your generation next inherits that gene. So if they inherit the bad gene, and then you breed to a dog that also was a sire of the one you want to breed to, he may have that mutation that's exactly the same copy as to what's in your kennel array. And the more and more you go, the more likely it is that that mutation sees itself again and then causes difficulty in breeding. Population bottlenecks are what happens when there is a disease and it may have a large quantity of dogs or animals that cannot be reproductively active, meaning they're infertile, or a disease actually eliminates a certain population of it, so you're narrowed down now to a certain percent. The classic example is actually like cheetahs. In cheetahs, there was a population bottom, like something that limited or hurt many, many cheetahs kind of limited their variation without humans, and they are very genetically homozygous, meaning their genetics are very similar, which makes it hard to breed them or help them as an endangered species. If they are, it is because they have this bottlenet happen. So they lost all of those genes that they could have had because of a disease or something. Founder Effect is also something that you can't take back, but this is what happens in the very beginning. So a breed club, it is established. The stud books are closed. No new genes from other dogs can enter that breed. So Founder Effect is those founding members of the breed, those can have disease, though they do have disease. Every dog has something that's going on that if you breed enough, it'll, again, find its match again, and it will cause disease. Founder Effect is when that disease is already inherent in those founding the population, and then a virus starts to spread. You may not see it at first, but you'll see it later. And then what I talked about with selection pressures, is it enough? Because there are things that we select, and the more pressure we put on that, the more we start to select for disease and not actually select against disease. So this has been going on for a while. In 1915, there was a study that looked at all of the Terriers that were out there, specifically Irish, Scottish and Fox Terriers, and then 40% of that population was sired by only 20% of the actual males that could breed. This was initially thought of as a positive effect, about preserving breeds. But now we have technology, or artificial technologies, where we can send chilled semen, we can send frozen semen, and in some animals or domestic species, we can actually perform, like, IVF and AI techniques like that. So it's becoming like, instead of being limited geographically, when it's becoming to the effect of where it's actually causing a detriment now . . . because, again, everybody in the breed club can have someone related to that male if they want. Because if he ships well and he’s a proven sire, it can be everywhere. And so this is something that is very difficult to watch for, because it doesn't show itself in the first or second generations. Things start to happen when it's already established. This was something that happened in horses, in the Quarter Horse, so most of them genetically had a marker to the disease, because they started selecting very hard for one sire. And this is just what happens in an example population. So you have: males are square, circles are females, anything that is like half, half is the one bad gene and one good gene. So this male has made it to four female dogs; the first generation that comes off of them, you can see there's dissemination of the mutation across these four kennels. And then if you take these females and mate them to a different male, and this one is mated to a different male, this is a different male. Still, there's that gene that's floating in the background that you can't see and no one knows about yet. And then again, you just create more hybrids of the disease gene with a normal one without knowing, and you still can't see it because there is compensation. There is another allele there that can actually help make the proteins or decrease the substrates that you don't want—that you can't see it yet, because it's compensating for itself. The problems start now. So when we have the third generation, or after we've bred twice, and we've really overused this male, the blocks now that are dark are diseased, so that you actually can see disease now. Before you could not, so you couldn't see anything until the actual third generation, where it's already everywhere. So limiting, maybe, if this was one kennel and these are your four females, then I would probably take half and not have had them bred to that male and then kept some from there. Because again, if you are using all of your females and all of your genetic stock just to this one dog, you're going to eventually see something bad happen. Now that's kind of the background. It's very simplified, or something that's extremely complex, but I just hope that the basics are there. The talk is about cancer and cancer genetics. Cancer is a disease of mutations, so it's something that either you acquire or something that is risked based on a certain type of gene you have. There is a very high level of environmental pressure that actually will elicit cancer. So the problem with trying to actually always breed away from cancer is it’s hard because it's not necessarily one gene, and it's not one gene and no environmental impact. It's usually all those together. So it's the genes plus the environment. There are some that we know. There are definitely some that you can inherit. But then there are, as a majority, I would say about 70% or more, is not based on a disease marker. It's just something that's acquired over time, because dogs and people were never meant to live this long. So the body's ability to reproduce its own supply itself with new cells that will either replenish your skin or your GI tract or something like that, because we shed cells all the time, and we have to replenish them in a certain way. If there is no check on the cells that are reproducing or dividing, then certain mutations can slip by the immune system, and cancer will grow, but the immune system doesn't recognize it, because it still presents itself as a normal but it's not. It's not showing the immune system, the regulation flags that they have on them, basically, to say that it's bad. It's mimicking a normal cell, but it's also, underneath, dividing too much to where it's actually causing a problem. But again, the immune system cannot see it or regulate it, which is usually what happens. If there's a reproduction of a cell, the immune system has a schematic, basically, of multiple different types of warriors that will check on this cell and say, “Okay, it's divided. It's appropriate. It's showing the correct markers on top, and it's not reproducing with DNA that is now mutated, or DNA that is starting to become not the blueprint of the animal anymore, or a human, or whatever it is.” It's just reproducing over and over and over again.

So again, cancer is uncontrolled growth of an abnormal cell. The body can't, for some reason, control it anymore, and it's escaping the immune system. It's not presenting anything to the immune system that says, “I'm bad,” so it's allowed to go on. Once that starts to happen, it starts to invade nearby tissues, and it's invading the tissues which have a function, a role in life. So it's invading these tissues, and it's not aiding them, it's actually just harming them, because it's not providing like the lungs, like it's not causing a barrier, or it's not actually allowing oxygen to diffuse, it's actually destroying that tissue. So it's not allowing the organ to do what it's supposed to and it's also using up a lot of caloric intake. So it's using up a vast majority of the calories that the organism takes in, which is usually what has the largest impact. This again occurs when DNA mutations are disrupting a cell cycle regulation. Some foundations that we know, or genes that we know affect cancer, are something called proto oncogenes, meaning before cancer-like genes, something that we can look at on a tissue sample, but not test for, is a KIT mutation. So KIT is basically a mutation that allows the cell to forgo the checks and balances it needs to before it keeps going on and producing more cells. So it just produces more cells, even if they're not exact replicates of its predecessor. It's just producing as much as it can. There are genes that are tumor suppressor genes. They inhibit cell growth. So again, it's very complex. The immune system uses a lot of these. These are evading the immune system in ways, because it's not saying that there's anything that's bad going on. It's just saying that we're good. We divided, but it's made maybe 100 extra copies of itself, because the checks and balances are not showing up. So it isn't all mechanisms of GI repair, and when the DNA doesn't repair itself appropriately or fix it, the errors can occur. So BRCA1 is actually a disease allele for a mutated gene for breast cancer that is highly associated with breast cancer. It's probably one of the ones that has the most impact based on having that gene versus not, where environment, again, will play a big factor with this. This is something that is highly correlated to actual development of breast cancer in human women and some dog breeds. So we inherit genes from our ancestors, but also cancer. We have to remember that this is something that's sporadic, and it does not have to have anything behind it in its genes that would ultimately say, “Okay, this animal was going to get cancer.” You don't know sometimes. Sometimes it's just luck, and not a lot of canine cancers and human cancers are inherited. A lot of them are sporadic, but there are some that we know of when we can test for, it's just that this phenomenon that happens as things age, as everything kind of starts to wear down, the body can't replicate like it should. So it starts to have these failures of actual mechanisms, which, again, check these cells.

So these are some inherited or common ones in dogs. We have lymphoma in Golden Retrievers and Boxers, osteosarcoma in Rottweilers and Greyhounds, hemangiosarcoma in German Shepherds, histiocytic sarcoma in Bernese Mountain dogs, and then transitional cell carcinoma, or urothelial carcinoma of Terriers; Shelties these are also in this category as well. This is not an exhaustive list, but this is just the most prominent breed that would present with this. We know that they are genetically linked, but we may not know the disease allele or the amount of genes that you have to inherit together that ultimately show cancer, meaning that there's like a threshold. So you may be okay if you have 15 out of 20 normal genes, and then five being maybe cancerous-causing. Let's say that out of those 20, once you hit about 10 disease copies and 10 normal copies, cancer starts to show because the threshold is about 10. So meaning that, like, as you inherit, this group of genes that are like come in, like the 10-pack, then the more you inherit. Sorry, so then if you go to 15, the more likely you are to have cancer, because you've inherited just more. These are more like complex, multigenic (meaning different gene) sites that ultimately culminate together to form the inheritance of some sort of disease, trait, or, like in our case, cancer. There was a study of osteosarcoma, which is a bone cancer, and this was in large, fast growing breeds, and the breeds at risk were Rottweilers and Great Danes. It presents at the metaphyses of long bones. Metaphyses are the area of the bone that actively grow. So it's the bone area that's actively dividing. This was thought to (but it has not been 100% proven) occur when there's micro-trauma to the growth plate continuously over time, so not major fractures or it just actually breaking, but the constant impact of the dogs on their forelegs or—it’s usually a forelimb—and causing micro-traumas at the growth plate continuously over and over, making the body replicate over and over and over. So the chances of getting a disease or getting this bone cancer starts to become higher and higher, because we have all of this trauma occurring continuously. So again, replenishment is there, but it then may go unchecked if something happens. This is a very aggressive cancer, and it has a high metastatic potential, meaning that at the time we typically diagnose this, there is a high chance that it is somewhere else in the body, typically the lungs. So the lungs do get hit hard in many different areas where we're looking at if the cancer has spread, because the lungs actually are given the entire blood amount of the body in the second when the heart pumps again. So how the circular system works is that there's one loop which is the body, and one loop that's the lungs. The lungs inherit all of the blood from the body at some point, so some of the cells that maybe leave the tumor site will be then drained by either the veins or the lymphatics into the lung, and then it sits there for a little bit because it's got to have oxygen come and then it goes back to the rest of the body. So it's flying past most of the body, but it's actually sitting in the lungs for a little bit longer. And then you get these sites of where the cells settle in, and they start to grow other tumors there. 

In Golden Retrievers and a couple other dogs, like Boxers, there's a large predilection for lymphoma, and this one, there is a gene marker for that we can look at. It's not 100% but it does have a high correlation with lymphoma. Lymphoma is probably the most common cancer of dogs and cats, and it typically occurs in the lymph nodes, meaning the areas of the body that the water portion, or the portion of the blood that does not have blood cells in it. When those go and bathe the tissues in nutrients and oxygen, some of it does not go back into circulation. It goes and drains into the lymphatics. So the lymph nodes that we have—and again, those are immune sites, so the immune system should be checking everything or other cells that may have come with them, but it doesn't recognize these as having a cancerous potential. It just sees them as, again, normal because they have ways of evading the immune system. Lymphoma is more along the lines of a treatable type of cancer, depending on some of the subtypes and some of the degree to which when we find it. Another very prominent kind of cancer is hemangiosarcoma, which is probably (as a clinical veterinarian) one of the most frustrating ones to deal with, because it is so aggressive and it is so difficult to find, usually we find it at the time when it's at a very advanced stage, and it's very refractory to chemotherapy. It is not very responsive to radiation. And the problem with hemangiosarcoma is a tumor of blood vessels. So blood vessels are all over the body. They're everywhere. When you find hemangiosarcoma, it's typically in the spleen or the liver, sometimes at the heart base, but these sites are within the circulatory system. So they have a main line into the circulation. So when we find hemangiosarcoma, it is sometimes everywhere, like a very large portion of organs can have micro-tumors, or actual large tumors that you can see. So when it's diagnosed, it's at a very advanced stage, and it's very hard to treat.

Mast cell tumors. Boxers are highly predisposed to getting mast cell tumors. They often occur with the tumor sites having this KIT mutation. When we have a mutation in the KIT gene, it doesn't allow regulation of the cell cycle like it should. So the cells, or the mast cells, which are kind of the ones that are involved in maybe the immune response for, like, a bee sting or something like that, like an allergy, can also be attributed to these—they make a lot of products. Mast cells make heparin, they make histamine, they make other factors. So when they start to get out of hand, usually there are secondary issues that occur with them. They can actually start to increase the gastric acid and start to have GI signs based on that that are pretty heavy. Clients will often say that the tumor grew overnight. And this one can because this one, if it gets traumatized, if someone picks it up or would like to look at it, they can think it's a pimple. If you disturb them, they can start to divide in rapid numbers. And they can also start to make products at high levels. So with making heparin and histamine, if it's making heparin, you'll start to see this tumor grow fast, and there'll be a ring around it, because the blood is not clotting appropriately. When we find these at advanced stages, the dog typically comes in with other signs than just the mass, because once it metastasizes, it's often causing other problems based on production of these components, such as heparin and histamine.

Where KIT becomes useful, it is when we want to treat mast cell cancers, because there are KIT inhibitors that we can give. And so these are not associated in early life, where you can identify a dog with the KIT mutation and say, “Okay, this is going to have a mast cell.” The KIT mutation happens because it's a tumor, not because it was predisposed, and because this has this mutation, we can use that to our advantage and treat actually that very specific disease gene that's causing this mutation by giving a medication, it's usually their orals, but it's helpful, because when you treat mast cell tumors with traditional chemotherapy or radiation, it's not always as effective. So it also, when we treat cancers, we have to think that there's not just one way. Yes, there are published standards of care, but as we learn more, it becomes a little bit more gray, or that we can actually use this disease gene, this cancer gene, to our advantage by giving a KIT inhibitor. But also, you may not initially know that the KIT inhibitor plus chemotherapy is the best option. So those are something that happens after or, you know, later studies that typically go on, and when these later studies happen, we can incorporate that disease gene to our advantage and treat it with chemotherapy and the KIT inhibitor to maybe have a higher effect and higher remission rate for a longer period of time. But our understanding of cancers and certain cell regulation genes is not the best right now. We know a lot about a very little bit, and with modern technology, it is starting to become faster and faster, the way that we actually identify these. But again, it's not always inherited, and it can be just because this allele or this gene starts to go aberrant later on in life that it starts to produce a mast cell tumor. Another highly prevalent tumor that we find is histiocytic sarcoma in Bernese Mountain dogs. Again, this one is a typically highly aggressive, very refractory type of cancer. It's very, very hard to treat. This is almost akin to hemangiosarcoma in the ways that it is difficult to treat. It's not responsive to traditional chemotherapies. It's not as responsive to radiation. Histiocytes are basically cells of the immune system too, so their cells within the part of the body are supposed to check everything or it's dividing inappropriately. And in these two breeds, it just happens that there is something within them that we don't know yet that is linked to histiocytic sarcoma. There's no really large testing for this type of cancer, which makes it hard to breed for or against. That's the very difficult part about cancers is, again, the amount we inherit from our ancestors does not always correlate to if and when a cancer will develop, because the environment plays a large impact and a very large source of types of cancer, whether it be certain pesticides or other things that have . . . you know, lymphoma has been linked to roundup types of weed deterrents, and not all the products that we use or genetically modified products are bad. There are some that we think are good and that we use, but we don't know its implications until later on. That's very hard with this, because, again, they don't have a particular disease collection of genes that we can test for, or single genes that will say, “Yes, this will lead to cancer.” But we do know that there is a breed predilection towards cancer in these two.

Transitional cell carcinoma, or urothelial carcinoma, is a cancer of the bladder. This has soft links to roundup as well. The disease genes may be inherent in breeds like Terriers, Scottish terriers, and also Shelties. However, we know that there are environmental exposures that will then start to have this happen. I have Shelties. I've had two that had this, and it's not the easiest to treat, but it's slightly better than some of the others. But again, cancer is very hard to treat because you are using techniques that can affect your normal cells. That's the problem. So chemotherapy is not selective. Anybody that's dividing when chemotherapy is given is hit, which is why we tend to see issues with the gastrointestinal tract or skin sensitivity, or other types of sensitivities that start to occur when we're doing treatments, because you're fighting cells that are extremely similar to the body and so normal cells are hit. Everyone that's dividing is hit. Chemotherapy is like cytotoxic chemotherapy, what everyone thinks of as chemotherapy, is like a nuclear bomb that just goes off. It kills everybody that's dividing. And the hope is that your body can compensate faster than the cancer cells can, so that you kill the cancer cells off, but the body can then replenish what it needs to before the next bomb goes off. And this one can be bad, because we can control it however, where it likes to occur—and cancer can do whatever it wants—but it tends to occur in the part of the bladder where the kidney ureters enter, and so then it can even that a small amount be obstructive towards making urine. And we know that there are, again, environmental exposures, but we know that there's a genetic linkage, or there's an inherited linkage among these breeds. We just don't know exactly what or why yet, because, again, it probably a lot of these lie in that multigenic or that area of inheritance where it's multiple genes, and it's not just one, it could be five, it could be 10, it could be two. We don't know. Shelties thus far, are the breed that have one of the only multigenic tests, meaning that it tests for a disease called dermatomyositis, which is a dermatologic disease where the portions of the face are very thin. Skin areas will start to have ulcers produced because the capillaries or the little vessels can't respond when they're crushed, or they're at the very tip of something because it's so delicate. And there are three genes that we know affect this. One of them is part of the immune system, and then two of them are actually just found. They're part of the somatic cell line. So the risks and the stratification based on this is based on three different genes, which is not easy to actually counsel, because it's very hard, because then you're talking about, like, triplicate probabilities, where you have these three genes, and what's the pattern that leads to disease? You have to go through all of the different, you know, patterns together, and so you know which ones are more likely to produce that disease, and then which ones are less likely? Like, what pattern do they inherit that makes it the least likely for them to develop this type of disorder? And to my knowledge, that's pretty much the only one that we have really right now. And like, it's complex, but the more that we start to study these, the more that we start to do full genome sequencing or looking at all of these areas, then we can understand or prevent. The problem right now is most of the tests that we can offer are only when there is cancer present, not to prevent it, but to establish a diagnosis as early as possible. There are very few actual disease genes that we can test for. 

In Golden Retrievers for lymphoma, there is a test, and it's for CDKN2A; that is a gene that we know is predictive of lymphoma. However, most of the lymphoma diagnostics or gene tests that we have are, again, after a diagnosis of lymphoma, and it's more along the lines of a prognosis, like, will this lymphoma respond to chemotherapy, or will it not? Is this lymphoma aggressive, or is it a chronic, indolent, non-aggressive form that we have to monitor and not treat? Is this lymphoma resistant to certain types of chemotherapy? So a lot of the gene tests are done on the cancer tissues after development of disease unfortunately. Because there are genetic and epigenetic mechanisms. Epigenetics is the environmental impact on genes. So basically, the most simplest way to think of it is like a lock and key mechanism. As animals or even ancestors go through life, the epigenetic types of inheritance are cells that then turn on and off certain genes. The body is told to turn this gene off or turn this on, and basically they either put a lock on it or they open it up, and the environment plays a large role on which ones are locked away and which ones are opened up. And these genes may open up when there is an environmental impact. And then this is not necessarily the only environmental impact. This is just a piece of the large puzzle. So the environmental impact also will either lock away or open up certain genes, aside from there are mutagens. We know that because of radiation; we stay away from radiation, unless we have cancer, to treat it, because radiation can cause trauma to the DNA, and the body has to then fix that. The more trauma that's caused to DNA, the more the body has to fix the higher the likelihood of something going wrong in the fixing process. And that's again, why cancer may happen, and it's why the environment, again, unfortunately, plays a very large role in a lot of these types of cancers that we want an understanding of. Well, why does this breed commonly get this? It's not always due to an underlying genetic mechanism. It could just be, again, the geographical area of where you live, and that's the problem. And that's why it's hard to figure out very simple tests that we have for, like, PRA and other types of diseases where we know that there's a simple Mendelian inheritance, meaning there's a good copy a bad copy, and if you have two bad copies, you show disease, and if you have two good copies, you don't; if you are a hybrid, you're not likely to show disease. That's simple Mendelian ones. We have the most of those, because those are easy to find, but that's really only a scratch on the surface. There's a lot more that we don't know, because, again, they're polygenic (multiple genes) environment. Also in dogs, there are other diseases or other inheritance patterns that predict whether or not the dog can even tolerate chemotherapy. So MDR1 mutation is not just for anesthetics. I think a lot of people will kind of get this wrong, and it's okay to breed an MDR1 mutant. Just stay away from Butorphenol or stay away from certain anesthetics. It doesn't just stay there, actually. If a dog score is MDR1 mutant positive or it shows it has no good copy (it's not a hybrid), then it can't handle doxorubicin therapy, which is probably the most utilized chemotherapeutic that we have. MDR1Q codes for a protein that lines the central nervous system. They are pumps, and they pump out drugs from the central nervous system, and they help metabolize it. When you give doxorubicin to an MDR1 mutant, the problem is that it has no means of pumping it or suppressing it from actually entering into the brain and spinal cord, so they can't process this chemotherapy. So when we're breeding dogs, this is something you also have to take note of, because if that dog does get cancer and the owners want to treat, but we didn't do our due diligence, and maybe like looking for MDR1, it may come back to us that we should have looked at that, because we can't proceed with treatment, because that is something that the dog cannot handle. And so these are known cancer genes of tumors. These are not known cancer genes, but P53 is a tumor suppressor gene that is widely associated with cancer. KIT and others, like I mentioned PTN, and I'm sure you've probably seen commercials for like EGFR, HER2 negative, HER2 positive—those are associated with the carcinomas, and they're genes that will go off or on actually in many different types of cancer. So HDR1, EGFR and HER2 are two genes that actually occur in breast cancer, but it also occurs in urothelial carcinoma or bladder cancer, and there are no great studies for bladder cancer that shows that using inhibitors for these two genes actually shows a good effect. The only thing that we know right now is that, in conjunction with chemotherapy, giving an inhibitor type drug may enhance the ability of chemotherapy to actually destroy that tumor and lead to some remission rates, which is the same in KIT. In breast cancer, though HER2 positive, HR1 negative—those are highly associated with prognosis. So you don't want what we call a triple negative type of breast cancer in women, because triple negative has no means of having an inhibiting molecule work in a drug that will then affect that tumor. It basically can evade 30% of what is available because it doesn't have that mutation. And we know that putting women or some dogs on inhibitors for those, it works really well. 

Which is the case in mast cell tumors. Typically, I have a surgeon remove them, then we do a biopsy that goes through a regular biopsy, confirms that it's a mast cell tumor. They grade it, and then I have it tested for genetic markers. There are genetic markers in the mast cell that show prognosis, not necessarily like how it was inherited, but how it will handle, or how it may proceed later on. KIT is one of them, because, again, this is something that I can add in a medication or a drug that will suppress that tumor, and it works in tandem with some chemotherapeutic agents. We talked about this as just types of inheritance. We talked about autosomal dominant, meaning that if there's one bad gene and one good gene, the animal will still show disease. Recessive: you have to have two deleterious copies, and then most traits actually and most cancers fall into the category of polygenic, or complex inheritance. It's very hard to identify this, because it's complex and it's polygenic. We don't know how many disease genes you need, how many are inherited, or even what they are right now, because when you try to look at a tumor and identify maybe a gene that goes wrong before it becomes a tumor, it's hard. The tumor is not making normal DNA. It's making abnormal DNA, like constantly. So some of the genes that may be inherited may be destroyed by the continuous replication, because it's just dividing and dividing without checking what it's actually writing in the blueprint. It's writing whatever it wants. So even the other genes that may not be affected are being affected because it's just dividing and it doesn't care about what it's coding for. It just wants to divide. Something that revolutionized some of the tumors is PDL1, which is starting to become available in dogs, but that looks at a cell cycle regulation point where it's the program cell death ligand, so it's programmed to identify when the cell should die and not move on, or if the cell should move on. So we continue to find more and more markers and means of helping treat cancer. But again, the hereditary part is very hard. 

We have the polygenic testing from Embark and Wisdom panel, which have some tests like I talked about with the Golden Retriever or screening them. But unfortunately, right now, we lie in the area where IDEXX has a test called the new Q test. There's also a liquid biopsy. These tests identify if there's cancer present at low numbers. But again, it's not saying that it is there. It was there before because of a certain gene. It's just saying that this dog potentially has cancer based on these biopsies tests, because it can find like products of the gene in the blood that shouldn't be there. So the test finds those. 

We are expanding vastly at identifying cancer before it's untreatable. A lot of the research pops out with these new techniques to find them at very, very low numbers. And then it's maybe beneficial if you have an older Golden to run one of the liquid biopsies or the nuke test based on age, environment, impact, familial inheritance. So it may be wise to screen them continuously for these types of cancer. In bladder cancer, we can screen certain dogs to see if they have it at low numbers; where it's more easily treatable is a urine test that looks for something called Cadet and the BRAF mutation. So those occur when the cancer has happened. But we have techniques where we can identify very, very low numbers of these cancer cells, maybe often, or maybe before they actually develop into a large mass or tumor. But again, these are expensive, and you have to constantly screen. When I talked about targeted therapies, we were talking about Toceranib for mast cell tumors. So this is Palladia, and the breed sensitivity may affect your chemotherapy responsiveness. So if it's a breed that is highly associated with this MDR1, it can't get a certain type of chemotherapy. And immunotherapies, which use the immune system to our advantage, are currently being explored. So sometimes in pediatrics, they can actually remove some of the immune system, take that, plate it in a dish, and then genetically modify it to actually understand where the cancer cells are supposed to be, by giving them the gene that they need and then putting them back in the body and allowing them to basically go and screen the body for this cancer that we know is there and it's going to find it, because we have basically taken the goggles off. We've taken off the mask. We are showing the immune system: “There's cancer here; this is what it looks like.” And then we let it go and do what it's supposed to do. The only thing we can do right now is avoid breeding known carriers, and really taking a look at our kennels and saying, “Do we have a lot of variants or not?” If we don't have a lot of variants, then that cancer type may be allowed to grow because the environment is causing an impact and your dog, we don't know, but there's a gene that the environment puts a heavy stress on, and by secondary effect, causes cancer. So we have to look and see geographically what's going on, and look and talk to our other kennels and see if they see it too. And then if we do have a screening for it, we can test for that. But it's unfortunately, very low that we can test for, and most of it is astute scrutinization of your lines and within your breed. 

So in summary, that inherited cancer is a breed-associated risk. We don't have a large number of tests right now, but it's growing. We have a large utility of tests that's growing faster in early detection. But the ones that we do know are predisposed or have an inherited type of cancer, we are starting to unmask certain types of genes that we can see that causes a risk factor, but there are not many that are highly predictive of “this will happen,” like it's not very black and white. And so we have to work together: veterinarians, breeders, and actually human doctors, because in medicine dogs are not so different from humans. Human pediatric oncology is very similar to dog types of oncology. They share the same environments with us. They share everything with us, and we can use therapies on them that would benefit us. The melanoma vaccine is actually something that is flipped from human to dog and dog to human. So dog cells make the human variation and human cells make the dog variation of the melanoma vaccine, which makes antibodies that stick to the melanoma types of cancers, and then the body goes and sees that flag and it takes it away. So One Health benefits us both, and One Health, one breeding veterinarian, and one MD is a very powerful tool. We know that, and everyone can test for this. Unfortunately, in my traditional veterinary medical school, this is not something that you're taught. This is something that I've always liked, and I fell into by accident, mainly because I started breeding Shelties, and I started getting into that kind of world. But it's hard. You need everybody together to figure out these techniques, these tools that we have, and when you run them on clear litters, we as veterinarians should be able to interpret them for you. But not everyone is taught the same. And that's kind of why I exist, is because I help. And you know, the larger testing sites have genetic counselors that will help you read this type of tool, because not every veterinarian knows and not every breeder knows. So there's now a focal outlet where people can look for help with these types of tests that we're performing. And again, the only way we get through the disease is if everyone works together, even at the general practice level. I do general practice in Brooklyn. I kind of do my specialty from my own personal clinic, but you still see everybody, and that's what I have for now. I think I'll take any questions, if that's available, and then I can answer them. If you have questions you don't want to ask, I'll give you my email, and you can also ask that as well.

Dr. Nate Ritter  53:15

Thank you, Dr. Stora, that was fantastic. I know you're under the weather, so we won't keep you too long. And you also touched on a lot of these questions already. We had questions on screening tests, One Health, so glad those were mentioned during the presentation. We had an interesting question: are there any types of cancer we've seen particularly great advancements in recently?

Dr. Victor Stora DVM, DACT  53:35

Lymphoma. Yeah. So lymphoma is highly treatable. The remission rate for lymphoma, even though we use an old protocol, and there are more immunotherapy types of drugs coming out, being studied for lymphoma, because that's the most common cancer that dogs get, and we just don't know their impact yet, but screening lymphomas has become highly advanced. The liquid biopsy can detect lymphoma lymphocytes that are aberrant at very, very low levels. It's very sensitive, and so is the new test, which is also helpful for determining course of action and continued chemotherapy, because if you finish the full protocol, and you screen every three months with the new test, you should be able to identify if they're relapsing earlier and maybe institute treatment faster. Again, it's not what everyone wants to hear. There are more rapid advancements in diagnosing when it's there at low numbers than there is like preventing it. 

Dr. Nate Ritter  54:29

Sure, thank you. I know you touched on epigenetics, environmental impact. We had a couple questions there. Someone asked: Does the consumption of colostrum have any impact on cancer?

Dr. Victor Stora DVM, DACT  54:37

Not that I know of, no. Regular disease? Yes. That really goes away rapidly in the young animal, because colostrum are antibodies from the maternal side. So after a while, the body says, “Okay, this is not me anymore,” and so it gets rid of them. It doesn't make them anymore. So it's only useful for that initial period, mostly for viral and bacterial types of disease. 

Dr. Nate Ritter  55:01

Thank you. In the same vein, are there any food supplements or other things you'd recommend people avoid? And then, conversely, is there anything you'd recommend in particular that people might be able to offer? 

Dr. Victor Stora DVM, DACT  55:13

So I think that a lot of people—for being by private practice—you know, food is love, and we heavily scrutinized the food, which I would say probably has a slightly low impact on cancer and actually has a high impact on how dogs remain healthy for a long time. There are lots of advances in canine nutrition, which make them basically live so long that they do get cancer, but even antioxidants, like fish oils and stuff like that, that may not prevent fully the development of cancer, but it may help preserve the cell lines that are existing already. It may not fully disrupt it, but it may help the body as body ages divide more appropriately.

Dr. Nate Ritter  55:55

Fantastic. And I think we'll finish on this one, as I think it's a nice, kind of general overview question: Say one of my breeding dogs is diagnosed with cancer. You know, obviously outside of the direction they take with that individual dog, but what steps should I take as it pertains to my program, and then also any pups or litters placed that were related to that dog? 

Dr. Victor Stora DVM, DACT  56:16

I don't think that you have to go immediately and, like, raise the red flag. Because, again, it could be that breeding prospect had just the chance of it getting cancer, and it did. If it's something that we know is linked, or we see the pattern, we know it's there, like we know there's no tests for, really, histiocytic sarcoma before happens, but we know it's there, so if it's one like that, that we know is inherited or has a high correlation with being a certain line, then I would probably tell my previous puppy buyers or something like that, just to be on the lookout. But it doesn't always mean disease will happen. That's the hard part. Cancer is very much a gamble. Internal Medicine and other medical types of diseases are much easier to prevent than cancer. That one, again, has its own subfield, like oncology is a division of internal medicine, and it's the more difficult one because it's a disease of genes, but, but again, they're not normal genes. So we're trying to, like, look at all this pool of genes and say, “Where's the abnormal one?” And again, when they're starting to divide unchecked, it can start to make weird mutations that aren't always preserved or showing cancer. So it's really, really hard. I wish I had a better answer, but we're learning more about the predictive side, like prognosis or early detection, or with lymphoma, there is a test where you can send off the sample, and they'll tell you if chemotherapy will work and to what degree. So there are advances in certain areas, and then there are some that we're still stuck in. That's the predictive one. And I think we're stuck in the predictive one is because the environment plays the largest impact on whether or not we're going to get cancer, because it can happen to anybody. You know, I lost my mom a couple of years ago to lung cancer. She didn't smoke. I mean, that's an impact factor, but it does what it wants. The body sometimes can't compensate, and that's what happens.

Dr. Nate Ritter  58:15

Yeah, I'm so sorry to hear that. I think that’s a fantastic answer, and I think a great way to end. Nicole, I will turn it over to you. 

Nicole Engelman  58:22

Thank you. Thank you so much. Dr. Stora, this was an amazing presentation, and judging by the comments, I think our community definitely agrees, and it sounds like they are so appreciative of your time—as are we. I want to thank everyone again for joining us. If you're not yet a member of our community, you can always apply to join at GoodDog.com/join so you can stay up to date on all of our future webinars and events, because there are a lot to keep up with. So with that, I want to just leave everyone with a sneak peek of our next webinar, which is infertility in breeding females with Dr. Andrea Hesser, who, if you've been joining our past webinars this year, she's been spending a lot of time with us already. We're excited to welcome her back as our primary presenter for our next webinar. So that's going to be on Wednesday, June 18, at 1pm Eastern. So coming up pretty soon, we are going to get that announced, get that RSVP link up for everyone, so you can make sure to join that. But until then, thank you again, Dr. Stora, for being here. Thank you to our community for joining and we will see you at our next webinar soon. Thanks everyone. Bye. Thank you for listening to the Good Dog Pod. We'll be back in two weeks with another episode, so be sure to subscribe to the Good Dog Pod on your favorite podcast platform.