Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today on the podcast, we'll be talking all things pancreatic cancer. Our guest for this episode is Dr. Despina Siolas. Dr. Siolas is a medical oncologist who specializes in the treatment of gastrointestinal or GI cancers, including cancers of the colon, stomach, liver, pancreas, gallbladder and esophagus.

She also conducts research on cancer genetics focusing on those genes that influence the immune microenvironment around tumors, and she has a special interest in pancreatic cancer and immunotherapy. So, I'm looking forward to a great discussion on the latest in pancreatic cancer care, research and treatment. Dr. Siolas, thanks for joining. It's great to be here with you today.

Dr. Despina Siolas: Thank you, Dr. Leonard. I'm so honored be able to have this one-on-one conversation with you.

Host: It's great to have you and this is a really important area. And I know we have a number of people in our audience who are really interested in this sometimes challenging type of GI cancer that we're going to talk about But first, it'd be great to hear a little bit about your background and, specifically, what drew you to working in oncology in general and GI cancers in particular.

Dr. Despina Siolas: I am from New York, born and raised. And I come from a family where there's no other doctors. However, there is a love and respect for education and science. So at a young age, I was really exposed to scientific topics. And I went to an honors program called the Da Vinci Math and Science Program at Cardozo High School in Queens. During this program, I was able to take classes on research and science

 but unfortunately, during my junior year of high school, my mother was diagnosed with colon cancer. This was the first person in our family to have a major illness and it really affected me, my uncles, grandparents, everyone around us. And luckily, she had a stage II rectal cancer that was cured, but it really gave me purpose in wanting to help others who were affected by cancer and also to try to understand from a scientific point of view how cancer develops, how we can stop it.

So from there, I decided that I would go to medical school, but I really loved research, so I ended up pursuing a physician scientist path. And that is what has led me here today, living out this dream which is to be able to do scientific research on cancer, while simultaneously treating patients in the clinic

Host: So, let's move a little bit to pancreatic cancer specifically. I think your story is really an interesting one and one that's important. how did you focus specifically on pancreatic cancer as a particular area of interest?

Dr. Despina Siolas: Well, I knew from my mom's diagnosis that I was interested in gastrointestinal cancers. I trained at a large major institution in New York City that was developing a program in pancreatic cancer. And I went to my thesis advisor and I said, "I'm really interested in cancer. What should I do?" And he's like, "Well, what about pancreatic cancer?" And so, it was really a combination of the allure of being able to study and tackle a hard and challenging problem combined with already being at an institution that had a lot of research available. So, I kind of combined opportunity with interest, and that's how I ended up going into pancreatic cancer.

Host: I think the audience knows that pancreatic cancer, tends to be one of the more difficult ones to manage, depending on the overall situation. But maybe we can get a little bit into the background How does pancreatic cancer form? What's known about how it originates and also, how it is detected and diagnosed in patients ultimately?

Dr. Despina Siolas: That's a very good question. So, we talk about pancreatic cancer, we commonly refer to adenocarcinoma, which is the type of cancer that makes up about 85 to 90% of pancreatic cancer. There is other more rarer types of pancreatic cancer, such as neuroendocrine tumors, which is a topic in and of itself. Adenocarcinoma commonly develops because of genetic or DNA defects in pancreatic cells. The cell of origin for this type of cancer is still under examination, But through a combination of genetics, environments, these tumors occur.

Taking one step back though, I do want to mention, because a lot of people don't really understand what the pancreas is or what it does, the pancreas is a digestive organ that functions to help create enzymes that break down food and then also make hormones that control blood sugar levels like insulin. So knowing kind of what it does puts things in perspective in terms of when patients present with certain symptoms. For example, when a patient has pancreatic cancer, they tend to present with symptoms that are related to abdominal pain or weight loss. Jaundice is another example. jaundice means yellowing of the skin, and this is often due to obstruction or blockage of the common bile duct, usually by a pancreatic mass.

Host: from the standpoint of patients being diagnosed, what are the common kind of presenting symptoms or how is it detected and are there ways to try to diagnose it earlier that are at least under exploration?

Dr. Despina Siolas: because the signs and symptoms are often non-specific, it's quite hard sometimes to diagnose. And so, very often patients present at a later stage. Because it's kind of hard detect. However, because we have such great imaging techniques, we're actually finding pancreatic cancer a lot earlier as well. And so, 10% of patients present with an incidental finding seen on a scan. So from there, certain tests are done to kind of tease out what is this pancreatic mass and is it actually a cancer or perhaps a premalignant or benign lesion.

Host: One question people ask relates to risk factors. What are the risk factors for pancreatic cancer that we know of and do many people have them?

Dr. Despina Siolas: Yes. So, the incidence of pancreatic cancer is starting to increase and it's thought that pancreatic cancer is actually going to be the number two cause of death by 2030. And some of the risk factors that are associated are cigarette smoking, obesity or pancreatitis, which is inflammation of the pancreas.

There is actually, a really interesting relationship with diabetes that we currently don't really understand that well. So, it's not really clear if diabetes is a consequence of pancreatic cancer or a cause. We know that anywhere from 25 to 50% of patients who get pancreatic cancer have a diabetes diagnosis within 2 to 3 years of their pancreatic cancer diagnosis, but not all diabetes patients get pancreatic cancer. So, there's an interesting relationship that is trying to be teased out through further research.

Host: From the standpoint of other genetic testing that patients might have either before they're diagnosed to look at things if they have a family history or ,after they're diagnosed as far as things that their family should do, tell us a little bit about the risk factors from the genetic perspective and what are the common strategies or concepts that people should know about there.

Dr. Despina Siolas: this is a really interesting subfield of pancreatic cancer that has evolved within the last five years or so. We know that approximately 10% of pancreatic cancer patients may have a gene that is inherited that can cause pancreatic cancer. And so, there's been a lot of push within the field to kind of identify who are these 10% of patients and what is the implication for their loved ones.

what has occurred is now there's national guidelines in place that state that, if a person has stage IV pancreatic cancer, they should undergo genetic testing to find out if they have a gene that they are carrying that will increase their risk of pancreatic cancer. And this is particularly important for all their first-degree relatives, such as their siblings or their children who would get into some sort of screening protocol with the hope of, if they do have the inherited gene, then they could be screened for tumor development.

Host: So, let's move now to a little bit about treatment for pancreatic cancer when patients are diagnosed. I know that surgery is the mainstay of treatment. Radiation oncology and medical therapies are also very important. Can you give us a little bit of an overview of how patients are commonly approached depending on the stage and the nature of the disease?

Dr. Despina Siolas: Unfortunately, pancreatic cancer is usually detected at a later stage where surgery is not possible. Well, why isn't surgery possible? It's not possible because the location of the pancreas is next to certain key blood vessels, which the tumor make envelope and kind of wrap itself around. And so, it can be really hard to get a complete surgical resection, meaning elimination of all the tumor.

And so because of this, only 10% of patients are really outright able to go to surgery. However, there has been a lot of interest in using chemotherapy or radiation upfront to allow patients to then go into surgery with the idea that you're going to downstage or shrink the tumor. And so, the patient would be able to then have a cleaner, more complete surgery later on. four groups. And this has all really been development over the last 10 to 15 years. there's the truly resectable, which are the patients who can go straight to surgery. There's the second group, which is called borderline resectable, and that group comprises patients who maybe can go for surgery, and it's based on a combination of how the tumor looks on imaging scans and discussions between the surgeon and radiology and medical oncology. So, it's really kind of an expert consensus amongst these groups. And then, the third group is locally advanced. So, those are patients who, the tumor is not only wrapped around certain key blood vessels, but also may have lymph nodes involved. And so, they really need more upfront usually chemotherapy to shrink that tumor. Plus or minus radiation And then, the fourth group is the metastatic setting where surgery isn't really possible, because the tumor is in multiple places. So, this group tends to get treated with chemotherapy or intravenous forms of systemic therapy.

Host: Can you give us a little bit more of a sense of the different types of therapies that patients commonly receive when they have more advanced disease in particular?

Dr. Despina Siolas: immunotherapy is a type of IV therapy. We'll start with that because it's also my area of expertise, is a type of therapy that it basically turns on the immune cells of a person's body to recognize and fight their own cancer. And there's been a lot of intense study into using immunotherapy because a lot of patients, mostly in other diseases, can have durable responses. They can live for many, many, many years without cancer. But the current available immunotherapies, which are mostly based on T cells, aren't effective for pancreatic cancer, with the exception of the 1% of pancreatic cancer patients, who are MSI high. MSI high is a term that means microsatellite instability, And so, these patients are particularly sensitive to the current FDA approved immunotherapies.

So, one of the things we do when a patient is diagnosed with stage IV pancreatic cancer is to, number one, test them to see if they are comprised as 1% that are MSI high. If they are, then they can get immunotherapy. If, unfortunately, they are not, like the vast majority, then we go more into chemotherapy. And chemotherapy has changed in that it's not just one single drug that is administered, but rather it's a combination of drugs that are given with the purpose to control the disease or shrink the tumors.

Host: How have the treatment

options changed over the last few years? It seems like there are a lot of new things

that either become standard of care or,

are in research at this point.

Dr. Despina Siolas: one of the most interesting developments that occurred is this idea of breaking down pancreatic cancer, not into just one disease, but rather into really personalized care, which is something that we offer here at Cornell. So for example, as I mentioned, a subset of patients with pancreatic cancer have an inherited gene that causes them to have an increased risk of developing pancreatic cancer.

So, one of the more famous genes is this gene called BRCA. And it's mostly famous because of its association with breast cancer but also because it's associated with an elevated risk of pancreatic cancer. So, it's thought that approximately 7% of patients have this gene and building on this concept, so extrapolating from other cancers, what we know is that BRCA or BRCA is a protein that's involved with DNA repair.

So, there are drugs that have come out for example, PARP inhibitors, that's another protein that's involved in DNA repair. And patients who have tumors with BRCA mutations are thought to be more susceptible to this type of therapy. And about five years ago or so, a large international phase III trial came out looking at this question. Can we isolate this subset of patients with pancreatic cancer and can we offer them PARP inhibitors? And the reason that this is particularly important is because it's an oral pill. This idea that you could take an oral pill and still go on and live your life is a really amazing thing for this type of disease.

And so, the trial was a big effort, and it looked at and stabilized patients with chemotherapy first, so patients got several months of chemo. Then, they transitioned to PARP inhibitors. And it became FDA approved PARP inhibitors in stage IV setting.

if you're going to give a patient a PARP inhibitor, you need to know who , which means they need to undergo genetic screening. So, there were two big developments that came out of this trial. One, a new type of therapy and the second, being able to offer genetic counseling to now all patients because you need to find all patients with stage IV pancreatic cancer, because you need to be able to find the ones who can qualify for the specialized therapy. So, that was a pretty cool advancement.

Host: What are you most excited about for the future?

Dr. Despina Siolas: where to begin? We have such good community, in that there's patient advocates, there's physician groups, there's a lot of resources devoted to tackling this problem, which we think will only increase over time.

there's certain things that I think are really exciting. The first is the research going into this because patients are mobilized to be a part of clinical trials. that really helps fuel our research, having patients that are able to donate or give their tissue, their time, their blood, so we can understand better some of the biology behind pancreatic cancer and then tailor new treatments and new clinical trials for the future. And at Cornell, we're really lucky in that we have clinical trials that not only look at things like, "Is this therapy going to work?" But rather, we also have trials that look at other symptoms related to pancreatic cancer, such as cachexia, which is a fancy medical term for weight loss, or sleep, Cachexia, weight loss, sleep, these are things that are important to patients, but are often overlooked because they're not pharmaceutical drugs, but we kind of need a better understanding of how their sleep patterns are affected, how their weight loss and so forth. So, being able to offer these exciting clinical trials to patients is really a privilege.

And then, the other thing, because you asked about treatment options, is that there's kind of one word that's really on everybody's mind, which is this KRAS. So, KRAS is one of the major genes that drives pancreatic cancer, meaning that 93% of patients have a mutation in this particular gene. And we've known about it for many, many, years. But it was largely thought to be undruggable, because of the confirmation of the protein, the location inside the cell and so forth.

But now, there has been new technology developing really targeting KRAS. And there's two types of therapies that are currently in clinical trials. One is this idea of targeted therapy or small molecule inhibitor, and that has already been a reality for patients who have a KRAS mutation called G12C.

So, there's an FDA approved therapy for KRAS mutant G12C. Unfortunately, G12C, this particular KRAS mutation, only occurs in, again, 1% of pancreatic cancer. So for the majority of patients, the current KRAS inhibitor isn't going to really fly. However, we do test our stage IV patients for it, because if we do find a patient who has this particular mutation, we want to be able to offer them this personalized therapy. because of the success of this one particular type of KRAS G12C drug, now a lot of groups are looking at different types of drugs that target the other mutations in KRAS. So, that's one type of targeted KRAS therapy.

there's another type of KRAS therapy that is currently in clinical trials and has garnered a lot of buzz. And that is called KRAS vaccine. We know the patient's tumors are going to have this KRAS mutation. What if we could make a vaccine that would help the body then recognize mutation protein as being foreign? And again, still in clinical trials, but everybody is really anxious and excited about this idea that you're having two different types of therapies that are, again, targeting a common protein or mutation in pancreatic cancer that could have lasting effects and also could benefit the majority of patients.

Host: Before we wrap up,

give me

Dr. John Leonard (Host): a

Host: little bit on your research. I know this has been a

key focus

Dr. John Leonard (Host): of

Host: your work, and I know you've,

made a lot of progress in this area. So, tell us a little bit about what you've been working on.

Dr. Despina Siolas: My excitement is now through the roof, because I love talking about what we're working on and we have such a great team here at Cornell, both on the clinical trial side and also in the laboratory. So, my laboratory has been at Cornell for two years now, and we're really interested in understanding how we can make pancreatic tumors more susceptible for immunotherapy. And we're doing this through various approaches.

One of them is to personalize the type of immunotherapy a patient gets. And to do that, we need a strong and confident understanding of a patient's tumor. So for example, one of the things I mentioned is that 93% of pancreatic cancer patients have this KRAS gene mutation. But as I also kind of alluded to, not everybody has the same mutation, but rather 40% have a mutation called G12D. Another subset have a mutation called G12V and another subset have a mutation called G12R.

Well, this sounds like a bunch of letters, but what does it really mean? It means that in the actual KRAS protein, even though it's the same position, having this small alteration can change the dynamics of the tumor And we know from clinical trials that the type of mutation in KRAS a person has affects their prognosis. So, patients who have, for example, a G12R KRAS mutation live longer than other patients who may have a G12D mutation. biologically speaking, we want to know why.

And so, our hypothesis, is that the immune system is probably involved in helping G12D tumors, for example, to evade the immune system. And so, we want to know what are the immunologic differences between G12D tumors, KRAS G12V tumors, G12R tumors. And then if they have different immune cells in these tumors based on the KRAS mutation, well then we want to be able to design immunotherapy combinations that we can use to personalize medicine for these patients.

But really, to understand or guide personalized therapy for different pancreatic cancer patients, we need aggressive experiments in the lab. So, we use preclinical modeling, which is using mouse models of cancer. And we also need tumor samples from patients who donate their tissue and then we can grow and cultivate them in the lab and try to understand these things and blood samples as well. So, we're using both preclinical modeling and correlative studies from clinical trials guide our understanding of pancreatic cancer and guide our ability to offer personalized treatments.

Host: That was

a great

summary and I want to thank you for all of your work

in trying to,

improve outcomes

for patient with, pancreatic cancer. And obviously, I think

Dr. John Leonard (Host): the

Host: goal of all of

us is personalized therapy so that we can figure out who can get away with less therapy and who needs therapy A versus therapy B versus therapy C based on their individual types.

 It's been really great to have you here with us today and hear a bit about what you've been on and your approach to this important area. I think this is also a really important reflection of how it's key for patients with many tumors to be treated at a multidisciplinary center like Weill Cornell and New York Presbyterian Hospital, where you can have access to all of the different clinical specialists, at supportive specialists, and research activities going on to really take advantage of

different expertise

as we try to deal with these complicated situations.

Dr. Despina Siolas: Absolutely, Dr. Leonard. I wanted to echo that sentiment, which is that if you know a loved one or friends or family who have this disease, it's really important to go to a specialty center where they can get expertise both from surgeons, medical oncologists, clinical trials, research, because the advancements that have been made are really changing the way treatments are going for patients with pancreatic cancer.

 I think it's really important to be able to speak about treatments, genetics and symptoms with patients and their loved ones. So, thank you for, for having me, and thank you for bringing awareness of this

Host: Thank you very much. I'd like to also

 invite our audience to download, subscribe, rate and review CancerCast on Apple Podcasts, Google Podcasts, Spotify or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see us cover more in depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care and research. I'm Dr. John Leonard. Thanks for tuning in. All right. Thank

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