Subscribe
Share
Share
Embed
The PancChat Podcast is a collaborative effort from Let’s Win Pancreatic Cancer and the Pancreatic Cancer Action Network (PanCAN), inspired by the long-running #PancChat Twitter/X chat.
Hosted by award-winning journalist Alisyn Camerota, each episode features conversations with leading researchers, clinicians, patients, and advocates who are shaping the future of pancreatic cancer care and research. Together, we deliver expert insights, personal journeys, and the latest breakthroughs—bridging the gap between science and lived experience.
Whether you’re a patient, caregiver, healthcare professional, or simply want to learn more, join us to connect, be inspired, and learn how you can help to accelerate progress in the fight against pancreatic cancer.
Julie Fleshman: Hi. I'm Julie Fleshman, President and CEO of PanCAN. On today's podcast, we take a closer look at hereditary risks and genetic mutations associated with pancreatic cancer.
Alisyn Camerota: Hi, everyone. I'm your host, Alisyn Camerota. Today's episode focuses on genetic mutations, including hereditary risk and some of the types of mutations that patients with pancreatic cancer may discover they have.
We want to thank our sponsor, Revolution Medicines.
Today's guest is Dr. Asaf Maoz. He is a GI oncologist in the division of genetics and prevention and the gastrointestinal cancer center at Dana-Farber Cancer Institute and an instructor of medicine at Harvard Medical School. Dr. Maoz, thanks for being here.
Dr. Asaf Maoz: Thank you so much for having me. I think this is a great initiative and great series of podcasts. I listened to several of them in preparation for this, and they were excellent. So thanks for doing this. I think it's really important to raise awareness and bring some of this data and information out to the general public.
Alisyn Camerota: Well, thank you. I really appreciate that. That means a lot coming from you. I learn something every single podcast. I hope our listeners do too. I mean, we're really going right to the forefront of what's happening with all of the progress in this horrible disease. So today what we want to do is explore genetic risk and mutations in pancreatic cancer. So let's start by understanding a little bit about medical genetic testing and why it's important for pancreatic cancer patients in particular and for their families. So first, can we just start with the difference between genetic testing, the kind of which so many people are now doing online, meaning ancestry.com and 23andMe versus medical genetic testing?
Dr. Asaf Maoz: Yeah, that's a fantastic question. I think there are different types of genetic testing that we think about. And one of the main distinctions is whether we are doing direct-to-consumer genetic testing, which is often made to understand what the ancestry that we have is, and less so to understand what the health implications are. Direct-to-consumer testing has been around for a while, and the FDA at some point said, if you are going to do health-related testing, you really need to make it FDA-approved. And so there are some tests now that do include some aspects of medical genetic testing. But it really is important to understand that it is very, very different than true medical germline genetic testing.
So for medical testing, the labs that do it go through a very large and long accreditation process where they make sure they're able to detect what we need to know. And it's a very rigorous process. And just a few examples of the difference. There was a company that said it was doing testing for BRCA1 and two variants. And in the initial days, it was doing testing for three variants out of thousands that can occur in these genes. And so that's like checking if you have mistakes in your book, looking at just a few lines in the first page, but not looking at the rest of the book.
So I think it's really important that people who are doing those types of direct-to-consumer tests realize that they are not the same as the testing that we do as medical genetic tests. And I think the other aspect of it is sometimes those tests are not good. Again, not going into specific companies, but I have had patients come into my clinic with a result.
I remember a specific patient coming in with the result from a direct-to-consumer test saying you have Lynch syndrome, because they had a germline variant, or sometimes we call it a mutation, in a gene that causes Lynch syndrome. And when we tested it through a certified medical lab, which we call CLIA certified, that variant was not found in their DNA.
And so I don't know until this day why they received their results. Maybe it was someone else who had that sample. Maybe direct-to-consumer testing was just not good. But I would really caution people from kind of acting medically on those tests without seeing a provider.
Alisyn Camerota: Yeah, I mean, I assume your advice to patients is not to do one of the online tests or as you say direct-to-consumer. I mean, why would patients do that instead of just going through their doctor? Is it faster? Is it cheaper? What's the impetus?
Dr. Asaf Maoz: Yeah, I would not recommend it. No, I think that if there's a reason to undergo genetic testing and what we call germline genetic testing, meaning testing for inherited predisposition to cancer, I would go through a certified medical provider. It's true that it's hard to find genetic counselors in some parts of the country and that genetic counselor availability is an issue. Certainly, we need more genetic counselors, and we need to understand better how we can test people on scale. And there are studies ongoing that are trying to understand whether, instead of doing pre-testing genetic counseling, maybe we can do something like an informational video and then do the genetic testing. We have implemented that in our clinics. Or other forms of genetic testing that are facilitated by someone who is not a genetic counselor.
We definitely need to work more on the availability of genetic counseling, but I think that I would definitely recommend to do testing through a medical provider. Usually, a genetic counselor, but if not, there are other forms of testing.
Alisyn Camerota: Okay, so let's talk about why now? Why genetic testing is now the standard of care for pancreatic cancer patients, because that hasn't always been the case.
Dr. Asaf Maoz: Yeah, it's a great question. You know, genetic testing in general has evolved in the sense that in the beginning, it was hard to do genetic testing, it was expensive to do the genetic testing, and it took a long time to get those results. And flash forward thirty years, and it's now much more accessible, much less expensive, and much more important for patient care.
So when we did studies looking at how many patients with pancreatic cancer actually have a pathogenic germline variant, or I'll use the term mutation because that's easier to understand, how many patients have a mutation, we get a figure that is in the ten percent range. Meaning one out of ten people with pancreatic cancer has a predisposition to pancreatic cancer or to another cancer on their germline testing.
And in the past, when we've tried to see who we should test for germline mutations, we've often tried to make these complex criteria. If a patient is less than 50 when they're diagnosed, or if a patient has a family history, and we now know that those criteria don't work well to detect who has the germline variant. And we presented some data that is related to that at ASCO this year, again showing that most individuals who have a germline variant and develop pancreatic cancer, actually don't have a family history. And that the age criteria is also not great. We looked at it more in the sense of screening.
And so we saw that a lot of the individuals who do develop pancreatic cancer and have a germline variant actually don't develop the pancreatic cancer very early. So if we were to limit testing to only those who were diagnosed early or only those who had a family history, we would miss a lot of those people. And so because of that, we are now offering testing to anyone with pancreatic cancer.
The other aspect of it is the implications. So we now know that if we detect the germline variant, there may be treatment implications. I know you've discussed this in previous podcasts a bit, but just to reiterate, if there is a BRCA1, BRCA2, or PALB2 germline mutation, there are treatment implications. Similarly, if there's Lynch syndrome, then we really need to test the tumor for microsatellite instability for the Lynch syndrome molecular feature to see whether there are additional treatment options.
And of course, I think something that we all think about are the families, where if we detect a germline variant, we can now do screening and prevention for family members, not only for pancreatic cancer, but for several different cancers that are associated with the predisposition to pancreatic cancer.
Alisyn Camerota: Yeah. Am I right? This is a bit of an aside, but the BRCA gene, if you have that, it is a little bit easier to treat pancreatic cancer in those who carry that gene?
Dr. Asaf Maoz: It's a good question. There are some data that suggest that individuals who have BRCA1, BRCA2 or PALB2 mutations, that's true both whether they were born with it or whether the mutation formed only in the tumor. There is more of a response to a specific type of chemotherapy, platinum chemotherapies. And the overall results, the overall outcomes are a bit better. But we still have a lot more to do to improve outcomes for all individuals with pancreatic cancer, including those with BRCA1, BRCA, 2 or PALB2 mutations.
Alisyn Camerota: In my case, my husband was diagnosed with pancreatic cancer when he was 56 years old and we were, well I was fairly convinced that they were going to find a genetic mutation because his uncle had just died of pancreatic cancer. So I was like, well, there it is. That's obvious. And then they didn't find a genetic mutation. So when somebody goes through the testing and it doesn't reveal any inherited mutations, what conclusion can you draw?
Dr. Asaf Maoz: That's a great question. I'm sorry for your loss. We do see this clustering of familial pancreatic cancer in some families. And again, it's up to 10% of cases, but it's not the same cases that have mutations necessarily. And when we see that clustering, we certainly recommend testing any individual who had pancreatic cancer.
And if they weren't testing, we recommend it for their relatives. But often we don't find a reason. We are going to present data to update those data and show that really we don't find a mutation in most cases, even in current times with updated testing techniques. Essentially, we don't know why there is an increased risk, but we think there is still an increased risk.
As Dr. Goggins mentioned on a previous podcast, the lifetime risk of pancreatic cancer we think is relatively low in the general population. But if you have two family members, close family members with pancreatic cancer, we think that risk often warrants pancreatic cancer surveillance for the relatives. And so even if we don't find a mutation, there is an indication to do screening in families who have a lot of pancreatic cancer. And a lot here is two cases. It doesn't need to be multiple cases because, again, pancreatic cancer overall is uncommon.
So, two cases in close relatives is already a warning sign for us.
Alisyn Camerota: Is it possible that the genetic mutation just hasn't been discovered yet?
Dr. Asaf Maoz: It is possible. We are always trying to figure out whether there are other uncommon mutations that we're not able to detect or not testing for right now. There are certainly researchers who are trying to find new genes in which mutations may predispose to pancreatic cancer. It's also possible that it's a combination of many, many small different changes to the genome where we don't necessarily have the ability to detect a single change that is causing the risk, but across the entire genome, there may be a lot of small risks that overall together increase the risk. That's called a polygenic risk score.
That is not yet in clinical use because we have not validated it well enough, but that's part of what may be affecting familial risk in people who do not have a detectable germline mutation.
Alisyn Camerota: I mean, part of why I love having these conversations with you and other doctors is because things are changing so fast in terms of the progress and the science and the research that, you know, what we don't know today, we might know, I don't know, months from now, years from now. That's because it just feels like you're all in the vanguard of figuring out some of these things.
Dr. Asaf Maoz: Yes, that is certainly the hope. I think we've made amazing progress both in the germline detection, you know, detection of germline mutations, but also in the treatment of pancreatic cancer.
Alisyn Camerota: So, what are some of the most common hereditary mutations that are linked to pancreatic cancer? You've mentioned the BRCA. And what do they mean to patients and their families when you discover them?
Dr. Asaf Maoz: Yeah, that's a great question. So the most common mutations are mutations in BRCA1 and BRCA2, and in a gene called ATM. The implications are most clear for individuals who have BRCA1 and two in terms of their specific treatment. So in pancreatic cancer, obviously, the treatment, as previously discussed on the podcast, depends on the stage of diagnosis and whether the overall plan is to go to surgery or whether, unfortunately, the cancer is found at a metastatic stage and then the treatment is systemic. Meaning chemotherapy or other targeted therapies. For individuals who have BRCA1, BRCA2, or PALB2 mutation, and again, this may be inherited, but it also is true for those who the mutation occurs only in their tumor.
They may be eligible for slightly different treatments. There are studies on the type of systemic treatments that we give that suggest that their cancer responds more to platinum chemotherapies. There are types of combinations that we would consider for those individuals that we don't typically consider for other individuals. So I know that the term FOLFIRINOX has been mentioned on the podcast. That's one of the most common chemotherapy regimens, and it has a platinum chemotherapy called oxaliplatin.
But there's another frontline regimen for pancreatic cancer that can be offered to these patients if ofuranox is not appropriate. And that one is called gemcitabine with cisplatin, another platinum-based chemotherapy. And we don't typically use that for other types of pancreatic cancer, but we do think about it in certain situations if someone has a BRCA1, BRCA2 or PALB2 mutation. The other aspect of treatment for individuals with those mutations are that if there is no progression, meaning if there's disease stability on Fulphiranox, they can be offered a PARP inhibitor. And we've seen that with the PARP inhibitors, some patients really have long term disease control without being on chemotherapy.
Obviously, PARP inhibitors have their own side effects, but some people who have BRCA1two or PALB2 mutations really get a long time off of chemotherapy and on these inhibitors. That's probably the most common one. I don't know how long you want me to talk about the other ones. I think one of the very important one, although it's not as common, it's maybe one percent of cases, is Lynch syndrome. And Lynch syndrome is really important to detect because if the tumor itself and here's a bit of nuance where you have to test the tumor itself and make sure that the tumor itself actually is Lynch syndrome related.
If the tumor has Lynch syndrome-related features, then immunotherapy becomes an appealing option. Immunotherapy for Lynch syndrome-related tumors can really make a huge difference. Some patients, who receive immunotherapy for Lynch syndrome related cancers, are disease-free for many years. So, that has major implications.
Alisyn Camerota: Oh, definitely. I mean, that would be a dream scenario for most pancreatic cancer patients. So, one of the things that I had to learn, and maybe you could explain this, look at mutations in the patient and in the tumor, and those are different.
Dr. Asaf Maoz: Exactly. We do germline testing, is kind of what we are talking about mostly in this episode, which means we're testing the genes that we were born with. But we also need to test the genes and the mutations in the tumor. Because, as I mentioned, most individuals, ninety percent of individuals will not have an inherited mutation. But over ninety percent will have a mutation in the tumor that I'm hoping that in the next few years we will be able to target a of care.
And we are now trying to target in clinical trials, and those are KRAS mutations. And so there are a lot of very encouraging clinical trials targeting KRAS mutations. Again, those are mutations that are only found in the tumor typically. They're not found in all the cells in our body, but they can be targeted. So we really need to test both the germline and the tumor to offer the patient the best treatment.
Alisyn Camerota: And in terms of the tumor, you do that through a biopsy?
Dr. Asaf Maoz: You can do it through a biopsy. You can now also do it through what we call a liquid biopsy. So someone is diagnosed with pancreatic cancer, the DNA from the cancer is shed into the blood. And so there are now tests that it's called circulating tumor DNA. There are now tests that can be done to try to find the tumor DNA in the blood.
Often, you can find the mutations that the cancer has in the blood. So, for example, for many of my patients, I do send circulating tumor DNA to try to understand whether they have a KRAS mutation. It's not perfect. We don't always find it in the blood. But when we do, sometimes if we don't have enough tissue to do testing on, that can be an alternative.
Alisyn Camerota: Do you encounter patients or patients' families who don't want to get genetic testing?
Dr. Asaf Maoz: I do sometimes encounter families who do not want to get genetic testing, and I think it's an individual decision. I think as an oncologist, as a genetics provider, I try to provide them with all the information and to explain why we think it is important, why we think it could be helpful, and why it may have treatment implications for them as well. But I think the decision is ultimately a personal decision and I try to help my patients make the decision that is best for them.
Alisyn Camerota: But what is the thinking when they don't want any?
Dr. Asaf Maoz: It's a good question. I think sometimes they wonder whether it would make a difference. And then I counsel them about the fact that there are potential treatment implications if we find a germline mutation. And there, I think it's really important to mention that we talked about doing both tumor and germline testing. If we only test the tumor, we can miss germline mutations.
So, sometimes patients will ask me, Well, instead of doing germline testing, can't we just test my tumor? We can and we will test the tumor, but sometimes that's going to miss a germline mutation. So, it's important to do both. Other considerations are if someone, for example, doesn't have siblings or doesn't have children or is not in contact with family, they feel less strong about getting tested for something that has implications for others. And I think sometimes it's a normal psychological reaction.
It's sometimes scary to discover that there is something that may be inherited and may be passed to family members that you love, and sometimes people don't want to know about it. I think that's a very natural and understandable reaction. I try to counsel them and walk them through it and explain, like I think the genetic counselor Everett explained in the last episode, it doesn't really change their risk if they don't know about it. If we know about it, we can do something about it, if that makes sense.
Alisyn Camerota: Yeah, I mean, of course, yes, it would be scary to know you have the potential of something. It's much scarier to know you actually have a diagnosis of something. Yeah. The sooner the better.
Dr. Asaf Maoz: Yeah, and we have so many advances in prevention. We're talking specifically today about pancreatic cancer. I know you had an entire episode with Dr. Goggins about pancreatic cancer surveillance, and we're seeing encouraging results there. But beyond pancreatic cancer, we're also seeing a lot of advances in prevention of other cancers, including breast, prostate, and colon cancer.
So there's a lot of other cancers where we're now doing much more screening, and we can detect cancer early or even sometimes prevent it. So, I think there are certainly a lot of benefits to detection of a germline predisposition to cancer.
Alisyn Camerota: So, Dr. Maoz, what else should we know? Have we missed anything?
Dr. Asaf Maoz: No, I think you had excellent questions. I think there are a few other syndromes that can cause a predisposition to pancreatic cancer that are important to know about if they're detected. And some of them have a very high risk of pancreatic cancer. The common ones that I mentioned, the overall risk of pancreatic cancer is still thought to be less than 15% percent over the lifetime, often less than 10%. But there are some syndromes where the risk is very high.
Those who have mutations in genes called CDKN2A or SDK11, those are syndromes where we think the risk is very high and we think the screening needs to start earlier in life. Screening needs to be done regardless of a family history. And I think one of the most important things to know, I think, in terms of recent changes to guidelines, is that recently the NCCN has changed the guidelines from saying certain individuals need to have a family history for screening.
NCCN has recently said, you know what, for those who have BRCA2 or ATM variants, which are again the most common hereditary causes of pancreatic cancer, and they're also pretty prevalent in the general population. For those individuals, we can do screening at the age of 50 or earlier if there's an earlier cancer in the family, even if there's no family history.
And I think that's a major change that has occurred recently where we understand that the family history criteria is not very good in determining who should undergo screening. Based on the mutation, for those who have BRCA2 and ATM, we currently should offer screening to everyone at the appropriate age. And I think that's something that's really important for individuals to know because that's a change.
In the past year or so, many individuals who would come to our clinics with BRCA2 or ATM in the past were told, You do not qualify for pancreatic cancer surveillance because you don't have a family history. And I think that there may be additional changes in the future in terms of whether we require a family history to screen because, again, as we presented data earlier this year and others have presented similar data, most individuals who have a predisposition and will develop pancreatic cancer do not have a family history.
Alisyn Camerota: But I mean, just so I understand, isn't this sort of a chicken and egg conundrum where if you don't have a family history, why would you get genetic testing done? And the only way to find out if you have the BRCA and ATM is if you get genetic testing done.
Dr. Asaf Maoz: That's a great question. So, one thing is that a lot of people get genetic testing done because of other reasons. If someone is diagnosed with breast cancer, if someone in the family is diagnosed with ovarian cancer, then often they will get genetic testing. Or in the case of Lynch syndrome, it can be uterine cancer or colorectal cancer, or other cancers related to Lynch syndrome. So, there are a lot of reasons to get genetic testing these days.
There are some studies that are looking at testing in the general population. Because we know that a certain percentage of individuals in the general population have a predisposition to cancer, even if they don't know it, and even if they don't have a reportable family history. And so in those individuals, to qualify for pancreatic cancer surveillance, they specifically have to have a family history of pancreatic cancer, not others. Or at least that was the situation for many years. And now NCCN has changed the guidelines and said, if you have the BRCA2 or ATM, the very high risk genes I talked about before that are less common, then even if you don't have a family history of pancreatic cancer, you are still eligible for surveillance.
And that may change in the future for additional carriers of other mutations.
Alisyn Camerota: Anything else you want to say, Doctor?
Dr. Asaf Maoz: No. I just wanted to thank you for highlighting this important field and for all the work that you do to get this information out to everyone. Thanks so much for everything you do.
Alisyn Camerota: Well, thank you, doctor, for all that you do also in treating patients. Dr. Asaf Maoz, really a pleasure to talk to you.
Dr. Asaf Maoz: Likewise.
Alisyn Camerota: And thanks, everyone, for listening. I'm Alisyn Camerota and we'll talk to you next time.
Cindy Gavin: Thank you, Dr. Maoz and Alisyn, for that informative discussion. I'm Cindy Gavin, CEO and co-founder of Let's Win Pancreatic Cancer. If you or a loved one have been diagnosed, we know it can be extremely overwhelming, and we are here to support you. There is a wealth of resources on both genetic testing and managing family history at PanCAN and Let's Win.
Please visit PanCAN at pancan.org and Let's Win at letswinpc.org. We hope you'll tune in next month, where we focus on the power of advocacy and raising awareness about World Pancreatic Cancer Day and its importance to the community.