Dr. Shannon Westin discusses germline genetic testing in gastrointestinal cancer with Heather Hampel and Dr. Matthew B. Yurgelun.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. This is our podcast where we get down in the nitty-gritty of articles that are published in the Journal of Clinical Oncology.

I am your fearless leader and host, Shannon Westin, the Social Media Editor of the Journal of Clinical Oncology, as well as Professor of Gynecologic Oncology at The University of Texas, MD Anderson Cancer Center.

And I am very excited to bring two guests in today to discuss a review article that was published in a special series on, 'Precision Medicine and Immunotherapy in GI Malignancies,' back in June of 2022, and this is, 'Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?'

And please note that our participants have noted no Conflict of Interest.

So, without further ado, let me welcome our guests. First is Heather Hampel. She is a Cancer Genetic Counselor, and the Associate Director in the Division of Clinical Cancer Genomics, and a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Welcome, Heather.

Heather Hampel: Thanks so much for having me.

Shannon Westin: We're also accompanied by Dr. Matthew Yurgelun, he is a Senior Physician in Medical Oncology at the Dana-Farber Cancer Institute, the Director of the Lynch Syndrome Center, and Assistant Professor of Medicine at Harvard Medical School. Welcome.

Dr. Matthew Yurgelun: Thanks for having me.

Shannon Westin: And we have all decided we were going by first names. So, audience, don't be alarmed. Okay, let's get right into it. So, this is a really great review. I learned a ton and I think, you know, just to kind of get back to basics, I think we've been seeing an increase in the use of germline genetic testing across a number of different cancer types. As I mentioned, I'm a gynecologic oncologist, certainly this is something we're doing for patients with ovarian cancer. What are the reasons this has become so widespread across all cancer types?

Heather Hampel: Matt and I probably agree on this one. I will, but I'll say you a couple of reasons, and see if Matt has any to add. I think that 2013 marked a major turning point in the field of cancer genetics for a couple of reasons. One was; the advent of next-generation sequencing, so that we could do multiple genes at the same time for a lower cost. The other was that that was the year the Supreme Court struck down the patent on BRCA1 and BRCA2, which allowed lots of different competitors into the market to offer sort of these pan-cancer panels, including, BRCA1 and BRCA2, among other genes. And the price has dropped precipitously since then, giving better access for patients. The competition, I think, has been good, so that a lot of the laboratories now will offer out-of-pocket maximums of $250. And then, we've seen a lot of research. Because of that, I think, where we've just done pan-cancer panels on different solid tumor cancers, just to determine what the prevalence of mutations is, all of this is sort of leading to, I think, just greater use of germline genetic testing across the board.

I don't know. Matt, what do you think?

Dr. Matthew Yurgelun: No, I fully agree. This is an example of the more you look, the more you find, and I think we've seen that both in the studies that have been done looking at multi-gene panel testing in virtually any setting across different cancer types and then I think people who use these in clinical practice, whether they are genetic counselors, oncologists, gastroenterologists, gynecologists, primary care physicians, I think as people have become more experienced and more comfortable using them in routine practice—I think it's not an uncommon phenomenon for those of us who use these to find things that were somewhat unexpected, which kind of naturally leads to the question, "Well, what else might I be missing if I'm not doing these tests further and wider?" What's made it a little bit difficult is that this is an example of testing that's become available commercially before we really understood how to use it. And so, we've been figuring a lot of this out kind of on the fly a little bit.

Shannon Westin: Yeah. I think it brings up, and not to get too nitty-gritty right from the beginning, but to me, it brings up the whole idea around variance of uncertain significance, right? I think we've really struggled with this on the GYN space, and I don't know how common that is for you all in the colorectal space, but we get answers, we don't know how to tell a patient what to do with that information. And in fact, we've personally seen people get risk-reducing surgeries, probably not appropriately in response to these variants.

Dr. Matthew Yurgelun: It's a real phenomenon, and it's the other side of the more you look, the more you find. You know, you end up finding a lot of these variants of uncertain significance. I think we've become a lot more comfortable and maybe even cavalier about them as panel testing has become so widespread. But there are data out there, and not to mention just anecdotes of people who are potentially being harmed by these variants of uncertain significance, as you said, whether it's through unnecessary surgery, whether it's even just psychological burdens and harms that come from the angst of those uncertainties. So, it is important that we be thoughtful about just how to use this technology.

Heather Hampel: And really it is, "the more you look, the more you'll find." So, on a panel of about 50 genes, there's about a 30% rate of finding a variant of uncertain significance, increase that panel to 80 genes, you're up to probably a 40 to 50% chance of finding a variant of uncertain significance. A panel of 150 genes, maybe an 80% chance of finding a variant of uncertain significance, and it becomes almost the rule and not the exception. So, this is where genetic counseling becomes really important in terms of having people understand that these are sort of common, and usually, not anything, and setting expectations so that people don't over screen, or overreact, or get in a situation where they're mismanaged.

And this is one of the things that Matt and I go back and forth a lot about when you start to think about testing all-comers because if you're testing all-comers, you kind of have to give up pre-test genetic counseling and kind of move to a post-test genetic counseling scenario more for the positives, or people with a strong family history or concerns. And I know Matt worries, and I do too, that that's where we've risked these variants of uncertain significance getting mismanaged, particularly in centers that aren't as used to dealing with cancer genetics.

Dr. Matthew Yurgelun: I would just add one more concept on that. We're probably also, in the case of some of these larger panels, dealing even with genes of uncertain significance. At the end of the day, it's the commercial laboratories in many cases that are really setting the agenda on some of these panels as far as choosing which genes to include or not to include, and a lot of these genes are genes where the link to cancer risk is sometimes very preliminary.

Shannon Westin: Those are some great points. I think just to kind of take a step back, since the paper's in GI cancers, and I want to make sure we have—we have a mixed audience out there, so I want to make sure we level set. So, can you tell us the current standard of practice for germline testing in GI cancers? What are you looking for specifically? What are some of the things that you know are of certain significance?

Heather Hampel: Currently, the NCCN guidelines recommend that all pancreatic cancer patients be offered germline genetic testing. And what is very new in 2022 is that there's now a consideration recommendation that you could consider offering germline genetic testing to all colorectal cancer patients. That is logistically much more challenging than offering germline genetic testing to pancreatic cancer patients because there are so many more of them. And it comes with a page of caveats of things that you need to think about before you would consider offering testing to all colorectal cancer patients.

And then, I'd say among the rest of the GI cancers, you're going to be offering testing in cases of early onset, multiple primaries, maybe three affected's on the same side of the family with cancers that could go together in a family, and raise a red flag that there could be hereditary, diffuse gastric cancer comes to mind when you think of the stomach, certainly, polyposis is an indication for testing as well. But for most of the GI organs, you're going to need early age, multiple primaries or some family history. The one clear exception being pancreas, and now, a lot of debate about colorectal.

Dr. Matthew Yurgelun: And I would just add to that from some of Heather's own seminal work. Tumor testing is often used to drive a lot of this in day-to-day practice. Certainly, the presence of microsatellite instability, and/or mismatch repair deficiency. This isn't limited to GI cancers, obviously, but it is where we often think about it the most. But any finding of mismatch repair deficiency in microsatellite instability should really strongly trigger strong consideration for germline testing, at least for Lynch syndrome, which is often, at least a way in the door for germline testing a bit further and wider.

Shannon Westin: Yeah, that's kind of what we've done in endometrial cancer, and it's definitely a less expensive way of kind of getting at that, and we use those same Amsterdam criteria for the full germline outside of that. But that's really how we've gotten to universal testing for endometrial is using the less expensive protein testing, you know, as a trigger to break down the door.

Heather Hampel: But it's not necessarily less expensive anymore. So, that's where things are getting a little challenging. You know, at most hospitals, if you're going to do four immunohistochemistry stains, you're going to take whatever they charge for IHC times four, then you're going to have a reading fee for the pathologist times four, and believe it or not, that adds up pretty quickly, and can become a test that's $1,500+, compared to potentially a $250 germline panel. I find it an odd situation for me to be in, who I've spent 20 years of my career advocating for universal tumor screening for Lynch syndrome. But I do feel that we really need to relook at the cost-effectiveness analysis now that the cost of germline genetic testing has gotten so low, and we need to think about what we're missing with universal tumor screening. So, yes, it will detect most of the cases of Lynch syndrome, and it should detect anyone who could benefit from immune checkpoint blockade therapy. And those are very important points, and I think that's the reason we're never going to go away from tumor screening. But it's not going to detect mutations in any other cancer susceptibility gene. And that's what you risk missing if that's your only approach.

Shannon Westin: Those are some great points. Again, bringing those of us that aren't GI experts, up to speed, what's the overall incidence of these germline genetic abnormalities in GI cancers? What are we looking for?

Dr. Matthew Yurgelun: I think it depends on which cancer you look at, and it also depends a little bit on even just how you define the prevalence here. Where it's been a little bit difficult, or where it's been kind of moving goal posts is that the panels that we're using in day-to-day practice are getting bigger and bigger, and certainly, the panels that are being used in a lot of the studies that are examining this are getting larger and larger. And as far as the number of genes being tested-- and not surprisingly, as you test more genes, you find more stuff. We make a point in the paper that some of the older studies, these are all still relatively new studies, but some of the older studies that have looked at gene panels of say, 30 genes or fewer, you actually find germline prevalence rates that are maybe 10% or lower across most of the GI tract malignancies.

But as you start getting into panels that are 50 genes, 60 genes, 100+ genes, that's when you start getting these prevalence rates that are 15%, 20%, almost across the board. But the prevalence is only part of the story, in my opinion, it's a matter of what you're finding, in addition to how many people you're finding stuff in. Because you know, finding a diagnosis of Lynch syndrome, finding a BRCA1 or BRCA2 abnormality, things that are high penetrance, clearly actionable that we understand reasonably well, I would argue is much more impactful than finding something like a monoallelic MUTYH pathogenic germline variant, which arguably has very little clinical significance for the person themselves, and is honestly, much more common than some of these other things too, and drives up some of these prevalence rates.

Heather Hampel: I agree, Matt, completely. And I struggle myself, sometimes, with how people should report out the incidence of mutations in series like this because when you include those MUTYH heterozygotes, you include your APCI 1307Ks, you're padding the numbers, but are you finding something that's going to really make a major management change for that family? I don't know. The one thing though that has stuck with me as I look at this is that it appears that people who meet the criteria for testing aren't much more likely to test positive than people who don't meet criteria for testing. And as a genetic counselor who, you know, loves to take family histories, and for years, liked to believe that if I took a good family history, and assessed it, I could pick who was going to test positive appropriately, it's been a little bit of a dash to the confidence to see rates of positivity that are pretty similar in the patients who don't meet criteria. And I think that's been a challenge for all of us. So, if we could pick these cases well, it would be one thing, but I don't think we can all the time, outside of Lynch syndrome. Lynch syndrome, I think we can pick, to a large degree, through tumor testing more than family history. But the non-lynch genes are much harder to predict based on age of diagnosis, family history, or any other clinical criteria.

Dr. Matthew Yurgelun: I totally agree, and for me, that's what moved the needle a handful of years ago with pancreatic cancer in particular, in my own mind, is that it was becoming quite clear that you could find some of these with clinical criteria or even just clinical intuition, but there were a lot that were just being missed. We were looking at age of diagnosis, we were looking at family histories of BRCA-related cancers, and family structures being what they are, in many cases, you know, the fact that pancreatic cancer, even in the setting of some of these germline variants is often diagnosed well after age 50, and often after age 60, or even after age 70, you know, our usual clinical criteria just weren't working.

Shannon Westin: I think you kind of already started touching on this, but I'd love to get a little bit more, you know, what would be the additional benefits to doing this universal testing? I think one of the things you just mentioned, like, not being able to completely pick the right people to test. I mean, this is exactly why we started doing this in ovarian cancer is because, more than half of the women that were testing positive BRCA, did not meet the age criteria, they had no family history to note, you know. So, we were missing tons of people. What are the other things we can gain from universal testing?

Heather Hampel: I think that's a key one. I think another one that Matt and I agree on is that from that proband there, are all those at-risk family members who get to benefit because of the cascade testing that begins from that first person who gets diagnosed in the family. And those are often unaffected at-risk people who you can really keep from getting cancer in the first place, and make a major impact in their health outcomes. So, not wanting to miss a potential hereditary family, and that ability to get to those at-risk family members, I think is a major benefit.

I think the one that hasn't really panned out yet in GI, and I'll leave this to the oncologists in the room, is a change in treatment. But I think it's coming. I hope it's coming; we'll see what research all you oncologists can do. But I think that what moved the needle on ovarian and pancreatic was the fact that we had mutations in the homologous repair deficiency pathway, leading to a change in treatment, and the use of PARP inhibitors that just hasn't born out in GI cancers yet, outside of pancreas. And the one thing that you do see a treatment change for is mismatch repair deficiency, which you can find by doing IHC for the mismatch repair proteins or MSI testing, so, you don't really need the germline panel. In fact, some people with Lynch syndrome don't have an MSI-high tumor, and won't benefit from immune checkpoint blockade therapy. And so, I feel like that's the one benefit that maybe hasn't been fully realized in GI cancer, but I hope it will one day. I don't know. Matt?

Dr. Matthew Yurgelun: No, I agree. I think the therapeutic actionability has been one that we've been hoping for more than what we've actually seen in real-world practice, the big exception being PARP inhibitors for pancreatic cancer. But even there, I think so far, the benefits have been maybe a bit more modest than people would've originally hoped for. I agree, I think the therapeutic benefits are ones that we're still trying to work towards.

Shannon Westin: Yeah, and you kind of got around this before, and I think this is what we're experiencing in some of the gynecologic malignancies is like, not every gene is created equally. You know, we originally thought, "Oh, any homologous or combination gene will do. We could do PARP for all," and then realized, "Actually, no, it's probably just BRCA, maybe PALB2, RAD51." So, I think it's exactly like what we're seeing in honestly, frankly, across precision medicine, right? Where it's like, not every PI-3-kinase mutation will lead to benefit from a PI-3-kinase inhibitor.

So, I think the science got ahead of us, or we got ahead of this science, and so, I do think that that's where the struggle is. Because I think once you've got therapeutic actionability, it becomes a no-brainer. And then, you've already hinted at this, but I just want to be really clear for everyone listening, why shouldn't we do it right now? What's holding us back from universal germline testing for everybody in GI cancers?

Dr. Matthew Yurgelun: You know, I think if it were a perfect world, then it would be a no-brainer - test everybody. The finances, as Heather alluded to, are in some ways kind of the least compelling argument against universal testing, that the cost of the germline testing itself has come down tremendously. But it's more than just the cost of the test itself, at least in my opinion. I mean, first of all, I think we've got massive work to do just to figure out the care delivery here. As it stands right now, roughly half of colorectal cancer patients meet criteria for germline testing, putting aside the recent update to the NCCN, which says, "consider testing for all individuals." But even if you just look at colorectal cancer alone, if you expanded germline testing to all-comers with colorectal cancer in the US, that's another 80,000+ new diagnoses per year in the US, who are all over age 50, have mismatch repair proficient tumors, have no striking family history, you know, where the odds of finding something truly actionable in my mind, is exceedingly low. Then you add in all of the other GI cancer types. You add in the literal millions of GI cancer survivors that are out there, and you're talking about bringing this testing to a whole lot of people.

On top of that, there's really all of the uncertainties and nuances that come from the testing itself, as we were talking about at the beginning of the chat here. Whether it's variance of uncertain significance, whether it's genes where there's really no link between the gene in which they have a germline variant and the cancer that they were ultimately diagnosed with, or whether they're genes we don't understand or don't have clear-cut management guidelines for, it's really all the unintended consequences in some ways of a lot of what we're doing. And I think too often out there, whether it's from the patients themselves, or us healthcare providers, or combination of the two, there's this misperception that genetic testing is giving black and white answers to what's going on. There's a whole lot of gray here, as far as understanding what needs to be done with this. Yes, if we could test everybody and get them clear-cut answers, and then get their at-risk family members in for testing, the benefits would supersede all of these concerns, but I don't think the real world is as simple and straightforward as that.

Heather Hampel: And I find myself just in the struggle between-- when I get in a room with people who discuss this, most people feel like we should be doing it, and the thing that's stopping us is that it's difficult. And that doesn't seem like a good reason to not do this. If it's the right thing to do, I think we have to figure out how to do it. And you think of, you know, Mary Claire King's Lasker Award talk when she talked about offering BRCA1 and BRCA2 testing to all women at age 35, population-based screening. And one of the things she recommended there was, not reporting out variants of uncertain significance. I realize it's a different situation when you're talking about population testing and healthy people, but are we doing more harm than good with reporting out variants of uncertain significance even in cancer patients? Whereas, you know, we could just ask the lab to let us know if anything ever got upgraded and avoid risking mismanagement of patients based on a variant that you know is likely benign.

So, I think there are things we can do. We've been working on some of them, I know Matt has done a little work with mainstreaming in pancreatic cancer patients. I did as well, my former job, because that was sort of the first new tumor outside of ovarian where we needed to recommend all patients get seen by cancer genetics. And the wait time often in cancer genetics is too long, given the prognosis for pancreatic cancer patients, we had to kind of come up with new service delivery models. And there's some great data out there, people are using genetic testing kiosks in the waiting room, videos at the oncology clinic. We can get creative, and the trouble is, I think we're learning while we're doing, which is coming full circle in our discussion here, that's a hard way to do things.

Dr. Matthew Yurgelun: I would just add on top of that, in my mind, the reason why not to do this, is really why not to do it. I think we can recognize that more germline testing is going to pick up more people with inherited risk to cancer. There's the unintended consequences, and we need to figure out how to deal with them. And as Heather said, just because it's hard, that shouldn't be a reason not to do it. At the same time, I think it's okay for us to recognize that this is where the field is heading, but to also recognize that we don't yet have all the answers, and to say, "Well, let's be thoughtful about it. Let's figure out how to implement these types of things, how to study them," because it's not going to be one size fits all.

What works in a major tertiary care academic medical center is going to be very different from what works in other settings and for other populations. What works for English-speaking patients versus non-English-speaking patients is probably going to be very different. And I think there's all sorts of permutations when you start breaking it down like that. And I think it's okay for us to say, "Well, this is where the field seems to be going, but let's really be thoughtful about it and make sure that we're not doing harm in the short term just because we think it makes more sense to just test everybody in a shotgun approach."

Shannon Westin: This has been great; I've learned so much. I was like trying to frantically take notes for thoughts of what we're doing in our clinic right now. I just want to thank my two guests. I think that I remain hopeful that we will get here. I think that you all outlined some really clear steps that we need to take to get there.

And audience, I just want to thank you all for being here with us. Again, this was a discussion of, 'Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?'

Thanks again for joining us on JCO After Hours, and we will see you next time.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.

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Universal Germline Genetic Testing in GI Malignancies

Journal of Clinical Oncology (JCO) Podcast

Universal Germline Genetic Testing in GI Malignancies