Myriad Oncology Live episodes are recordings of an open-forum webinar hosted by Dr. Thomas Slavin. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, visit myriad-oncology.com/myriad-oncology-live for a list of dates, times, and subjects.
Myriad Oncology Live episodes are recordings of an open-forum webinar hosted by Dr. Thomas Slavin. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, visit myriad-oncology.com/myriad-oncology-live for a list of dates, times, and subjects.
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0:00:11.5 Dr. Thomas Slavin: Welcome. This episode of Inside the GENOME is a recent recording of Myriad Oncology Live, a webinar hosted by me, Dr. Thomas Slavin, Senior Vice President of Medical Affairs at Myriad Oncology. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, please visit Myriad Oncology, for a list of dates, times and subjects. I look forward to exploring the world of genetics with you all.
0:00:38.8 DS: Okay. Hello everyone, welcome to Myriad Oncology Live. Thank you for coming on today. I know it's late in the day for many people, but this is why we're here. I don't know what people heard, but yes, this is a open forum, you can ask anything you want. We do them theme-based, and today is tumor versus germline. So today is a later one, 6:00 PM Eastern. So we normally don't do them this late in the day, but I wanted to get some on the schedule, we try to sprinkle it in for people on the East Coast, maybe they can join after clinic. I do try to generally keep the later ones a little bit more generic in terms of the discussion points, that way people can come on and ask literally whatever they want.
0:01:27.8 DS: So tumor versus germline testing, and everything in between is a pretty broad topic. And next week... Next week is actually an off week, and then we're gonna be getting back into Polygenic Risk Scores, June 10th. I've had a few people email me about, "What is PRS?" So it's Polygenic Risk Scores. So we'll have to... I probably shouldn't have put the acronym on there. And then June 15th, we're gonna be talking about cancer survivorship, so I'm trying to get special guests for both of these, just was sending out some emails today, so it should be exciting. And then we'll come back in July with hereditary genes limited guidelines. I do wanna also point out, we've been putting these... Now, when you signed on, you probably saw it's recorded, so there's been requests for these, as you would guess, to record them in some way, shape or form, so people can listen to them later.
0:02:28.6 DS: So what we're doing now is we are recording them, we're not using the video though, we're gonna just use the audio and we actually already started posting this online. So I saw all of this today, I was just like, "Woah, what's all this?" So these are the... This is a podcast series that I do, that's at the bottom of that link, and it's called Inside the GENOME, and we're just gonna put these in. There's a whole bunch of them right now that just got uploaded, since we just started this. But you'll start seeing a more, just sprinkled in... Amongst podcast. The Myriad Oncology Live will always be MOL, this is a work in progress, we might need to even change... This probably isn't the best acronym right now, most people would have no idea what this means. So I think we need to do a little work here. But yeah, the difference is the Myriad Oncology Live ones now, these are gonna be 45 minutes to 60 minutes that you can just go back and listen to, but we've got some really good ones lately, and if you didn't listen to the LGBTQ one... If you weren't able to make that webinar, that was a fantastic one.
0:03:35.4 DS: We had Eduardo Vilar on a week and a half ago, that was a really... Two weeks ago, that was a really good one. Talking about vaccines and chemoprevention for Lynch syndrome, and then the podcast themselves are only about 15 minutes, so these are usually similar topics, but these are essentially me sometimes joined by Shelly and just sitting down with one guest, just kinda going through hot topics and things. So yeah, definitely take a peek there's plenty of content, it's kind of shocking, I've been here for a year and then when I'm looking at this, I'm even impressed sometimes myself to now see how much is on there. But today we are joined... I'm gonna stop sharing my screen. We're actually joined by a special guest, Mallory... And Mallory, I have no idea how to say your last name. [laughter]
0:04:29.5 Mallory Sdano: That's okay. No one does. [chuckle]
0:04:31.4 DS: I apologize in advance but Mallory is from Intermountain Healthcare, and I invited her on because they've been really just impressing me, we've been doing some work with them and yeah. Mallory, if you wanna... Yeah, unmute and kinda tell people what you do there, a little bit about the program, I think that'd be fantastic, and people can... Oh, and one other quick housekeeping before we leave things and go there, if you... I always encourage you to just unmute, ask questions, especially now that we're putting this in some sort of audio format. If you don't want to, you can always just send questions to Diana. So Diana is running the chat today and she will just read them out, so we can capture them for the recording, so thank you very much. So yeah, Mallory, if you wanna introduce yourself a little bit.
0:05:24.1 MS: Well, thanks so much for having me, TJ. My name is Mallory Sdano, so pronounce the D like a T. My husband's family tells me it's a made up name, so there's a kind of a fun story with that. But I am a laboratory genetic counselor with Intermountain Precision Genomics. I wear many hats, actually, through my role. I'd like to tell people that I kinda have three main areas that I focus on. So first is kind of your traditional laboratory genetic counselor supporting our Intermountain Precision Genomics or IPG clinical testing laboratory. We have a menu of tests that we can talk about in a minute, but supporting the team there, through R&D, process development, liaising with clinicians, working with the variant science team...
0:06:09.6 MS: All that good stuff that supports a laboratory. Another hat that I wear that I'm pretty passionate about is laboratory stewardship, specifically in the genetic testing space. So I'm working with the genetic laboratory stewardship committee, I'm currently the chair of that committee for all of Intermountain to work on stewardship efforts, as they relate to genetic testing, and then in my last little bit sliver of time, I'm also doing some clinical neurology, genetic counseling via telehealth, love that helps keep me grounded and keep me realistic when I'm doing stewardship efforts as well.
0:06:44.7 DS: Yeah, the stewardship... Can you go into that a little bit more? I don't completely understand what that is.
0:06:50.4 MS: Yeah. So really, the goals of the stewardship program are to make sure that the right patient gets the right test at the right time. So one branch of that can be reviewing send out genetic testing, so testing that's gonna be sent outside of our system, just giving it a quick once over, "Hey, is this... " If it's an outpatient testing, was there a pre-auth that was obtained so that we make sure the patient doesn't get stuck with a huge bill. If it's inpatient, how is this gonna impact the inpatient stay, what are the costs to the family, to the system, what medical management is gonna occur if we do this genetic testing. And then within the committee, another aspect that we've been doing is looking through our test menu and finding is there testing that's being over or under utilized within the system, and then how do we target that testing? Are there nomenclature changes we need to make in our test menu to make it more clear that test A is what you're actually looking for instead of test B? Is there something that just needs to be completely removed from the testing menu entirely? And we've done that recently as well.
0:07:56.8 DS: Oh, okay...
0:08:00.3 MS: So, it's pretty broad.
0:08:00.4 DS: Yeah, yeah, definitely. And I have been thoroughly impressed by your system, traveling the country, there's... A lot of systems are getting... Health systems are really getting involved in precision genomics much more than they have in the past, but there are some that are really leading in my mind, in the world, and Intermountain, I put on a pedestal kind of up there with the way I think of Geisinger now, and I know there's one of your geneticists, Nephi, I've spoken with him, came from Geisinger, but you're starting to... There's some similarities there. And just the work that you're doing. I was thinking if you could kinda give a little... I don't know how long you've been there, but maybe you can give a little back story of how your organization really turned into where it is today, and maybe kind of where it's going on the precision genomics side.
0:08:57.4 MS: Yeah, so I'm a little bit newer to the team, I've started right before the pandemic shut everything down, so I have a little bit of any typical experience at Intermountain thus far, but it's been a fabulous group, there's some really dedicated people and really wanting to make precision medicine the best it can be. One of our big initiatives is a big research study called HerediGene, where we're looking to enroll 500,000 individuals and to do whole genome sequencing on them, make a huge research database that then various researchers can use any time they have clinical genomic questions in the future, and just really providing that resource to them, and so we can improve treatments, we can improve care and really use DNA and use genomics as a way to improve patient health. So I think that's a really exciting initiative that we're really pushing forward with.
0:09:52.6 DS: Yeah, and tell us a little bit about that 'cause that's one interest of mine. As an organization, how are you... A patient walks in the door, go. How do they get into HerediGene? What do you do with those results? How was the patient consented? What's the kind of feedback that you've been getting since you've been doing that? 'Cause again, there's not many health centers doing that, I mean... You can tell me, but I can think of... You, again Geisinger, not many, maybe a handful of others, some cancer centers are starting to do this, but not on this kind of scale.
0:10:32.2 MS: Right, it's a huge initiative. It's a huge lift there are a lot, a lot of people involved. There's a great group that's involved, even just in enrollment, so we've got several different enrollment outreach programs, I guess you could call them. So one is just ad campaigns and having people hear about the study and be interested and reach out to us, but we're also being very proactive in reaching out to maybe a patient that's been to the laboratory, had a blood draw just for their routine clinical care. We've got teams that are identifying, "Hey, there's a little bit of blood left over from doing your CBC." And then we've got teams calling saying, "Hey, we're doing this research study, would you like to participate, we could actually use the rest of this sample that's left over from the testing you've already had, so you don't even need to go back and get another blood draw." There's also a digital enrollment that just went live recently, so patients and healthcare providers, anyone can go online, go through the consent process online, and then whenever is convenient for them head over to an Intermountain draw lab and get their blood drawn to participate in the study.
0:11:40.1 DS: So, the patient can go directly through that e-consent or a provider can do it with a patient in the office, is that how you set it up?
0:11:48.2 MS: Yeah, providers can absolutely refer patients to the HerediGene study, head over to our website...
0:11:54.2 DS: Do you just give them the email for the e-consent or say, "Can you come down and consent my patient" kind of thing?
0:12:01.8 MS: Yeah, they can contact our group. I believe the website is heredigene.org. Now I'm double-checking that. But yeah, and we can also... Our genomics team at Intermountain is happy to direct if a patient has specific questions about what the study is, and sometimes you hear weird things about genetic research on social media or whatnot, and so I think sometimes they get some unique questions from patients and the consent team is great for that.
0:12:33.4 DS: Yeah. What's the uptake been from the patient side?
0:12:36.6 MS: It's been good. Most people are really excited about the study, most of them are really... It really kinda hits at the altruistic heart strings, I think of people that they want to contribute to genomic medicine, they want to contribute to a better future in medicine, they're thinking about kids, grandkids, nieces, nephews, friends, neighbors and thinking, "Wow, if I could, I can contribute some blood and some information to this study." And then hopefully, in the future, those researchers will be able to use that information to really benefit others. And so I think it's a really cool initiative. And again, just pulling at people's altruistic heart strings and the desire to make the world a better place.
0:13:19.3 DS: Yeah. Do the patients get anything out of it themselves?
0:13:23.7 MS: They do. So what we've set up is that any time... So all patients get the testing, and then if we find what we call a "clinically actionable result". So for this audience, say a BRCA1 mutation, we are returning those results to patients. We send them a letter saying, "Hey... " It's a pretty generic letter, "Hey, we think we found something. Here's the information to contact a genetic counselor." We get any patient in touch with our awesome genetic counseling team. And so they're able to go in, have a discussion with that genetic counselor about, "Hey, this was a research test, this is what we found. We'd like to confirm it clinically that the study will pay for all that and coordinate it all and will confirm this variant in a CLIA lab, and here's what the implications could be for you and your family and for your healthcare." So it's a really great way to link together the clinical genetic counseling with the researchers and with patients, and have everyone just really work together to improve health.
0:14:24.6 DS: Yeah, yeah, that's great. And how long are you looking at doing this? Is this gonna be a five-year project, 10-year, indefinite? Is there...
0:14:34.4 MS: It's definitely a five-year project. We need to finish enrolling everybody, and then again, as long as it takes to get through all that data, contact all those patients, get them in for a genetic counseling session. So I believe enrollment is at least five years, and I would anticipate that the returning of the results would stretch on for several years beyond that as well.
0:15:00.3 DS: Yeah. And what results are you giving? ACMG 59 results, anything?
0:15:06.2 MS: Yeah, yeah. So most... That type.
0:15:08.4 DS: For now, I guess it's 73.
0:15:09.8 MS: Right, yes, exactly, that type of results. So things that are important for healthcare, clinically actionable. Like I mentioned, BRCA, Lynch syndrome mutations, cardiology... Mostly in that category, thinking along the lines of the ACMG 73. I'm gonna have a hard time switching that up, I'm still used to saying 59. [chuckle]
0:15:30.8 DS: Yeah, for those of you have not seen... And I actually still have to even look at the publication, but there's been a few other genes added to the ACMG 59. It was 56, and yeah, will probably continue to go up over time. [chuckle] No, good, and what other kind of things are you doing? I know... We're involved a little bit on the tumor sequencing side, which I've been very impressed. I was down in the St. George, Utah laboratory, I don't know, two weeks ago or so, and I was really blown away just by the sheer amount of lab space and equipment and everything else. For a health system, you guys are really doing great things and have a great infrastructure. But what other kinds of... So you have the tumor side of things, you're doing the HerediGene project. What other kind of genomic initiatives do you have ongoing?
0:16:26.5 MS: Yeah, we have a couple of different clinical tests. So the TheraMap or the TSO 500, which we're partnering with Myriad on, is a fantastic platform, a fantastic test, something we're all really excited about. We also have a pharmacogenomic test called RxMatch, as well as clinical germline hereditary cancer panels. So compared to the Labcorps of the world, we're a little small, our test menu, but it's pretty exciting for our system...
0:16:54.8 DS: Yeah, no, that's a lot.
0:16:57.9 MS: To have this menu and have this kind of diversity even. As you know, the team and the expertise required to have both the somatic and a germline test in-house is a pretty big lift. So it's really neat that we have both of those and that we've got such great people working on both of these products.
0:17:16.4 DS: Yeah, no. It's really been incredible. And what kind of strain has it put, if any, on the system? Here you are, you're really ramping up genomics, you're doing genetics on everybody walking through the door for the most part. What have you seen from the infrastructure? How have you adapted the clinics and things?
0:17:37.1 MS: That's a great question. I think my bias as a genetic counselor is that we just need to hire more and more genetic counselors, always. [chuckle] Diana agrees with that. But I think providers...
0:17:50.4 DS: There's usually a largely genetic counselor audience, so you're probably making a lot of friends right now.
[chuckle]
0:17:56.8 MS: Yeah, and I would say most of the providers have been very supportive. There's a lot of support and involvement in the TheraMap process internally, and part of that TheraMap process is, we do a molecular tumor board every other week, and that's just a fantastic opportunity to cross collaborate. I know I learn a lot every week from the various oncologists that attend, and get a glimpse into their world and the treatments and just what they know about the medications and the course of a cancer. Whereas I'm coming at things from a germline perspective and we've got our clinical variant scientists there as well, it's just such a cool opportunity to collaborate. And I think a lot of people are really excited about that and knowing that, "Okay, I'm a provider, I wanna integrate genetics into my practice, but I don't have to know everything. There are other specialists here within the system that I can lean on, there are genetic counselors that we can share patients, and there's clinical variant scientists, if I don't fully understand what's going on in a report." And so it's nice to have that all within the system and it's definitely been great.
0:19:04.3 Diana: Yeah, I was gonna ask you a question about that, but I thought maybe the audience would connect with, 'cause they seem very in tune with it. You're on the phone or they're in clinic or whatever the version might be. Do you have a standard set of guidelines to say, "Hey, refer this patient to me," even if it's a lung patient that's 79 but there's this finding, or are you... Is your idea to be there so that they can ask those questions in the moment, or a little bit of both?
0:19:38.8 MS: Great question. So our oncology genetic counseling team is fantastic and they have built a lot of relationships directly with providers and done some education in that realm of, "Hey, these are the patients to send over to us." But specifically with our TheraMap process, we've got a great collaboration between our clinical genetic counseling team, our variant science team, and then myself and our other laboratory genetic counselor, to review these TheraMap cases and flag, "Hey, I think this patient should actually be referred for germline." We meet as a committee... We kind of flag all the cases, meet as a committee, go through each of them to say yes or no, and then the clinical team actually reaches out to the providers saying, "Hey, based on these TheraMap results or based on your patient's cancer type, referral to genetic counseling is indicated. Here's some information about how to refer your patient and do that reach out." So that's a really neat follow-up step that we've implemented to help support the providers in doing this testing.
0:20:34.9 DS: Yeah. And it's a fine line, and Diana was bringing up kind of the lack of clarity and guidelines. Is a lot of it just kind of like, "Yeah, this is a high risk for... We did tumor sequencing, this person has a high risk to have a germline mutation based on X, Y and Z." Or is it kind of, "And this person is at almost no risk, so we're not gonna recommend them." Or I'm assuming there's a lot of gray zones and things like that. And is it kind of just going with your gut to some extent right now, where it's like, "Yeah, it's probably unlikely." I don't know... There's a good learning for everyone.
0:21:09.1 MS: There's never a gray zone in genetics. Yeah, it's definitely been a learning experience, and we try to follow NCCN guidelines as much as possible. So when we see someone... We did TheraMap on a pancreatic tumor. Okay, based on just their history of a pancreatic tumor, let's refer them. But then when it comes down to actual variants, it's a lot of, "Well, this was about 50% allele frequency." And our variant science team looks at it and the germline team says, "Yeah, I think if this was in the germline, it would be classified as pathogenic, so it would be actionable and... Alright, let's reach out to the provider then." Sometimes it can get really tricky 'cause TP53, we think about as genetic counselors and germline as, oh my gosh, the worst mutation ever. But it's in all kinds of somatic tissue and it's there all the time, so it's interesting having to shift your perspective a little bit and recognize which mutations and which genes are just very commonly mutated in somatic tissue compared to germline, and kinda where that level of concern is. We try to lean on the side of maybe over-referring a little bit, 'cause if nothing else, it's a great conversation for the patient to have with the genetic counselor about family history and risks, and they may decide to not pursue any sort of germline testing, but they've at least gotten some information and had that opportunity.
0:22:37.7 DS: Yeah, I do personally think the field's ripe for an online algorithm that somebody... If someone's on there... Yeah, if someone's online and wants to develop one, I fully support you. But I think we're starting to get more data, 'cause I was looking into some of this when I was at City of Hope, because you kind of have a priority risk. So if you're seeing somebody with an ovarian cancer and they come back with a BRCA1 or 2 mutation, that's pretty concerning, that it might be in their germline. Whereas if you see someone with an ovarian cancer and comes back with an ATM variant, and I guess I'm getting at kinda allele frequency somewhere in the middle. ATM, we just know is common in the population and the germline, it's not really a driver of ovarian cancer. So you can start making these kind of, what is the likelihood that this particular variant... And I do think that, yeah, probably plugging in variant allele frequency, the variant, the cancer type, we probably have enough data starting to be out in the public realm that could really just get at what's the real risk that this is maybe in somebody's germline? Maybe even pulling in family history or something like that, so... It'd be a great project.
0:23:55.9 Diana: So I just dropped in the chat for anybody that wants to play around with it, 'cause we've been messing around with it lately just to see what's in there, but mycancergenome.org, you would be able to put in... It asks for... You can go by disease site or gene, but you could put in breast cancer and see, "Well, how frequently is P10 mutated in the tumor?" to know, "Hey, this actually isn't very common in the tumor at all," or it really is, so I don't know how clinically useful it is, but it might give you just if it's...
0:24:32.6 DS: I think it's like the first part of that, but I think we definitely have a... I think something could be developed that then takes that information and really gets it... Kind of like a likelihood or something. But yeah, there's... Mycancergenome's great. C.portal is kind of similar, if you wanna look at frequencies amongst tumors, a lot of these used TCGA data sets or the published data sets from Memorial Sloan Kettering or something like that.
0:25:00.5 MS: So what would you use then as your cut-offs for this algorithm? Does that just kick the can farther down the road of, "Okay, now what's borderline there?" And which way do you lean?
0:25:10.0 DS: Yeah, no, it's really tough. And allele frequency, by itself, is that what you're getting at?
0:25:15.5 MS: Yeah, or just thinking of... Thinking ahead to your algorithm that's been developed, and then where do we make cut-offs there?
0:25:22.4 DS: Yeah, right. That's a whole 'nother conversation.
[laughter]
0:25:24.8 DS: Honestly, by the time that algorithm ever gets to develop, we'll probably be just testing everyone with cancer anyways for germline mutations. I do think that that's where it's going. I know that Invitae, they're really pushing this hard. They have... In the last probably two years, they've had numerous publications just on testing all comers, rates of germline mutation seen in those individuals with cancer. We'll see what's shown at ASCO. I haven't looked at the abstracts yet, but I think they have at least one podium on this, they have two or three abstracts or something, so I think it's a matter of time. And even right now, if you look at the way the HBOC/NCCN guidelines are written, there's kind of these cut-offs and it's like, well, 5% or above prevalence, yeah, we should be doing germline testing, and between 2.5 and 5, it should be kind of this, "consider germline testing". Below 2.5, don't worry about it. But it's kind of like, even those numbers, where did they come from?
0:26:32.9 MS: Yeah. Exactly.
0:26:32.9 DS: And if somebody has a 4.9% chance...
0:26:36.4 MS: Do we round up, do we round down?
0:26:39.2 DS: Yeah, so I think we... I think there's... The side of history that will probably win out here is most likely... Yeah, we'll probably just be testing everybody ultimately with cancer, just because we know that there's mutations that we're gonna find in those populations. It could potentially be beneficial for their treatments also, obviously family members and things like that, and... Yeah, is it 1 in 20 where we should put that or 1 in 30... I don't know. As costs have come down and everything for all these type of tests, I think it will just become more accessible.
0:27:13.7 MS: Yeah, that reminds me, there is a study going on through Intermountain right now, we're calling it the All Cancer Study, where they're trying to do that. They're just doing a 105 gene germline panel on anyone with a solid tumor, regardless of indication, and looking at what are the incidences of pathogenic findings and would they have gotten to clinical care based on family history, personal history? So we're about a little over 100 patients in on that one, so it'll be exciting to see what the results are from that study.
0:27:43.9 DS: Yeah. Oh, I'll show this... Let me show this real quick. Because if people haven't seen... Sorry. I'm taking forever over here. Can people see this article? Does it look normal or is it strange?
0:28:02.8 MS: A little skinny.
0:28:04.0 Diana: And it's showing the Myriad Oncology Live website.
0:28:09.0 DS: Okay, yeah. Let me... Monitor issues. Let me reshare. There, this will be better. Yeah, and this is a paper that friends from Invitae also put out, Steve Lincoln. Many people probably know some of these authors, and it was looking at... So this was data, if people wrote on the TRF that somebody had a tumor mutation, what's the chance it was in the germline? So for those that haven't seen this paper, it's actually pretty interesting because it kind of shows you that again, it's getting that... That whole concept that [0:28:45.6] ____ a priority risk and everything to some extent, where if somebody came back and the tumor with an exon 2 variant, which was very rare, of those two, they were both in the germline essentially, is what this is saying, and that what you were getting at, if you go down a TP53, unlikely... If somebody wrote on the TRF, like this was a something tumor with a TP53, whatever mutation, and then the germline testing was done, yes, very unlikely that it was gonna come back positive. Same thing with APC.
0:29:20.4 DS: So you see really common genes and not surprising, P10 would be on this list, I don't even have to see this to guess which ones, like you were saying, would probably be unlikely culprits in the germline. But you see some here, like ATM, almost 50%. So that kinda gets to that high background rate of ATM germline mutations, look at CHEK2... Probably most of those are 1100delC. There's some of the founder mutations, S428F or I157T. Here's the MITF, probably the E308K. So yeah, MITF is not gonna be a standard somatic type driver mutation, so when you probably do see that founder variant, it's most likely germline. So yeah, interesting article. It kinda came up on one of the old Myriad Oncology Lives, where we're talking about Kirsten Timms, who's one of our laboratory scientists, and I've always personally wondered to myself, "If a founder mutation is ever seen in the tumor, can you, at that point, really just assume that it's germline?" and she actually said that they have documented a 185delAG BRCA1 mutation, that was not in the germline, so it was just in the tumor, which was really interesting...
0:30:45.8 MS: Interesting.
0:30:46.6 DS: On our tumor side. It's kind of an aside, but... So you always have to be suspect. I distinctly remember at City of Hope, sitting in front of someone that had a thyroid cancer, that had somatic testing and showed a CHEK2 variant, and I was just... And it was 1100delC and they were asking, "What's the chances it's germline?" I was just like, "99.9%." It's obviously pretty likely at that point. And it can be tricky because the allele frequencies themselves, they can be helpful if something is in the tumor at a really high allele frequency, that's definitely helpful. Sometimes it's germline, but because tumors can be so unstable and have aneuploidy and loss of heterozygosity and everything, you can only kinda hang your hat so much on the variant allele fraction. It's like a good guide, but... Yeah, you have to take it with a grain of salt. So yeah, no, interesting paper, if anyone ever wants to really look through this.
0:31:47.1 DS: Some of the cases, they really missed by tumor testing, so, these were germline mutations that weren't on tumor testing, most of the time, it was because the gene wasn't either on the tumor test which is kinda gets at this whole concept, a lot of people are like, "Eh, I am not gonna do germline testing 'cause this patient already had tumor testing." Well, it's like, what's the gene you even care... Were all the lynch genes even on the tumor test you just did? Or whatever spectrum of a syndrome that you wanted to look at.
0:32:19.8 DS: I can tell you, from past research with Guardant, I don't know if things have changed on Guardant360 but at the time, I mean, only MSH2 Exon 12 was part of the Guardant assay. So if you were seeing somebody with colon cancer that was young or something, and you thought that that was a good test to get at... Whether that person maybe had a germline mutation of Lynch syndrome, it certainly wasn't because the other lynch genes weren't even being evaluated, so... Yeah, you really need to kinda know what assay you're testing, but I think there's no way to know everything about all these assays... Nobody... Few people are molecular geneticists, so I always just say, "If your interest is germline, just get a germline test. If your interest is tumor, just get a tumor test." I do think that there... It gets really confusing if you try to make one out of the other.
0:33:09.9 MS: Well, the intent of the two of them is different too and they have different interpretation criteria and rationale, and so something may show up on a somatic test that doesn't get reported on a germline test because of those differences.
0:33:24.4 DS: Right. And that's kind of captured here that they had 11 that had variant interpretation differences, so... Yeah, you will see that. Germline labs have expertise in germline classification, tumor labs have their expertise. There are actually completely different ways to evaluate variants and I have that kind of... Does this work? What screen are you seeing now?
[overlapping conversation]
0:33:51.9 Diana: There's something, Lincoln paper...
0:33:53.7 DS: Oh, you're still seeing... Let me stop share this, 'cause this was the other thing I wanted to show today, but I...
0:34:00.4 Diana: I was gonna say, this might be a good time. I don't know if she's got her mute button ready, but Anisa from Intermountain is also with us...
0:34:07.6 DS: Thank you for coming on. I'll show this in a second... Yeah, Anisa, do you want to tell people what you do at Intermountain? Thank you for coming on. Oh.
0:34:20.0 Anisa: Wow, yeah, sorry, I wasn't expecting.
0:34:22.1 DS: Put you on the spot.
0:34:23.2 Anisa: To be called up... Yeah, I work at Intermountain and I'm a variant scientist that... I have been with Intermountain on the variant scientist team for about a year and a half now, and I work with the a team, we classify variants and write interpretations according to, I guess that figure you had up and yeah, I mean, I don't work in the germline space, so I can tell you that it is very different, but I don't work in germline. I mostly classify somatic variants and we usually pay attention to whether or not they're actionable more than if it has a predisposition to a cancer, and usually we recommend on or off-label therapies, based on the tumor type for variants.
0:35:20.0 DS: Yeah. Well, thank you for coming on, and that brings up a thought I had earlier. I think the field of genetic counseling right now is trying to figure out its footing in the tumor world, so the training... Last time I checked, it was still on the hereditary side, I assume tumor now is more in the training, but people can correct me if I am wrong. But yeah, the world now is getting very different, and how do you see, at Intermountain, the genetic counseling team fit into the tumor space? It sounds like, Anisa, you're in the lab pretty heavily and now, or you have some overlap there too, but are people doing some of the counseling on the tumor side or ordering the tumor testing, or is it still being largely from the healthcare provider? Or [0:36:10.9] ____ MDDA, I should say APP.
0:36:11.4 MS: I would say, most of the time, it's an oncology provider, a non-genetic counselor, is how I should say it, that's ordering the tumor testing and the genetic counselors are mostly sticking to the germline, but we've definitely been trying to cross-collaborate to, again, educate each side of when should a patient be referred for germline testing because of a tumor result and how do we teach our genetic counseling team to counsel based on tumor results, and that's where the partnership with having them being able to talk to Anisa and say, "Tell me more about this variant, what is this?" Is just an awesome resource.
0:36:53.4 DS: Yeah, absolutely.
0:36:55.4 Diana: Have you guys changed any of your initial counseling or informed consent to be more clear about germline versus tumor? If you know these... Certain patients, like a colon or an ovarian is definitely gonna get a tumor, do you spend a couple of minutes differentiating the testing?
0:37:19.2 MS: You know, that's a good question. I don't think anyone directly from our oncology team is here. I think they're currently being done independently, maybe a little bit more siloed of, this is, I am the oncologist, I am doing direct treatment, whereas I am the genetic counselor and I am more interested in the germline. So I think that's really an interesting point, Diana, and something that I will ask our team, and how often do the two tests happen simultaneously, and do the patients come, saying, "Well I already had genetic testing on my tumor." I am sure that happens and that at that point, they're gonna explain somatic versus germline and certainly they're able to differentiate between the two and explain that to a patient, but I am not sure if, as a kind of standard, if they're discussing the two.
0:38:10.3 DS: Yeah.
0:38:10.4 Diana: Yeah, it fits our skill set well, so.
0:38:11.8 MS: Yes.
0:38:15.1 DS: I'm gonna show that... The thing I was showing that Anisa also mentioned. So, for those of you who do not know, just from an education standpoint, somatic testings or tumor testing variant classification is very different than a CMG. There's some overlap and nuances and things, but the actual tiers are very different than themselves. Tier 1 is really that there's an FDA-approved therapy of some type, or really well powered studies, so you see right there, it's coming at it from a therapeutic angle, and not from a syndromic or matching with hereditary family history or anything like that. There's no Chompret criteria here or anything, so it's a different way to look at this world. And then it really kinda downgrades quickly to the point where, there might be some with potential clinical significance and you would call those 2C or 2D, and then that's kind of it. Then it kinda gets into just VUSs and benign variants, that really don't have any known targetable actionability.
0:39:23.6 DS: So, yeah, very different and it's been... I've seen that interesting journey throughout my career already, with tumor and germline classification. And I remember when tumor sequencing first started getting really popular, like in the beginning of the 2000s, there was this weird concept kind of floating around, that I'm glad that it really is kind of been going away, that... If you have a mutation, the tumor, that you really do need to treat it totally separate from a mutation in the germline. You could classify something as pathogenic in the tumor, but that doesn't mean it's pathogenic in the germline, even if you saw that same exact variant. It was almost like the two worlds were just completely split and people are looking at... Particularly around like TP53 and things. It was just... Well, this is a TP53 driver in the tumor, but even if this was in the person's germline, we would just call it a VUS, even if it's the same base and amino acid position and everything. So I think that's really merged together more and you're seeing some reporting guidelines now from like ClinGen, and things starting to merge, if it's been seen as a hotspot in tumors, that yeah, it should be considered as, even in the germline for variant classification and things like that.
0:40:43.7 DS: So, I am glad to see that there's more continuity now between the two, but it's still a very confusing world, and a lot of this doesn't take into account all the low penetrant variants that are floating around out there and how those work into whether they're associated with germline risk or tumor risk, so, we have a lot to learn here, as this world really intersects. And they really have been separate worlds. Really, until the past few years, we've been... People have been largely getting tumor sequence, people have largely been getting germline sequencing; tumor sequencing now is really revving up, but even today, there's not many labs offering like a well-synced tumor and germline offering or anything like that. So, there's still... The worlds are still fairly separated. And I think there's a lot of room to grow. You brought up pharmacogenomics before, Mallory, it's like, yeah, we're talking about hereditary cancer, but if you're treating somebody with chemotherapeutics and things that... Why not bring some germline pharmacogenomics into that? I think there's a lot of opportunity, where we can really start using the germline to inform treatment much better than we're doing right now.
0:41:54.3 MS: Absolutely. There's so much opportunity. It's almost like, where to begin? It's all the options.
0:42:04.3 DS: [0:42:04.3] ____ to do. Yeah, so Diana, I don't know if you have any questions on the chat.
0:42:08.8 Diana: I did have one a minute ago that... When you were talking about the mutations, so would you expect a germline mutation to always show up in the tumor and I guess, be a driver of that cancer, or have you seen instances where it's not?
0:42:29.3 DS: I can defer to our guest here, if she wants to take a stab at it.
0:42:34.0 MS: Yeah, and I will not claim to be a variant scientist by any means, but from my understanding is that no, a germline mutation doesn't always show up in the tumor, and that can be for several different reasons. Well, sometimes it could just not be in the report 'cause maybe it is pathogenic in the germline, but maybe there's no associated therapy with it, and so, it's something that gets classified as just benign or a VUS in the tumor because it's not gonna drive any therapeutics, and so you could "miss it," but again, that goes back to that idea that, the testing is kind of for different reasons, so you can't use... One can inform the other, but it's not the best way to go about testing if you have clinical concerns. There can be different filtration metrics that might filter out a germline variant for various platforms. The percentage of tumor that's in the sample that's being sequenced can also have an impact. So, there's many reasons that a germline variant might not show up in a tumor sample report.
0:43:41.9 DS: Yeah, a big one is, in my mind is, copy number variation or rearrangement... Yeah and we'd even get into that, but tumor testing, it's not set up to look at copy number variation, if people know about... A good example, even an inversion like MSH2 inversions, like the Boland inversion, for Lynch syndrome, these are things that just wouldn't get picked up on tumor testing, the test isn't designed for that. It might be able to do it, but you have to be... It really takes a lot to be able to do next generation sequencing, copy number variation, where you're not using techniques like MLPA and things like that. So that's always a big one for me. Also reclassification, that's one that I think slips people's mind a lot and look at many variants we've...
0:44:34.6 DS: Our lab's done tons of reclassification. There was a [0:44:39.1] ____ article last year, I mean I had a JNCI article in 2018 that looked at kind of all the major labs of reclassification rates, and it's pretty... Getting pretty common. About 1 in 5 germline VUSs are becoming reclassified over time. So I think as we learn more and more about VUSs in particular, you're gonna see more reclassification. Tumor testing, that's just really not part of it, I mean it's kind of a one and done. You test, you figure out if you can do a treatment, and then if anything, in the future, you don't really necessarily care as much about a reclassification as you do, has the tumor changed, if it comes back, and then it might bring up re-biopsying or liquid biopsy, or something like that, to now reassess the tumor, and again, that's another point in time evaluation.
0:45:31.5 MS: Yeah, it's an interesting difference between the somatic and the germline, 'cause you know the germline is the germline and it's not gonna change, and so we have... We now have that data and it's good. We know that variant is there, and we just have to wait for the information to catch up, but the tumor can change, and so it is very much a point in time and just a nuance.
0:45:49.2 DS: Mm-hmm, mm-hmm, yeah, yeah. It's good. Any other questions from our audience? Anything on people's minds? Ask anything you want, you're seeing challenging cases out there.
0:46:05.1 Diana: That's what I was gonna ask to Mallory or Anisa, if they've had any interesting cases lately that have popped up that you thought, "Oh, good thing that genetics was involved or we've found this therapy for somebody," purely because of the collaboration between everyone.
0:46:26.5 DS: Yeah, as an integrated unit.
0:46:28.8 Diana: Yeah, I know that's totally putting you on the spot so... [laughter]
0:46:35.9 MS: I'm trying to think of one. I'm sure there are several... I lose touch a little bit when our clinical GC team takes over, but certainly, we've referred plenty of patients for germline genetic counseling, I don't know if they've received it and had testing, we're hoping. I believe that they're out there tracking that data, and we'd love to have either a GC student or somebody, work with us to publish those findings and share that experience more publicly, what did we find and what were the implications and which patients did we help?
0:47:09.2 DS: Mm-hmm.
0:47:10.1 Diana: There was a good case this week, it was a young woman with breast cancer, so it made sense that she had genetic... She had germline testing way before she had any other tumor testing and was BRCA positive, but unfortunately, she experienced a metastasis, and having that information from your clinical team was great for the medical oncologist, and it became a part of a discussion of putting her on a CDK inhibitor, putting her on a PARP inhibitor, and all the trials around that, so it was neat to see the germline already impacting... It was the information ahead of time, which is really valuable. [chuckle]
0:48:01.3 MS: Yeah. Sometimes I'm like, "Oh, those are my favorites" is when there's already been germline testing, but then that also makes me sad that there's already been concern and that maybe then that this is a recurrence, and so it's a difficult topic as well, but yeah. It's exciting when we can find... Anisa certainly loves the PARP inhibitors, but it's exciting when we can find treatments and find answers, and help take care of these individuals better, and help them experience a fuller life for longer.
0:48:31.8 DS: Yeah.
0:48:33.7 Susana: Mallory, I do have a question. My name is Susana, I'm a genetic counselor with medical support here...
0:48:39.3 MS: Hi.
0:48:40.0 Susana: At Myriad, hi. So my question has to do with implications for tumor testing that are not treatment-related and how we're gonna deal with those. For example, our team talks to patients that have possible somatic TP53 mutations in their blood about the higher chances of developing a hematological cancer down the line. There's no NCCN guidelines for that, what are the efforts from our field to provide some guidance to clinicians on how to manage these patients? And we also made... We're starting a study on TP53 for all mutations found in blood in this gene that were in the mosaic range. We followed these patients over time, and the common consensus in my team was that, a year after these patients were tested, most of them were deceased. That really was very notable from our study. It wasn't completed, but, I guess my question is, when we look at these findings and from the clinical standpoint, we know that they might mean something else, that there's some concerning data there, how do you... Do you bring them up or do you target your conversations around treatment only?
0:50:10.6 MS: That's a really good question. So far, I think we've been pretty focused on treatment only. Certainly, there's been a couple variants pop up that are maybe suspicious for germline for a non-cancer syndrome, which is a little bit related to your question. So certainly we've been trying to advise on those and refer to genetic counseling as well; specifically in the myeloid space, we do have a myeloid malignancies panel that we've been also trying to focus on, identifying patients undergoing that testing who could have a germline mutation and what that could mean for them and for their family and their prognosis. But as far as, specifically with your question, with TP53, we haven't been digging quite that deep at this time.
0:50:57.7 Susana: Got it, thank you.
0:51:00.7 DS: Yeah, we were doing a lot of that at City of Hope, Susana. I believe when people order Mirus right now, if a TP53 variant's found, there's an insert for that study, which is the LiFT UP study that's with Dana-Farber and was with City of Hope and Baylor. It sounds like you were talking about something else maybe with Brad Coffey?
0:51:25.4 Susana: Yes, with Brad and Debbie. The study, it was really difficult, so it actually was not completed, but you're right about the LiFT study. I've seen those inserts, but yes, it was a study that was started by the lab directors with the...
0:51:43.1 DS: Yeah, yeah, yeah. And I had that paper a few years ago when I was still at City of Hope with Debbie and Brad, and then... That was the follow-up to Brad's paper, looking at common variants that were likely clonal hematopoiesis on Mirus. So it's ATM, CHEK2 and TP53 were the common ones that we see on the germline side and yeah, it spun out a ton of research, and one of those was that TP53 study. And so that's a good study, so people have... It's R01 funded from the NIH NCI. I was a co-investigator, not anymore, since my new job, but that... If you look at L-I-F-T U-P... So LiFT UP study for TP53, yeah, they'll take samples. There's a serial follow-up component of that and outcomes data collection and... Yeah, that's kind of what it's for, is really to sort this whole thing out, as you brought up, Susana, how much is it...
0:52:49.7 DS: What's the phenotype allele for many, in the patients that have germline variants? We were looking for other modifiers, potentially of penetrants, using array data and then following people with clonal hematopoiesis, long-term to try to get a sense of what other variants... 'Cause that might just be the tip of the iceberg, if it comes back on... If you see a TP53 variant come back on a germline panel, you don't know what's going on with the other genes, like DNMT3A and ASXL1, and all these other genes. So we were following them with a panel, actually, that I made at the time. And then looking at serial changes over time and then tracking the people who developed leukemia. So there's so much to do there... And heart disease, jeez, it's a very complex topic and it's very scary for a lot of even well-informed genetic counselors, because people that take care of genetics patients don't tend to think about testing somebody for hypercholesterolemia or atherosclerosis or doing bone marrow biopsies for leukemia rule out. So we need to learn a lot more on how to take care of these patients and... Yeah, but like you said, Susana, it's probably not the best thing to have high variant allele fraction, clonal hematopoietic variants floating around in your blood, but more to follow.
0:54:20.8 Susana: Thank you...
0:54:22.0 MS: We do flag some of these on our TheraMap reports, we have a list, if we suspect that there's clonal hematopoiesis or clonal cytopenias, we do flag these to let the physician know that... We have limited information on the solid tumor side, but it's possible from the variants we see.
0:54:43.2 DS: So you're saying, in the tissue, if you see maybe like a DNMT3A variant or something like that?
0:54:49.7 MS: Yeah, stuff like that. And it's based on the tumor cellularity and the VAF. It's suspicious if it's a low VAF but a high tumor cellularity, then we'll be like, oh, maybe some clonal hematopoiesis going on, cytopenias, and we flag it. We can't say definitively that that's what's going on, but those could be floating around, if it's a high tumor cellularity, low VAF.
0:55:17.4 DS: Great. Well, we're at time. So thank you so much, Mallory, for coming on. Anisa, thank you so much. This was fantastic discussion. I hope people got a lot out of it. Thanks for leading the chat and everything and chiming in, Diana; very helpful and yeah, join us again in two weeks. We'll be getting into Polygenic Risk Scores, it'll be really exciting and yeah, hopefully we have some good guests at that time. But yeah, thank you, Mallory, again for coming on and really diving deep into all the fun things going on at Intermountain in genomics, you guys are world class for sure.
0:55:58.9 MS: Thanks so much for having me and thanks for the last minute assist from Anisa, unexpected assist.
0:56:04.3 DS: Yeah, came in, came in, helped out. Right, thanks everybody. Have a good rest of your night.
0:56:10.5 MS: Thank you.
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