Myriad 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.
0:00:12.8 Dr. Thomas Slavin: Welcome. This episode of Inside the GENOME is a recent recording on Myriad Oncology Live, a webinar hosted by me, Dr. Thomas Slavin, Chief Medical Officer for Myriad Genetics. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetic or its affiliates. To participate in a future recording, please visit Myriad Live for a list of dates, times, and subjects. I look forward to exploring the world of genetics with you all.
0:00:40.7 DS: Hi everyone, welcome to Myriad Oncology Live. I was looking for a break in the music, but it was starting to get more intense. [chuckle] I decided to stop it. Thank you for coming on. This is the first of the new year. I should have counted up how many we did last year, we did a lot, we probably did 30 or 40 of these, and they've been pretty successful. We've been putting them up on our podcast as well. I wanted to bring everyone's attention to a few things, one, just for some housekeeping as always, new year, new web page. So, I've been kicking this around for a while. I wanted to probably drop the Oncology since I've moved up to Chief Medical Officer and now I have some responsibilities over, also the prenatal work that we do at Myriad in women's health, and I'm intimately involved in some of the work being done in our pharmacogenomics around gene site, which is a test to look for treatment response to SSRIs, or other antidepressants, ADHD medications, things like that.
0:01:53.2 DS: So, one thing I wanna do in 2022 is hereditary cancer and tumor testing will likely still be the bulk of what we discuss on a weekly basis, but I'd like to sprinkle in some prenatal topics, pharmacokinetic, pharmacodynamics just to keep us all fresh and hear what others are doing in the clinical genetic space since these are major areas of clinical genetics. And with that, again, so I dropped the Oncology Live here, we have a new web page, nothing really amazingly different, it's just a little bit different logos and things, but you will still keep the same flow as we've had in the past. Well, I only have one listed right now in January, this is being really managed by Becky in our marketing department, but we've picked a few other dates, we have some really good ones coming up. We'll be talking about renal cancer, hereditary renal cancer next month. We also have Dr. Richard Boland who will be coming on, I think we're finalizing the date now, but I think it will be either the end of February, like the first week in March. For those that don't know, he's just a legacy expert in Lynch syndrome and a wealth of knowledge, so he's gonna talk about the historical perspectives of Lynch syndrome and how he's seen the field change where he thinks the field's moving.
0:03:31.6 DS: This is our new CEO. So, I haven't actually seen this page a lot, but yes, here. Now, there's the link to the Inside the GENOME Podcast. So, we still have the link at the bottom there. Yeah, it sounds like people are listening to the podcast, the updated numbers are pretty impressive, they've been impressing me. And for those that haven't really looked at our podcast, it's called Inside the GENOME, you can grab it anywhere really. We have been posting all of these, so these are recorded now, just because a lot of people who are in clinic or can't make 'em, wanna listen in on the topics, so they're at least all stored here, just the audio, we don't put your face or anything on there, or any of the video or the PowerPoint slides, so it's just the audio. But they're all there. So anything that says Myriad Live is from this series, and then anything that doesn't say Myriad Live, I know it's not the most straightforward, but if it doesn't say Myriad Live, these are just one-on-one podcast with me and a special guest, so sometimes we'll list the special guest in here, sometimes not.
0:04:47.3 DS: We have like three or four that will probably get posted pretty shortly. We had, yeah, just multiple. We had a really good one on OlympiA recently with Judy Garber, so if you don't know what OlympiA is, we'll go all through that study. So, that's a study looking at PARP inhibitor treatment by germline BRCA1 and 2 status, so that will be a good one coming up soon. Alright. And I wanna also now I kinda switch gears to our topic today. So, talking about testing for cancer treatment, it looks like we have a good audience. We have Shelly Anne as always, who will help run the chat, so if this is your first time, we love conversations, so you can unmute yourself, ask any question you want. If you don't wanna unmute yourself and ask a question, completely fine, you can send a question to Shelly in the chat and we will make sure to triage it and answer it. We also have Lynette Poyser, and then also just making sure, yeah, Lauren is on as well. I don't know if you both wanna introduce yourselves, so if you wanna unmute and tell the audience what you do.
0:06:17.0 Lynette Poyser: Sure, my name is Lynette Poyser. I hope that audio is coming through clearly. I'm one of the medical science liaison in oncology, and my clinical background is, I'm a nurse practitioner, and I was in practice for approximately 18 years in the New Orleans area at Auctioneer Foundation.
0:06:37.4 DS: Thanks, and Lauren?
0:06:38.5 Lauren Sferrazza: My name is Lauren Sferrazza. I'm also a Medical Science Liaison in oncology at Myriad, and prior to being a Medical Science Liaison, I was in clinic for about four or five years, and I specialized in hereditary cancer and PGT-A/PGD and preconception counseling.
0:06:57.9 DS: Yeah. Well, great. Well, thank you both for coming on today. We were talking... They'll be here for moral support, but also for helping with some questions and keeping me honest. I was gonna just start and unless anyone has any burning questions, and again, feel free to ask whatever you want. The topic today is really testing to treat, but hey, if you got a question about a pharmacogenomics, feel for you to shoot it up off. I will try to see if we can answer it. But yeah, I was gonna just start with some general background, so let me share my screen. Where is that? Alright. We've been flip-flopping between different web platforms with Teams and everything else, okay. So hopefully, people can see that. Can people see that? I'm gonna try switch it.
0:07:56.3 LP: Yeah, we can see it.
0:07:58.9 DS: Great. Okay, so it should be in presenter mode now.
0:08:01.5 LP: Yes.
0:08:02.9 DS: Yeah. Great. Okay, so yeah, I was just gonna go through a little bit about historically, at least what's been going on in the BRCA1 and 2 space leading to treatment for testing treatment in the field. And we are excited to be launching very soon a comprehensive genomic assay that I'll talk about at the end, and we can make sure any questions are answered, but it's pretty exciting. But I wanted to bring everyone... Just went way back. Let me... Yeah, because I restarted. So don't worry about all the risk score. We're not gonna get into risk score today. [laughter] But yeah, this is what I wanted to talk about; Testing to treat. And I just saw some of the work that we did with friends of cancer research, which is a national initiative right now to try to better clarify homologous recombination deficiency. That paper just was published today, I think, or yesterday, and so it's in the oncologist journal. So it's e-pub right now. It's a good reference, but I will talk about... Some of this was flavored by some of the work we did with The Friends of Cancer research, and really the purpose of that is just to define ways we can have common nomenclature specifically around homologous recombination deficiency.
0:09:39.5 DS: We had Kirsten Timms, who's one of our scientists here. Was a big part of that project, as well as Diana Turco, who was a Medical Science Liaison at Myriad, that probably a lot of you know. And I thought it was good working with them in the sense that it helped frame up, at least in my own brain, causes and consequences of homologous recombination deficiency as we think about specifically use of PARP inhibitors. And we'll go way beyond PARP in today's webinar. But I wanted to start here just to frame some things, and a lot of people on this call are very familiar intimately with BRCA1 and 2. These are genes involved, they're kind of like the master genes of DNA double-strand break repair. There's also a whole another mechanism of single-strand break repair. You see mismatch repair here for Lynch syndrome, Nucleotide excision repair, base excision repair is another big one. So, essentially what this figure is trying to get at is if there's a problem with double-strand break repair the cell then really does a tumor or whatever is really then gonna rely on these pathways. And PARP inhibitors come in in this arena and try to knock out partial base excision repair.
0:11:04.8 DS: And yeah, I made this slide really from Jeff Weitzel when I was at City of Hope, used this analogy, and I really liked it that if you think of homologous recombination deficiency, so if you have a BRCA1 and 2 mutation, it's like you already have one leg of a table missing, and so the table can still stand, and if you use something that can knock out then another leg, the cell just ends up in cell death. So that's really the goal of PARP inhibitors. They take advantage that the cell is already pretty disorganized, already having problems with double-strand break repair, so it's really relying heavily on another leg. You can use a chemotherapeutic at that point come in, knock the other leg out and the cell really dies. And it's been incredibly successful. Sorry, I'm just changing my heater situation. I'm freezing up here. Hopefully everybody is staying warm. But this was the New England Journal of Medicine SOLO1 trial looking at... If you take women with BRCA1 or 2 mutations in their germline, follow them and then treat them with either Olaparib or placebo. Olaparib is a PARP inhibitor by AstraZeneca, and it was the one used in this study, that they get much better disease, overall less disease, better survival, better progression-free survival. You name it.
0:12:44.5 DS: So this is some of the results is really why ovarian cancer, it was really this study that really changed the course of PARP inhibitors or this and another study, I should say, but I think I have some of the other first-line studies in here as well, but this was pretty amazing looking at first-line maintenance. And then we have some similar trials in breast cancer. This one's called EMBRACA. I Just heard a little noise. Hopefully, I'm still... Can people still hear me?
0:13:21.9 LP: Yes.
0:13:23.3 DS: Okay, great. Okay, I just heard a noise like I fell off the call or something. The EMBRACA trial, similar things in breast cancer, this was locally advanced or metastatic breast cancer. But you'll see similar survival curve separation when patients who survived without progression just looking much better when they're treated with a PARP inhibitor than just standard therapy in this case. I mentioned the OlympiA a little bit ago. So there's OlympiA and OlympiAD, makes it very confusing, but OlympiAD was in advanced breast cancer. OlympiA is in earlier stage of breast cancer. So these are germline BRCA1 and 2 mutation carriers. And you see nice separation. Big numbers in this trial, over 1000 patients. But yeah, you see at least in first-line maintenance situation, if you have a germline BRCA1 and 2 mutation much better overall outcomes. So pretty exciting led to recent changes in the ASCO as well as the NCCN guidelines. I won't belabor this, but Myriad was really behind a lot of the testing for these studies that has led to a lot of companion diagnostic labels. So if you ever see that, a lot of people are familiar with MyRisk. Also, some are familiar with BRACAnalysis CDx. BRACAnalysis CDx is really the FDA-approved BRCA1 and 2 tests that was in these trials and has an actual labels for those indications.
0:15:00.3 DS: But, thinking more about homologous recombination deficiency there's much more to explore. BRCA1 and 2 are not all the causes of homologous recombination deficiency. There's a lot of other things. As many people on this call, know, PALB2 has been pretty strongly implicated in homologous recombination deficiency. Partner and Localizer of BRCA2 is the other name of PALB2. Lives in the same pathway. ATM, CHEK2 even, the RAD51, CD genes. A lot of these are involved in some fashion in that double-strand break repair pathway. You can have promoter methylation of some of these genes, particularly BRCA1, and then a bunch of unidentified causes of who knows what. Here's the pathway, here briefly showing a lot of these genes playing together. We've looked at ovarian cancer really the cause of homologous recombination deficiency when a cell looks like it's unable to... Has a defect in homologous recombination deficiency, definitely BRCA1 and 2 jump out in front. That's usually the cause, but not always, and that's what this little pie chart shows here.
0:16:17.1 DS: These other genes do cause some forms, but really, this little light gray piece is really unknown. So who knows what? There's a signature in the cell that it looks like it can't perform homologous recombination deficiency, for whatever reason, and we don't have an actual understanding why. Many years ago, before I came to Myriad, there was a test developed called myChoice, which looks at the signature of homologous recombination deficiency using these three different measures. So these are all ways to look at genomic instability, essentially, and together, we called it Genomic Instability Score. So, if you're missing telomeres, or the ratio is off or you have big chunks of your... These are chromosomes here pictured, but big chunks missing or there, loss of heterozygosity, it is really looking at single alleles, whether they're missing, and you can really see if a cell is unstable, versus highly unstable, or normal, really, when it comes down to trying to figure out if it looks like something, like a tumor, essentially, it has a BRCA1 or 2 defect.
0:17:33.9 DS: And we have since come up with a score to help understand if a tumor looks like a BRCA1 or 2 mutated tumor, and this is some work from ovarian cancer, but there's actually a pretty nice score of separation when we use our genomic instability score, so these are scores between 40 and 45, 50 and 55. It's written a little strange, but these are bins of scores. And yeah, when you go down pretty low, like below 30 in particular, you really don't see a lot of cells. When the score is really low, almost none of these cells have BRCA1 or 2 mutations. So when you look higher, you'll see a lot of cells that have BRCA1 or 2 mutations. And if you don't see a BRCA1 or 2 mutation, and the cell still looks very disorganized, it just means that there's some other factor causing homologous recombination deficiency. So that kind of comes back full circle to this concept of the cause or the consequence. So we think about causes of homologous recombination deficiency as really being like, you can identify the actual gene problem double hit. Germline mutation plus a second hit and BRCA1 for instance. So that would be the cause of homologous recombination deficiency.
0:18:53.0 DS: And the consequence is really just on the back end, you can really look at just the phenotype of the tumor. Somewhat similar to how we use microsatellite instability testing in Lynch syndrome. And myChoice as a test, the reason it's really a valued test is, not only do we have a bunch of FDA-approved label indications for it, but it does measure very accurately BRCA1 and 2 tumor status. Really is tiled well for large rearrangements outside of anything else on the market. And then also brings in the genomic instability testing. One of the assays that led to an indication, or one of the studies, I should say, that led to an indication was at Paola, and this was people receiving either bevacizumab plus olaparib versus bevacizumab plus placebo, and it was looking at first-line maintenance in ovarian cancer, and these are pretty impressive results. The tumor, so now this is tumor BRCA1 and 2 mutations, not germline; however, many of these people have germline mutations, but these are now specifically looking at the tumor because germline mutation carriers in ovarian cancer 15%-ish, but about 30% will actually have a BRCA1 or 2 mutations in the tumor itself, so it kind of doubles essentially.
0:20:26.6 DS: Patients with tumor BRCA1 and 2 mutations, those treated with a PARP inhibitor, again, this was with olaparib, so AstraZeneca. Those treated with a PARP inhibitor, much improved disease progression and death. And then here's the placebo, so if you just use bevacizumab alone, which is a lot of times it was kind of considered like a standard of care at the time, and then here's now this is pretty interesting because these are people that have genomic instability on our test that at the same time, they do not have a BRCA1 or 2 mutation, so these are BRCA1 and 2 wild type individuals that have a tumor that looks like it has a homologous recombination deficiency similar to somebody that has a BRCA1 or 2 mutation, you still see a really nice separation. And in the negative group though, if they don't look like they have a homologous recombination deficiencies, so they don't have a BRCA1 or 2 mutation, and they don't have significant genomic instability, those people really are really get added benefit from the PARP inhibitor at that point.
0:21:36.2 DS: I kinda went through this a little bit, that about what we see overall is about 50% of patients with ovarian cancer have some form of homologous recombination deficiency, and a good chunk of that is BRCA1 or 2 mutation; however, a lot is just due to some other cause and many are just unknown. I won't really belabor that, but that is myChoice is also an FDA-approved test and has labels with Lynparza and Zejula, niraparib. Thinking about some cancers of note, we really have been speaking mostly about ovarian. I pulled in EMBRACA and OlympiA that have really been changing the field, it's why now really anybody with... It's kind of confusing guidelines, but high-risk breast cancer was used in the OlympiA trial, it's anyone with high risk. OlympiAD was again very high risk, so mostly, actually, I think all metastatic for OlympiA, but OlympiAD being the high-risk group. And so breast cancer, we're starting to see a lot of movement now, at least in the germline BRCA1 and 2 setting, and thinking about PARP inhibitors, so it's really the reason why there's more of a push now for understanding some of these BRCA1 and 2 status at the time of really treatment because you're now a lot of times giving a chemotherapy.
0:23:12.9 DS: If they are a BRCA1 or 2 carrier, really do need to consider one year of PARP inhibitor therapy per the recent NCCN and ASCO guideline updates. And then ovarian it's, I would say, well, well established for PARP inhibitor treatment. PARP inhibitors have really completely changed the game in ovarian cancer, particularly stage III, stage IV, where the outlook; which is most of ovarian cancer where the outlook has just been very grim. As I showed, 50% of people will have a tumor that looks like homologous recombination deficiency, so that's a lot, that's half the ovarian cancer cases out there, and those people are fairly responsive to PARP inhibitors, which is great; a lot of other things we can always talk and unpack there. Pancreatic and prostate are two other areas. There was a Profound study; Polo One, Polo One was a germline study, Profound was a tumor study and germline, BRCA1 and 2, but both of these cancers, there's a lot going on in the PARP inhibitor space.
0:24:21.9 DS: And then just to take a step back, a lot of these cancers in general, it's no surprise if you take a step back and say, well, what are the BRCA1 and 2 germline susceptibility cancers? You're pretty much looking at it, so there's no surprise that these are the best targeted cancers for this type of PARP inhibitor treatment. Let me pause there for a second and see if we have some questions, or Lauren and Lynette, if there's anything you wanna add to this? Thanks for posting the Oncologist, Shelly.
0:25:00.7 LP: One of the things that I would add is that at the recent San Antonio breast conference, there was a lot of discussion around OlympiA, with several different presenters really emphasizing the importance of knowing the patient's germline status early on at time of diagnosis because of the availability of this new trial, and so I think we're gonna see a continued broadening of guidelines in the germline space, especially for our breast cancer patients before that trial.
0:25:29.6 DS: Yeah, good point. I would assume that we're really headed towards anybody going on chemotherapy, because if you're considered high risk enough breast cancer to go on chemotherapy, it seems like a natural place to consider PARP inhibitor, like a maintenance kind of therapy after your chemotherapy if you have a germline BRCA1 or 2 mutation, or arguably, I think over time, a tumor BRCA1 or 2 mutation. I did ask that to Judy Garber when we had the podcast, which will be uploaded hopefully soon, and she said that they went for more of a high risk group just because they wanted to make sure that there was good signal differentiation, because if they brought in more low-risk cancer patients, they got chemotherapy and we're a little on the low-risk side, these curves would be closer together, and it increases the chance that there'd be no significant difference between those treated with a PARP inhibitor, like Olaparib and the placebo, so again, these trials tend to be step-wise, so it kinda sets the stage for the next trial to maybe go down a little deeper. Maybe one day everybody would with chemotherapy from breast cancer. It's a good point.
0:26:51.5 LP: TJ, can you expand on what percent of ovarian cancers have somatic BRCA1 and 2 mutations and the same for breast cancer?
0:27:03.4 DS: Yeah. So this is... Sorry, that's ovarian?
0:27:09.2 LP: Both, for ovarian and then also what percent of breast have somatic B1, B2?
0:27:15.4 DS: Yeah, it's a good question. So this is pretty much ovarian. Yeah. And we don't really have the exact percentages listed here, but I always think in my brain, somewhere around 25%, 30% will have a BRCA1 or 2 mutation, another 20% or so, 25%, I know it's a little bit bigger wedge here, but there's different studies on this, we'll have genomic instability for some other cause, and again, that could be like anything, PALB2 mutation, it could be methylation of one of the genes, like BRCA1, it could be just something we don't know, cause the homologous recombination deficiency. Breast cancer, so breast cancer germline rates, and you know, germline rates for ovarian cancer for BRCA1 and 2 seem like they have around 15%. For breast cancer, much lower. All-comers breast cancer was like two and a half or something a little lower to a little over two probably. So much lower overall. And I don't know off the top of my head, I feel like I knew this at one point in time, I don't wanna mis-quote something, I don't know if anyone on our call knows the percentage of BRCA1 and 2 mutations in breast cancer. I think it's much lower than ovarian cancer, though. I don't know if there's anyone on...
0:28:46.8 DS: What I will say is, we had a, and I'm trying to remember the results off the top of my head, but we had at San Antonio Breast Cancer, we showed some data on triple-negative breast cancer. Yeah, I'm trying to remember exactly.
0:29:06.1 LP: I thought the somatic for B1, B2 is about 1-2% in triple-negative breast cancer, and about 4-6 or more in ovarian cancer, but that's some of the earlier stuff before all of this, HRD, animal parser, all of this work was done. So the number in ovarian is much higher than it was, but I don't think that the triple-negative number in breast has changed much.
0:29:31.4 DS: You're saying for germline or tumor?
0:29:34.1 LP: Somatic. Yeah, tumor.
0:29:35.7 DS: Somatic. Well, I mean, that also takes into account people... In my mind, at least when I'm putting these numbers, I'm taking into account on the tumor side that these are people too with germline mutations. So, yeah, the germline mutation rate in triple-negatives seems like it's in the 5-8% range for all-comers for breast cancer, and yeah, I could probably pull up that abstract, actually, while we're talking, and that way I'm not mis-quoting something. Let me stop sharing here. I can find that abstract really quick, 'cause that was good from San Antonio, 'cause what we looked at was the genomic instability in breast cancer, so we'll get to this question. Exactly. So what other questions are out there, like dig this up?
0:30:28.1 LP: We don't have anything in the chat right now.
0:30:31.3 LS: I don't have a question TJ, but I think it's interesting you put up the different cancers associated with BRCA1 and 2 pancreatic, prostate, ovarian, and when I was back in clinic, we weren't talking about targeted therapeutics, specifically pancreatic cancer, polo is brand new, so I think it's exciting now to see genetic counseling and genetic testing kind of taking a shift into this treatment that the germline testing results are gonna be very useful for these patients to have targeted therapeutics. And for many years, you have a patient with pancreatic cancer or some of these other cancers that are pretty tough and doing testing and saying, "I'm sorry, we don't really have too much to provide," and now being able to provide that level of information and giving them additional support for treatment, I think is exciting, and I see it expanding, obviously, into some other cancer types as well.
0:31:27.0 DS: Yeah. Yeah, and it's interesting to see kind of even the history that was paved here of really starting these FDA treatment labels in germline, and you see OlympiA. I mean, you're gonna see a lot of this push over time into the tumor space itself. I did find that abstract, so let me share that here, 'cause it's pretty illuminating for the question that was asked. So this was looking at HRD in breast cancer and really looking at triple-negative breast cancer and then ER-positive breast cancer, and you can see the genomic instability scores, kind of the main things are... Yeah, there's definitely genomic instability in a large chunk of breast cancer, you see triple-negative breast cancer looks truthfully, very similar to how ovarian cancer looks, which is kind of no surprise if you think about susceptibility of BRCA1, germline mutation carriers to both ovarian cancer and triple-negative breast cancer, ER-positive also had just some genomic instability.
0:32:36.9 DS: And then the numbers that I didn't wanna misquote are somewhere up here. So where are they? 'Cause it was actually a large chunk of the tumors, so, yeah, here using a threshold, so some of this work is to refine our genomic instability thresholds too but using a threshold that looks like it captures almost all the BRCA1 and 2 mutation carriers for ER-positive breast cancer, which is a good signal that you're getting your homologous recombination threshold correct, about 45% of ER-positive breast cancers fell into that space, that's a ton, and then when you look at triple-negative breast cancer, the score mimics more what we see in ovarian cancer for the homologous recombination deficiency, and we saw 64%. So a very good chunk, more than half of triple-negative breast cancer show genomic instability, so it doesn't get at the exact question of how many had a BRCA1 and 2 mutation, 'cause I don't think we put that data in here, but at least from a genomic instability score, it's pretty high.
0:33:53.4 LP: Yeah, so that's what I was gonna ask, TJ, so this is a great poster, but it doesn't parse out what part is B1, B2 versus all of the other consequences for genomic instability.
0:34:08.1 DS: Yeah, I don't think we've done that yet in breast cancer, but again, anybody can correct me if I'm wrong, maybe Kirsten, Timms, who I don't think is on, might have some of that data floating around. Good. Go ahead.
0:34:21.5 Dominie: TJ, this is Dominie, I'm in Texas, and I just wanted to just give an update from some of the data that we had from Quadra, which is one of those studies that 19% of women were found to have a tumor BRCA mutation, 13% of those were germline right down on the 19% and 6% were somatic only, and then 29% were found to have that genomic instability. So when we go back to that picture with that 48% overall, that's how it breaks, that's how I have it written as it broke down to 19% and 29%.
0:34:57.7 DS: Yeah, that's still pretty good. The germline rate though there sounds pretty high, but those were big line people.
0:35:05.6 Dominie: One study.
0:35:06.2 DS: Yeah, one study of an academic type setting. Yeah, we'll probably still need a little bit more data in that sense, and we'll be getting it soon enough. Okay, so let me re-share. So I wanna show what we're up to these days.
0:35:24.1 Michelle Wilver: TJ, It's Michelle Wilver, Missoula.
0:35:27.4 DS: Hey, Michelle.
0:35:28.2 MW: Can you go back to that slide that had the prostate on there?
0:35:33.0 DS: Absolutely.
0:35:36.4 MW: I noticed, I thought I saw cell-free DNA. I'm just wondering if you could talk about that a little bit. It was like there was four different... That one. So I'm trying to wrap my head around that, and of course have other companies coming in asking me to be doing cell-free DNA.
0:36:00.8 DS: Yeah, I think this is based on the foundation medicine label for BRCA1 and 2 in the tumor, so it's a circulating tumor, BRCA1 and 2 floating around for the foundation liquid biopsy test. But it's still looking at tumor, it's just circulating tumor.
0:36:22.0 MW: We're looking at tumor, okay. Alright. So there's tests coming out about looking at the tumor and then also doing serial blood draws on patients to see if those numbers are going up, and of course, if they do, you can't really do anything about it 'cause you don't know where it's at, and so I've just been seeing a lot of buzz about that, and then when I saw that, I was just like, What's that all about?
0:36:50.7 DS: Yeah, there's a lot going on in that space, in the liquid space in general, so minimal residual disease detection is gonna be a big area of focus in the future, particularly probably for things like breast cancer where you have now treated someone or even during treatment, you're trying to figure out, Do they still have tumor popping up in their blood, in their plasma, indicating that they're not fully treated? After treatment is there still in the monitoring phase in survivorship, are you seeing their tumor pop back up? We know about 15-20% of breast cancers will just recur even after full treatment, so these are gonna be huge tests, and right now, specifically focusing on breast cancer, there's a real deficiency of biomarkers in this space, there's like CA 15-3 or whatever, it doesn't really work that well, I would argue there's not really any great blood marker, and then following women, it's really mammography, which is only so good, and what if somebody had a bilateral vasectomy or something, these are real deficiencies in how we can follow people long-term.
0:38:12.0 LP: I highly recommend Michelle and others to pull that, the oncologist article that I sent the link to, because it goes over each of the studies by these disease types and talks about the approval, the tumor type, the test that was used, and it's a really great, great article, as a review. And so, that was one comment, question TJ, we've talked a lot about BRCA1 and 2 here, but what is the status of ATM when we think about germline somatic and targeted treatments for other genes beyond ATM.
0:38:51.8 DS: Yeah. So, good segue. [chuckle] This is some of the other things I wanted to talk about really quick. We are working hard to try to help people make sense of this whole world of selecting therapeutics, treating patients with cancer. There's a ton going on, you see from 2018-2021, there's 74 plus now biomarkers and NCCN, we're adding some constantly, we're working towards having a whole solution for all of this, it will be launching very shortly. And we'll have our germline testing, which we just went through the FDA approved BRACAnalysis CDx after they approved myChoice CDx, we'll bring in what we're gonna call Precise tumor to this whole mix, and that is a pan-cancer assay, we'll have MSI, TMB, PD-L1, and this is a beautiful slide, I really like it from Lynette and Lauren. I don't know, Lynette and Lauren, who put this together? This is a really good, good slide.
0:40:04.1 LS: We had a template, we won't take all the credit. [chuckle]
0:40:07.4 DS: Looks great.
0:40:08.5 LS: Thank you.
0:40:12.3 DS: [chuckle] So yeah, we'll have pretty in-depth testing for the 523 DNA genes, it's exon coding, we'll have 56 RNA variants reported, and then the immuno-oncology biomarkers, so MSI, TMB will be on there. But yeah, any gene that you would expect to see is gonna be on there, so you'll also have the Lynch Syndrome genes, you could arguably put in this area as well, and then PD-L1. And with that, we'll be having a whole new portal coming out with seamless ordering, would be very nice, we'll have a clinical trial matching as part of this, we have a research registry that's being built out and is the bane of my existence at the moment, [chuckle] I'm just kidding. But we're putting a lot of work into it, needless to say. And then, a summary sheet will have all three tests, so it'll be really nice. So, I have germline testing, top line, the HRD status, the tumor tests for those people that order two or more of those three. And the registry itself will be really the first registry that combines clinical de-identified patient data with tumor germline HRD results, as long as you're ordering off the test itself from the requisition.
0:41:45.6 DS: You can apply to be part of the research registry, freely available, look at data, do whatever you want with it, we're building out an amazing cohort browser as part of this whole thing, which has been really the bane of the work that I've been doing, as well as Shelly and Lynette in particular. And it's really coming on swimmingly well. So we're gonna launch with data on about 4000 patients that have had paired tumor normal testing. So, most of the time myChoice with either, which is the genomic instability test with their BRCA1 and 2 tumor status, but then also germline, BRCA1 and 2 status, and a lot will have MyRisk results as well. We'll have a bio-bank, as I brought up, we're gonna bring another research. Use opportunities over time, and then we're looking at ways to do electronic outcome capture, it's pretty exciting. There's just so much that I'm personally learning from even the research registry days working with Jeff Weitzel at City of Hope. I just think this will be like that registry kind of on steroids, essentially, so it's pretty exciting.
0:43:02.5 DS: And then, the cohort browser is really gonna be a sight to see, so it's amazing, you're gonna be able to actually look through your tiles of whatever you want, germline status, cancer type, family history of cancer, you'll be able to play around with the data, we have a contact form, people can do registry projects, download data, it's like layers of onion really, it's as deep as you want it to go. And I won't demo that, but I'll end on this, that really we're working hard to kind of be a one-stop shop to getting back to Michelle's point about liquid, we're currently looking at ways to also marry some of this liquid biopsy, we're looking at minimal residual disease testing. So, just wanted to stop there for questions, Shelly, I know you brought up ATM. And ATM is a perfect example of where it's nice to have three things to try to figure out what's going on with an ATM mutation. So, we know ATM mutations are really common in germline, about 0.38% of European individuals have an ATM germline mutation, you could cite Slavin 2017 for that, but as some of you know my KO8 Award from the NIH was in ATM, so I know a lot about it.
0:44:30.5 DS: And so, looking at ATM in particular, it's really not a driver in certain things. So, if you take a person with ovarian cancer, for instance, and you see an ATM mutation come back on a tumor test, you really do need to think like, "Okay, so what does that mean? I see an ATM mutation, their tumor tests are they gonna be a response or potentially they're like... " Treatment like a PARP inhibitor, who knows? But if you have the germline mutation status, you can see it like, "Okay, there's a germline mutation in this patient in ATM, and it's the same one that was found in their tumor." We know that the person's got ovarian cancer. ATM is not really a driver of people... Isn't a pre-disposer to ovarian cancers isn't thought to be a driver of ovarian cancer. It just starts making it more likely that that person just at that point had just a happenstance ATM mutation in their germline when you did their tumor testing and it may not have anything to do with really what's driving their tumor and may not also be amiable to treatment, and to try to figure out if they're amiable to a PARP inhibitor treatment, then we'd have something like myChoice that would come in and really help understand if that person's tumor does look like genomic instability, and it could, it may be a would.
0:45:49.9 DS: I mean, about one out of two will look like there's genomic instability, but if it doesn't, you just save that person treatments potentially with a PARP inhibitor just based on finding a ATM variant in the tumor, and now you know it was in the germline by happenstance, and it doesn't have genomic instability with it. So that's just kind of a general example of how using all three of these together just gives you massive amounts of power and in understanding what's driving somebody's cancer. So I'll stop there for questions as well. Yeah, so it's gonna be exciting times, and I know many people on the call are really intimately involved with getting our training and our teams all up to speed and turning a germline primary company into a tumor company.
0:46:47.7 Susanna: TJ, this is Susanna with the MIL team.
0:46:51.1 DS: Hi, Susanna.
0:46:53.0 Susanna: Happy 2022. I wanted to ask, so we work a lot in the HRD business with other countries like Japan, for example. Is that database gonna be open to them or does it have any limitations as far as...
0:47:18.2 DS: Yeah, great question, great question. So the research registry itself, so we're calling it the Precise Treatment Registry. So it will be U.S cases, and the way we're doing it is for various compliance reasons and things is, it will be people ordering off the new test request form for Precise. So Precise will be that tumor product, but we'll also have the germline, the BRACAnalysis CDx, you can reflex the MyRisk, it'll have myChoice on it, so any patient that's coming in through that pathway, the de-identified data will flow seamlessly into the cohort browser and the Precise portal. The tumor residual DNA RNA will be de-identified and will be stored as well, and so it's just mainly a process flow, but we will have thousands and thousands of cases very quickly. Again, we'll be launching with over 4000, so you could immediately start doing research with it, even with version 1.
0:48:25.9 Susanna: Okay, thank you.
0:48:27.1 DS: Yeah, good question. Yeah, anything you wanna add, Lauren or Lynette?
0:48:43.6 LP: Yeah. I think you bring up a really prime example with that ATM case that you were just referring to, because a lot of times we're left with questions. What does this one particular assay tell us about the tumor and treatment decisions? And oftentimes it's putting all these pieces together that really gives the overall picture of whether or not a patient is truly gonna benefit from a treatment, and equally important in identifying benefits to treatment is avoiding toxicities, both financial and physical, in those patients that we don't think are gonna respond very well. So I think a combination of having all of these assays is really gonna complete the picture for our patients and it's really exciting.
0:49:23.5 DS: Yeah, yeah. It'll be really exciting. And yeah, this will go well beyond getting back to Shelly's other point, ovarian cancer, which we've been pretty focused to the myChoice, so now we'll be really going into tumor testing into these other tumor types as well. And we have tons of other studies going on right now. We're looking at bringing myChoice going beyond ovarian cancer, that's always been a big aspiration, so yeah, hopefully over time, just like the research I showed from San Antonio, a lot of that is Prep work, so we can understand how to use genomic instability and looking at homologous recombination deficiency in other cancers like triple-negative breast cancer for instance.
0:50:12.4 LS: Yeah, I would just echo what Lynette said. And I think from a process standpoint, this is gonna be huge. We always have clinicians that struggle when they're doing germline testing through one place. We're waiting for slides or block from another lab to come back, and then unfortunately, sometimes there's not enough left to do testing that's really crucial for these patients for treatment. So to have a place where you can send everything and get all the answers you need for that patient's treatment is gonna be really just nice, seamless, easy. So I'm really excited about that, making it very simple for the clinicians, making it simple for the patients to really get what they need and get on the treatment path. It's gonna be beneficial.
0:50:58.1 DS: Yeah. So everybody keep their eyes open for this. There'll be launching pretty soon. And yeah, if you're interested in joining the research registry, we'll be looking for people. So it'd be a shame if we put all this work into it, and no one use that. But I think there'll be a lot of interest. We've had an external committee really helping us here. And they're very excited about it. So I think everybody's just pumped to see it released, and start using it and asking really interesting questions.
0:51:27.5 MW: EJ, it's Michelle, again, I just have a comment about access for patients, and especially within large hospital systems. I know that a lot of times, I've been trying to do some work with one of our Providence facilities here. And it all comes down to billing and reimbursement and them getting deals for other tests to use a certain lab for their hereditary cancer testing. And I think that's a barrier to patient care. I have a patient really upset right now because the provider, that healthcare system, even though it's a Providence system, there's all these little intricacies within that there's other Providence systems using this test. But there's a problem with the hospital systems themselves. And I know, you guys know that when your reps go in there and try to get them tucked into something. But the pathology department is saying, we don't have enough people to be sending all these tumor blocks. And we get a deal on our whatever other tests if we send them to this lab. So I don't know if you have a comment on that, because that, I think, is a big barrier for some patients getting opportunities for lab that like this is happening right now with you guys.
0:52:56.5 DS: Yeah, yeah. Our sales team, once this launches they'll be involved in these conversations. But yeah, I've been involved in tons of these conversations with different health systems at this point. And, it is interesting, and some valid different health systems have different desires and not all tests are equal. And we've spoken with many that really just needed some education truthfully, like, "Oh, we didn't know, there are no other FDA-approved label diagnostics in ovarian cancer. And this does make a lot of sense for us to think about, offering myChoice test, for instance." So, yeah, I mean, a lot of it is just education I think like risk score, for instance. If you're taking care of an unaffected woman, and if you wanna know if that person... If you wanna have a genomically informed result, essentially, for breast cancer, Risk work kind of it. From a polygenic risk score standpoint, where you're gonna get BRCA1 and 2 and all the other gg1, to know how to take care of somebody. So that's a pretty differentiated test compared to just BRCA1 and 2 testing and off the shelf or something. So, yeah, I'm just flavoring what you said, Michelle, so I agree with you, and it's only becoming more and more fierce, I would say, because a lot of health systems are recognizing that they're just looking for solutions for their patient population and trying to pick the best one and trying to do the best they can.
0:54:36.5 MW: Yeah, and I know the providers are busy, everyone's busy. And I don't even think... Most of the places here in Missoula won't even see reps. So that makes it hard to get education. I try when I present cases at tumor board, but I'm not necessarily on, I mean, I do see the oncology patients, some of them. But it's hard. I tried, but it's just hard to get in there, 'cause I'm a little private practice all by myself and not a medical oncologist at all. So, yeah, I just wanted to have that conversation 'cause I do think it's part of the barrier of our patients getting care. So this patient that I'm talking about is going to seek care in Spokane to get the test done that she wants to get done.
0:55:27.3 DS: Oh, yeah. Wow. Yeah.
0:55:29.5 MW: We're three hours away and another consult.
0:55:32.8 DS: Yeah, it's a lot.
0:55:33.9 MW: And it's a waste of healthcare dollars, I think.
0:55:35.5 DS: Yeah, yeah. Yeah, there'll be interesting to see how this all keeps playing out. And EMR is another big part component of this. That's a big movement towards a lot of the hospital systems wanting consolidation. They are trying to bring tests into their EMRs. We've been doing tons and tons of EMR integrations, really ramping things up over the last six months in particular. So that's another huge component that the health systems want the structured data ideally in their electronic medical records that could be used for other purposes too. Yeah, well, great. Well, we are at time, I appreciate everyone coming on, really some great discussion. Thank you all and sorry if I spoke too long. [chuckle] A lot to go through and we're really excited about the new launch of our Precise tumor, which will be a whole suite of solutions for taking care of patients. So I appreciate everyone keep your eyes open for that. And if you're interested in joining the registry after it launches, the registry will be coming out a couple of weeks after the original launch and let us know and your reps know, and we can get you plugged in there as well.