Inside the GENOME

Myriad Live - Let's Talk PRS

June 14, 2021 Myriad Oncology Season 1 Episode 19
Inside the GENOME
Myriad Live - Let's Talk PRS
Chapters
Inside the GENOME
Myriad Live - Let's Talk PRS
Jun 14, 2021 Season 1 Episode 19
Myriad Oncology

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.


Many studies were referenced in this episode, please see links below:

Yanes T, et al. Clinical applications of Polygenic breast cancer risk: a critical review and perspective of an emerging field. Breast Cancer Res 22, 21 (2020). https://pubmed.ncbi.nlm.nih.gov/32066492/

 Mars et al study link: https://www.nature.com/articles/s41467-020-19966-5

Rosner et al study: https://cebp.aacrjournals.org/content/cebp/early/2020/12/04/1055-9965.EPI-20-0900.full.pdf

Lakeman et al study: https://www.nature.com/articles/s41436-020-0884-4

Barnes et al study: https://www.nature.com/articles/s41436-020-0862-x

 https://www.nature.com/articles/ng.3841

https://pubmed.ncbi.nlm.nih.gov/25862352/

This is the study where the chart comes from : https://pubmed.ncbi.nlm.nih.gov/32620971/

Here is the abstract from ASCO about ancestrally unbiased breast cancer (BC) risk assessment. Dr. Pederson also presented this material during the meeting. https://meetinglibrary.asco.org/record/197017/abstract

Here is the Tischkowitz paper Dr. Slavin was discussing: https://www.acmg.net/PDFLibrary/41436_2021_1151_OnlinePDF.pdf

Gallagher paper (chart was from this paper) https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767768

 Yanes T, et al. Women's responses and understanding of polygenic breast cancer risk information. Fam Cancer. 2020 Oct;19(4):297-306. https://pubmed.ncbi.nlm.nih.gov/32430685/

https://cancerpreventionresearch.aacrjournals.org/content/early/2020/10/23/1940-6207.CAPR-20-0154?versioned=true

Hughes et al paper where data from chart is derived: https://ascopubs.org/doi/full/10.1200/PO.20.00246

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score https://ascopubs.org/doi/full/10.1200/JCO.20.01992

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer  https://www.nejm.org/doi/full/10.1056/NEJMoa2105215

Show Notes Transcript

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.


Many studies were referenced in this episode, please see links below:

Yanes T, et al. Clinical applications of Polygenic breast cancer risk: a critical review and perspective of an emerging field. Breast Cancer Res 22, 21 (2020). https://pubmed.ncbi.nlm.nih.gov/32066492/

 Mars et al study link: https://www.nature.com/articles/s41467-020-19966-5

Rosner et al study: https://cebp.aacrjournals.org/content/cebp/early/2020/12/04/1055-9965.EPI-20-0900.full.pdf

Lakeman et al study: https://www.nature.com/articles/s41436-020-0884-4

Barnes et al study: https://www.nature.com/articles/s41436-020-0862-x

 https://www.nature.com/articles/ng.3841

https://pubmed.ncbi.nlm.nih.gov/25862352/

This is the study where the chart comes from : https://pubmed.ncbi.nlm.nih.gov/32620971/

Here is the abstract from ASCO about ancestrally unbiased breast cancer (BC) risk assessment. Dr. Pederson also presented this material during the meeting. https://meetinglibrary.asco.org/record/197017/abstract

Here is the Tischkowitz paper Dr. Slavin was discussing: https://www.acmg.net/PDFLibrary/41436_2021_1151_OnlinePDF.pdf

Gallagher paper (chart was from this paper) https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767768

 Yanes T, et al. Women's responses and understanding of polygenic breast cancer risk information. Fam Cancer. 2020 Oct;19(4):297-306. https://pubmed.ncbi.nlm.nih.gov/32430685/

https://cancerpreventionresearch.aacrjournals.org/content/early/2020/10/23/1940-6207.CAPR-20-0154?versioned=true

Hughes et al paper where data from chart is derived: https://ascopubs.org/doi/full/10.1200/PO.20.00246

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score https://ascopubs.org/doi/full/10.1200/JCO.20.01992

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer  https://www.nejm.org/doi/full/10.1056/NEJMoa2105215

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0:00:11.5 Dr. Thomas Slavin: Welcome. This episode of Inside the GENOME is a recent recording at 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.

 

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0:00:38.8 DS: Hello everyone and welcome to Myriad Oncology Live. I hope everyone's having a good day. It's a little earlier in the day, for this is... We've been doing some of them later in the afternoon, especially, for East Coast times. A little housekeeping to start, as always. If this is your first time on Myriad Oncology Live, it's just essentially an open door discussion. We do them theme-based, but they are meant for your education, and just discussion, if anything's on your mind. We try to stick to the theme, but you don't have to, if you have... Today's theme is Polygenic Risk Scores, but hey, you wanna talk about PALB2, that's fine. It's up to you. We have some guests on today, and thanks for joining, Holly.

 

0:01:30.6 DS: So we have Holly Pederson, she just joined from... She's at the Cleveland Clinic. We also, let me see who else is on. We should have Elisha and Jerry. Jerry is our Chief Scientific Officer, and Elisha is our Head of Biostatistics. Or maybe Elisha couldn't join, actually. I see Jerry. So thank you for coming on. And we may have Alexander Gutin, also known as Sasha, pop on as well. So we have a good arsenal of folks to talk about all things Polygenic Risk Score related. And then next week, actually, is gonna be a really good one, if you have time in your schedule. It's gonna be survivorship. We have two cancer survivors coming on. One, who had, unfortunately, pancreatic cancer about 15 years ago. And another, one of the first BRCA1 carriers tested in this country in the '90s.

 

0:02:33.5 DS: So it should be really exciting. We'll have a really lively show. And the schedule is built into July. I'll probably post some new topics and times soon. Other housekeeping, we have... Shelly, I do see that you're on. I don't know if you wanna do any presenting, but let me know. But we have Lauren Giannetti, who is helping with the chat today. And Lauren, I haven't seen that you're on, but... Yeah. Oh yeah, I didn't see that you're on, so...

 

0:03:07.5 Lauren Giannetti: I'm here.

 

0:03:08.2 DS: Yeah. Great. Thank you so much. So if, again, this is your first time... Essentially, we like a lively show. So definitely unmute yourself, ask questions. If you don't want to unmute yourself and ask questions, and something's on your mind, just feel free to put it in the chat, and we'll make sure it's addressed. So you can privately chat to Lauren as a pretty easy way. Also, before I forget, since I constantly do, about five or so shows ago, we did start recording these. We are posting now the audio, and I'll show you what we're doing with it, so everybody's knowing what's going on. But if you go to the Inside The GENOME podcast, which is a podcast that I do, which I think we just put in... Yeah, we just... We have some new ones up. This one is with Annie Parker, so she'll... Annie will actually be on the show next week, so... But if you wanna get a little back story, this is about a 15-minute podcast. So we just posted that one. But then all these MOL podcasts that just got posted, these are from Myriad Oncology Live.

 

0:04:21.2 DS: So we're just literally taking the audio and then just putting it up. But it is editable. If anyone has any concerns, please let me know. This is essentially just to make sure that people... We constantly get requests to, "Hey, I can't make this time." "Is this available?" "Can I listen to it?" I think people ideally would want it in some sort of video format, but that brings up other complexities without getting consent to show faces and things like that. So yeah, hopefully this is a nice resource. And honestly, I was listening to some of these the other day, and this one in particular... I went back to the LGBTQ+ podcast, and I found it incredibly [chuckle] entertaining. I mean, because sometimes when I'm doing these, or when people are actually interacting as hosts and things, or co-hosts, you can't really pay attention as much, and you're trying to organize everything so it comes out smoothly. And when I went back and listened to that, I went, "Oh, that was NPR quality." [chuckle]

 

0:05:26.9 DS: So I really appreciate Lauren in particular. She helped put this one together. And Rob Finch helped immensely there. And that's a great one if anyone wants to go back and listen. But they're all great, they're all fantastic. So let me stop sharing my screen real quick. And so, oh yeah. Okay, so... Yeah. Shelly is, yeah, doing a few other things, but she will listen in. So I did wanna start off the show today just with a little bit of background. And this was a deck that Shelly had put together. She has some expertise in Polygenic Risk Score across different diseases. So let me... Hopefully, this looks alright. No, that's not... Let me reshare, sorry. I lost it. Let me pull this back up because I think it helps frame where the field's at right now, which is nice. Okay, see, this is exactly the reason I can't really listen to these well until after 'cause I'm doing 10 million things. Alright, can everybody see that. Can people see...

 

0:06:46.6 LG: We can see the PowerPoint. But if you wanna put in presenter mode.

 

0:06:51.0 DS: Yes. Great, and I'll switch it. Okay, so here's the presenter mode. I am not Shelly Cummings, but I play her on the show, at least for today. So yeah, Shelly has been... She helped with this article in particular, this Yanes article, and she has a few slides in the back that I'll walk through quickly, but it's a great article just about kind of the state of the union of Polygenic Risk Score. And if you were at ASCO, ACMG, ASHG, you're starting to see just a flood of Polygenic Risk Score data come out. If you look at common journals in our space right now, for at least the GenEpi side... Yeah, the Polygenic Risk Scores are all over the place, across a host of diseases, not just cancer. So this is just a very quick just snapshot and it's more just kind of like, "Boom, these are all the things going on right now." I went back and I was looking at even things just 2019 and above, and it's pretty jaw-dropping these days, even just in our breast cancer space.

 

0:08:16.3 DS: And there are some really good articles to put on people's radars. Some of these are just excellent prospective studies at very large cohorts, a large finished cohort of 122,000 people. This was a great study, MARS, that was in Nature Communication the end of last year. Nurses Health Study here, this was with Graham Colditz, and an excellent study looking at a 77 SNP PRS. This Genetics in Medicine, Dutch prospective cohort, CIMBA just did another one that was Barnes 2020, looking also... I was an author on this one too, looking at BRCA1 and BRCA2 PV modification. Here are some other kind of larger case controls that came out over the last year or two, BCAC, which is a large international consortium for breast cancer, did a very large study. This [0:09:20.6] ____ study is excellent. I really like this one because it compared three different PRSs.

 

0:09:27.6 DS: It really showed that... Interestingly, people think more SNPs are better. Clearly they are, it's kind of the same argument of are more genes better? Sometimes it kinda depends on what the genes are and everything for hereditary cancer testing. But the argument is interesting when you look at it in SNPs, because if you keep adding SNPs, yeah, you just get kind of an incremental benefit at some point. There just seems to be this core set of about 70, even you could argue almost 50. And then after that, it just becomes kind of an incremental benefit, adding up more SNPs on top. These two papers were from our team, this JC... Both were in JCO Precision Oncology, which is a little confusing. One was validating the 86 SNP score that we use commercially, and then this one combined, this one just came out and this one included that, but then brought in Tyrer-Cuzick as well as the base platform. And then we've been looking at European, this is a big topic. Our SNP data to date for Polygenic Risk Score has been largely derived from women of European ancestry, so people have been looking at how this current SNPs function for people of other ancestries. If you think about it, BRCA1, BRCA2, ATM, CHEK2.

 

0:10:56.0 DS: These genes were largely found in European cohorts, but then adapted to risk in other cohorts. Similar things are going on with SNPs. It does seem like these are major SNPs across all ancestries for the most part. Now clearly there's some uniqueness to other ancestries for specific SNPs, and there's a lot of work that needs to be done in this area for sure. But there are some good ones here. This paper looked at European and Asian individuals, this was a US Latina population by Susan Neuhausen and Elad Ziv. And then I kind of alluded a little bit to this a little bit ago, that there was our one paper internally showed adding Tyrer-Cuzick again as a base model and then putting PRS on top of that, that you get a little bit of a better model fit, and that's... People are looking at other clinical and family history variables that you can really lay as a base foundation and then bring Polygenic Risk Score on top. And it continues to hold up that, probably one of the biggest things is family history.

 

0:12:17.7 DS: SNP Polygenic Risk Scores are changing pretty substantially by family history, and it's been well documented at this point. Really, when you're looking now at Polygenic Risk Score studies, ideally, you wanna see how family history was taken into account in whatever model that was used. This is becoming incredibly important, and that's what's being shown here. There's these two figure C and D, both are Polygenic Risk Score, 10-year absolute risk by the... How, I guess, significant somebody's Polygenic Risk Score is, unfavorable versus favorable. And you can see that if you have a family history of breast cancer, your risk goes up even with the same Polygenic Risk Score. So you do have to take all this into account.

 

0:13:08.9 DS: Colon cancer has been similarly following pace. I think breast cancer is really leading the space right now. Prostate cancer, I have some on as well. Colon cancer is moving pretty quickly. There's about a set of about 140 SNPs that have been... Are starting to become a little bit more common place now, being looked at in colorectal cancer in different populations. So there's some good studies in that context. Colon cancer is interesting because I was thinking about it the other day. Breast cancer, we have pretty good base models, and this is just me talking at this point, this is the way I'm thinking about some of this, but we have pretty good base models of, what is a high-risk woman with breast cancer lifetime risk? What is a low risk? If someone is high risk, what do you do with that? Do you do more intensive screening, etcetera? Colon cancer, we really don't have that setup as nicely formed, I would say.

 

0:14:11.2 DS: Right now, we don't have... If you think about all the models that we have in breast cancer, Gail, Tyrer-Cuzick, CanRisk or BOADICEA, all these. Colon cancer doesn't have that same kind of clinical usage of those types of models. And really the current major recommendation is just to model screen based on family history of colon cancer. Like if you go to the NCCN guidelines, it's based on whether you have a family history of colon cancer, when you start colorectal cancer screening and the interval and things. So we need some work here because if we don't have really widely accepted base models, then it means that as Polygenic Risk Score comes in and we start understanding like, "Okay, this person is two-fold risk or this person's three-fold risk," like we are in breast cancer, we then don't really have an easy platform to adapt that to what it would actually mean for their screening. So I think there's a decent amount of work to be done.

 

0:15:11.8 DS: And you could argue the same for prostate cancer, and maybe this has been some of the... Prostate has been something that we know there is significant SNP load that adds up in a Polygenic Risk Score that does seem to modify someone's risk for prostate cancer. However, again, it's kind of that tricky thing where it's like, well, we recommend prostate cancer screening anyways, based on either if you're high risk, if your family history or... You get yearly screening, even if you're at average risk every year after 50. So we have to work out the clinical utility, I think, of some of these Polygenic Risk Scores more than others. And this is just a chart again, Shelly gave it, it was a Steve Channick courtesy. Thank you, Dr. Channick. And looking at that there's about almost 200 SNPs. Essentially, all of these diseases, multifactorial diseases have hundreds of SNPs, and I don't think there's a perfect SNP set by any means, but more work to be done.

 

0:16:18.3 DS: But clearly, when you're looking at some of the literature, you have a very small single Mendelian gene risk of BRCA1, BRCA2, HOXB13, etcetera. And then a lot of the excess familial risks, similar to other diseases seems to be coming from polygenic risk to a large extent. And there's some other prostate literature that's been recently coming out courtesy of Shelly, so thank you very much. And then even beyond cancer, which we've been just focusing on, you're starting to see not only genome-wide association studies that have been going on for a long time, but now the fruits of those genome-wide association studies, which really helped lay the foundation for finding solo X SNPs, now you're adding all those SNPs together and you're trying to figure out risk, because taken alone, one SNP, that may just increase your risk very minimally for a particular disorder. It's hard to argue that you need that... Someone needs specific testing for that. However, if you add up a bunch of those and now you start getting a larger effect size, that's where the Polygenic Risk Scores are having some utility.

 

0:17:36.4 DS: So we're seeing them coming to psych disorders... Cardiology is actually moving pretty rapidly trying to understand who's at much higher risk for atherosclerosis and cardiovascular events, and this is... I do wanna point people, this is a very good article that Shelly was the last author on, Yanes is the first author, and this is in Human Molecular Genetics in 2020, and it really goes through by cancer type, by disease type really nicely, kind of, what are the things we're thinking about? What are some of the monogenic diseases? What populations have been studied for the Polygenic Risk Score? What are the base platforms that can be improved upon? Cost benefit, LC, which is ethical-legal, and then clinical trials that are currently going on for some of these.

 

0:18:38.8 DS: Many people have heard of at least WISDOM, but there are a few other ones going on for breast cancer right now that we'll probably start seeing some results of sooner. And then cardiac disease as well, schizophrenia and bipolar disorder also laid out here, so... Yeah, there's just a ton going on. Here's some select cardiovascular references as well for coronary artery disease. So I'll end there, I just wanted to give a little background of where the field's at. So, thank you Shelly, for putting that together. I'm gonna stop sharing my screen. I did see the chat Lauren's keeping busy. Sorry, Lauren [laughter]

 

0:19:20.3 LG: Okay.

 

0:19:21.2 DS: Sorry. [chuckle] She has been putting a lot of the citations. So I'll stop there and just pause for questions, just general thoughts about Polygenic Risk Scores across... Not ancestries, across diseases. I didn't mention, but the reason I just stumbled into across all ancestries is because we had a ASCO presentation recently that was looking at Polygenic Risk Scores across ancestries, we can certainly get into that if people want. And Holly is on as well, she was the person giving that talk, if anyone saw it, so... Thank you, Holly, again. So let's see, so any chat, anything on the chat, Lauren? Any questions? Let's just kinda open it up.

 

0:20:11.7 LG: No, not yet, no questions yet from the chat at this point. I think it would be interesting, you know PRS, obviously, you've illustrated and Shelly illustrated is in many different, not only cancer types, but disease states, and I might wonder if anybody can comment if they've used PRS in other fields, other than what we have used it for, obviously we have risk score, but if anybody has experienced using PRS elsewhere, just because I think it's interesting that there is some commentary in NCCN about the utility, but I'm wondering if others have other commentary on it as well, utility.

 

0:21:01.0 DS: Yeah, and we are starting to see it move into certain guidelines, like there was a recent... I didn't even know this was coming out, Mark Tischkowitz put together a ACMG guideline on probably two mutation carriers and management, and if you go take a peek at it, you'll see a whole section on PRS and discussion of using that as a consideration to modify PALB2 using mutation carrier risk using BOADICEA, which is now called CanRisk, so it's a nice article. Yeah, and Holly, I mean since you're on... You know I was just wondering, your kind of general thoughts on the field, I mean you're external, you're seeing patients weekly. Where do you think this whole fields going? You've been an advocate for a while.

 

0:21:52.5 Dr. Holly Pederson: Yeah. So I work at Cleveland Clinic. I run the High Risk Breast Center there, and we do diagnostics, high risk identification and management and long-term survivorship care. You mentioned that there are a lot of breast models, but you know none of them are really very good. We use a lot of them and are reassured by our stratification to what it is, but the reality of it is that 70-75% of women who get breast cancer don't have family history or any identifiable risk factors, and so until we really delve into this type of risk stratification, and in my opinion, breast density, which I really do think plays a large role, we're not gonna have effective risk models. Was that paper by Mark the JCO moderate risk gene one, or is that a different paper? Robson? 

 

0:23:17.8 DS: The... You're saying the one I was showing? Oh the PALB2? It was Mark Tischkowitz is the first author.

 

0:23:25.5 DP: Oh, Mark Tischkowitz. Okay, I thought it was Mark Robson. I'm sorry.

 

0:23:29.8 DS: Yeah. No, it's a good paper. And also the...

 

0:23:35.6 DP: Yes, send that one to me. But anyways, patients are clamoring for this information, and I bring up the conceptual idea of Polygenic Risk Score and share with them the lovely bell graph from the Gallagher paper. And if you haven't seen that, it's a really patient-friendly way of explaining the sub-stratification of risk among carriers and non-carriers.

 

0:24:12.1 DS: Yeah. I can find that, real quick.

 

0:24:14.5 DP: Yeah, I've got a copy of it. Just a paper copy that I can show 'cause...

 

0:24:25.2 DS: Yeah, I have it here.

 

0:24:26.3 DP: I literally just use it in my clinic [chuckle] but...

 

0:24:31.5 DS: Yeah, it is one of the nicer figures, this is a pre TJ at Myriad, but whoever designed it was thinking very well...

 

0:24:41.3 DP: Yeah, I literally get messages in my in-basket every day saying, "When can I get this test? When will this would be available? Am I the right kind of person for this test?" It's a very... Patients are interested in it, and I think it's gonna... I think it's gonna change stratification at all levels, at women at the highest risk and women at average risk, and I'm really excited about it.

 

0:25:18.5 DS: Yeah, I'm...

 

0:25:19.8 DP: Yeah, there it is.

 

0:25:20.7 DS: Yeah, this is what Holly was just referencing, so you have non-carriers here, and this is the paper... It's probably hard to see. I can throw it in presenter mode real quick... See, now I lost it. Alright, that's gonna be hard. [laughter] I might just... I'll just go back, but yeah, you can let see if I can make a little bit bigger though... Yeah, but yeah, there you go... Yeah, so the risk... You can see non-carriers fall about 10%, so on average... So and the way I think about it is, if you have a more favorable Polygenic Risk Score, meaning that you have more favorable SNPs pushing you towards not getting breast cancer, you had tend to fall down this area, and if you're a non-carrier with an unfavorable Polygenic Risk Score yeah, you're gonna fall up in here, and we did see top out, and this has become pretty consistent throughout studies, usually in the high 30s, it's rare to see somebody much higher. I mean, in our cohort, very few, like 0.5-0.6% will be above a really high risk, like 50% kind of risk. And then this paper kinda shows a nice distribution of what you would expect to see with check to PALB2, and BRCA1 and BRCA2. People keep this figure in their mind... There was a paper published yesterday, I'll come back to... If we have some time at the end.

 

0:26:46.8 DP: Yeah, I had my first... One of my first patients with PRS was a young woman who, 40 years old, first visit, first mammogram, but she had gone in for testing. Her mother had breast cancer at 42. And she had my risk panel testing, which was negative and had a risk score of 42%. Which is really unusual, and it was one of those situations where I sent her over to imaging and then I planned to see her back and gave me a little bit of time to kind of decide what I was gonna do with her, and of course, she had cancer on her first mammogram, so that kinda makes you grateful...

 

0:27:41.2 DS: We heard anecdotally actually a bunch of those, yeah, where we've had... People have chimed in that even our president of Myriad, she had a very high risk score, and ended up having a DCIS at time. And we've heard that from multiple external people. Now, again, you're probably not gonna hear... We're probably not gonna hear the people that get screened and don't have anything, but it is a little bit saying that we're, I think on the right track with all of this. And so in clinic, you're using it, what do you think about the carrier modification? We just showed... And actually there's just CHEK2...

 

0:28:25.7 DP: Oh I think that's gonna be profound. I think that there are so many women trying to make decisions even about MRI, much less preventive medication and less frequently about surgery, that the people who are making decisions about surgery are those who already have a more likely than not risk of getting breast cancer throughout their lifetime. And so you're already having that discussion, but I think it's gonna be really useful for the... For the 85% of patients who are on the fence about taking preventive medication that we talk to every day and diligence about their screening in terms of women who are at high risk, but also now that we have the opportunity to offer abbreviated MRI or fast MRI to women with increased density, if those women are identified as having a higher than normal PRS, they may be more likely to stay on top of that type of screening, so I think across the board, it's clinically gonna be so useful, but in terms of carrier sub-stratification I think that we're gonna see the most utility in the CHEK2 and the ATM populations, where it really is such a wide spread and it could really be helpful for them.

 

0:30:16.3 DS: And you're gearing up a study, as we were talking, that's on chemo prevention? I'm trying to remember exactly...

 

0:30:22.6 DP: Yes. So we will be participating with Mayo Clinic in a study called GENRE2, and it's a study looking at the PRS and its aid in helping women make decisions about chemo prevention. And these are already women who are at very high risk, gene carriers or women with a 10-year risk, per the TC model of 8%. It's really quite high. So they're women in whom we would be recommending consideration of chemo prevention anyway, it's not a population that wouldn't already be offered the opportunity, so to see whether the PRS helps them in that decision, and I think it's a slam dunk that it will. But that'll be nice to show and of course, we'll learn a lot more with that data, it'll be a 10-year prospective study with a lot of information that's collected over time, so...

 

0:31:39.3 DS: Yeah, that's a great study. It's exactly what we need. And I think Ferguson, maybe you were on it, I just saw paper on chemo prevention attitudes by PRS a couple of weeks ago.

 

0:31:51.5 DP: Oh, I didn't see that one.

 

0:31:54.0 DS: Yeah it wasn't too long ago. Yeah.

 

0:31:58.5 LG: Hey TJ, if you're thinking of looking for that paper, I wanted to just grab some questions from the chat for Dr. Pederson, if that was okay? 

 

0:32:06.7 DS: Yeah, I will look for that other paper, I just saw it.

 

0:32:09.3 LG: Okay. Dr. Pederson, we had a question, it was a little bit further back so you probably have already alluded to this a little bit, but Brynn directly asked, "Do you change clinical treatment or practice based on PRS?" And I would add to that, based on PRS in terms of an unaffected patient with no CHEK2, and then I would also ask on, of also CHEK2 modification what does that look like for your patients? 

 

0:32:39.1 DP: Yeah, so, the PRS... And this is a really important point. Do I change management? I provide information to the patient, so that she can make the best informed choice given the information that she has, and this is another piece of information that needs to be carefully communicated and put in the context of the rest of her personal and family history. And so, I think it's really critical that we remain non-directive, just as we are with discussions around risk-reducing mastectomy, that we use this in a way, where we provide the information and the risk data and help women to make their own decisions.

 

0:33:42.3 LG: Yeah, thanks for that. I think it's... I really agree with you to the point of, it's a piece of information that we have to present and it is important to present. As a genetic counselor, what we are describing to the patient, giving to the patient, is only a piece of it, and so what's interesting in my conversations with genetic counselors versus the breast surgeon or the medical oncologist is that, genetics is a piece of the puzzle, but it's not the end-all, be-all, and there's other factors that have to be considered when making a decision, and there have been a lot of patients who have decided differently than when I met with them, because of other factors that were going on that were not part of my consult because they were just not in my purview. So I do agree with that statement. There was just some other comments in the chat, thinking about protective SNPs, and I think anybody that's gotten a risk score knows that when you get a PRS score, it doesn't mean that patient's risk is always going to be high. I think that that's a misconception that I see a lot with different people I'm interacting with. But there definitely are protective SNPs and, comparative to Tyrer-Cuzick, there are patients that their risk score will be lower, and I don't know if you can speak to your experience with that as well, Dr. Pederson.

 

0:35:00.8 DP: I think that, we do see that, we do see that there's certainly... Not a down staging, but a reduced estimation of their risk as a result of the PRS, and that can be very reassuring to a patient. I think that you brought up the CHEK2 spectrum, and we often were offering patients an estimate of 30% risk over their lifetime, but with this sub-stratification, it could be 6.6% or 70%, and that's just a huge spread, and so that's an example of where it really could be significantly reduced, and it's been shown with ATM that a good proportion are reduced in risk, and, in the average risk population, I think it's going to be interesting from a public health standpoint, to identify very low-risk women and counsel them appropriately about risk-based screening. And so, I think it's an interesting point in terms of lowered risk...

 

0:36:27.7 DS: Yeah, in our cohort, we tend to see... Obviously, it's biased. We clearly are seeing a largely weighted family history of cancer, personal family history of cancer. So when we look in our cohort, we see about a third of people with a risk score over 30%, but yeah, getting to this conversation, a lot do go down, and I'm gonna share this really good figure that... Let me pull it up, that...

 

0:36:56.1 DP: Anyone I go out to dinner with and talk about this presentation or this testing, wonders if they can do it, regardless of the risk level...

 

0:37:10.0 DS: Yeah... This is courtesy, I guess, of Pat Whitworth, I would say, because he was the one that kept... He wanted this figure, and at first I didn't understand his mindset originally when he reached out and he was like, "Can you help me put together this? And it came together beautifully. So, it's now a figure that I use.

 

0:37:32.6 DP: It's terrible TJ, I don't know.

 

[laughter]

 

0:37:37.2 DS: Very, very nice, for the folks that were working on it. But, essentially, this was some data from the paper referenced down here, which is the Hughes 2021 paper. Now, this one looks at Tyrer-Cuzick risk, compared to... This is Tyrer-Cuzick plus Polygenic Risk Score, so the CR, means combined risk score, so Tyrer-Cuzick plus a Polygenic Risk, and it shows the flow. So I mean, yeah, a lot of people don't change. If you run their Tyrer-Cuzick, and then run their PRS, a lot, 88%, if you're under 20% lifetime risk, you're not gonna change, if you're over 20% lifetime risk, 71% aren't gonna change. But I do, a bunch do change, and that's what's nicely shown here, in this flow, and I think this is called a Lluvia diagram, I could be mispronouncing that.

 

0:38:32.1 DP: Alright, I get it now.

 

0:38:33.4 DS: It's a nice diagram, and so it shows if you had a Tyrer-Cuzick risk above 20%, a third of those individuals will flow into a lower lifetime risk based on our data, from the cohort, and then... And this was the performance cohort of 32,000 people. And then similarly, if you had a lower than 20% lifetime risk, about 12% of those individuals went up, and then if you really add these two together, it actually ends up being about a fifth of people end up switching around that 20% threshold, so.

 

0:39:05.9 DP: And it's so reminiscent of Oncotype where people who you thought were low risk about those same percentages were re-classified both up and down and...

 

0:39:20.9 DS: Yeah. Good point.

 

0:39:22.4 DP: It's biology, and it took a while for the medical oncology community to accept Oncotype and I think that it's likely that we're gonna be facing that same sort of resistance or barrier to understanding with this biologic test as well going forward, but...

 

0:39:55.0 DS: Yeah, no agreed. What other kind of questions do we have in the chat? I saw a couple of few different things we should make sure we're addressing as we're... We have about 15 minutes left. Yeah, I worry about true negatives, Michelle, feel free to unmute yourself... Well, I think you have trouble unmuting if I remember, but...

 

0:40:15.2 Michelle: I'm unmuted.

 

0:40:18.3 DS: Oh okay. Yes, thank you. What were you getting out with that true negative question? 

 

0:40:22.7 Michelle: So I'm BRCA positive and both of my daughters are true negatives, but I feel like we...

 

0:40:28.3 DS: Oh I see.

 

0:40:29.2 DS: That population of people that could still be at higher risk. My oldest daughter is in her late 30s and has never had children, so what is really her true risk of getting breast cancer as a true negative for BRCA? And then I posted another question after that, so then I have my mom who's been a smoker and an alcoholic, most of her life, and my maternal uncle, who's been a smoker alcoholic meth addict, and both of them are BRCA positive, my uncle died at 75 from his stroke, from his meth, but my mom's still living and'll be 80 next week, so what's been protective for them, with their lifestyle choices that they've never had cancer? 

 

0:41:14.4 DS: Yeah, you've teed me up well for this, this was the other paper that I kinda alluded to earlier, this came out, I think yesterday, so probably not many people have seen it, it's a really, I thought it was a nice well-written paper, it's Peter Craft is the last author, and it's looking at very similar to that first, the thing that we were showing, just by modification, they didn't put as beautiful of a picture in there I will say, but this goes through... Yeah, risk modification of the BRCA1 and BRCA2, ATM, CHEK2 and PALB2 carriers by Polygenic Risk Score. So essentially, if you have no family history of breast cancer, and you just what you just brought up, Michelle, so you're BRCA1 carrier, zero family history of breast cancer with a very favorable Polygenic Risk Score like in the lowest 10th percentile, you could have down to about a third in their paper risk, which was pretty similar to what we saw, even if you remember those diagrams that I showed in the beginning, that Holly brought up. So there's clearly a wide range. BRCA1 at the worst with a family history of breast cancer at the highest, most unfavorable SNP profile, here they had almost 60%, 57 so not quite a doubling of risk, which is... There's some argument that, yeah, BRCA1 and BRCA2 carriers just aren't quite as modifiable for their breast cancer risk, which really gets at that...

 

0:42:51.3 DS: Hey, the reason you got breast cancer with a BRCA1 or BRCA2 mutation is largely because of that BRCA1 or BRCA2 mutation, and then yeah your Polygenic Risk Score may have influenced slightly, but probably not that much. Whereas if you look at CHEK2... And this is again what Dr. Pederson brought up where ATM and CHEK2 some of these moderate risk genes, you start to see these pretty substantial swings, and I guess arguably the swings are similar, you have about a 20% swing here in BRCA1 similar in BRCA2, but you at least have about a 30% swing in ATM and CHEK2. So the swing seems to be a bit bigger, having a very favorable Polygenic Risk Score no family history to having unfavorable Polygenic Risk Score with a substantial family history, and you could envision. Yeah, we're probably headed towards a future where we maybe don't need to be if a ATM carrier walks in and has a very favorable Polygenic Risk Score and no family history of breast cancer. I don't know, do they need the level of screening as this individual who arguably has a risk higher than a BRCA1 or two carrier with no family history and a favorable Polygenic risk.

 

0:44:09.1 DS: So I think we're gonna start sorting this out, and the papers like these are really helping, understand all of this. So they showed... They weren't... This was a nice little figure in the paper, it was a five-year absolute risk based on gene and Polygenic risk. So yeah, I encourage people to take a peek at this paper, and while I do have my screen shared I did find this other paper on the endocrine therapy, and this just came out as well. And I wonder if this set the stage a little bit high for the Fergus's work in this area for the chemo prevention. So I was looking.

 

0:44:45.7 DP: I just wanted to say one other thing. I think it was about Michelle's comment with the true negatives. So I think for one, clinically, I always keep true negatives in our clinical practice and follow them once a year. I think that for those of you that are clinical, despite the advice that they've returned to population risk, the life that they've led and the cancers that they've witnessed is such that it really is difficult to believe that they're actually at population risk. So I think it's important to really keep those patients in your clinics for reassurance and keep in mind that they have another parent and the Polygenic Risk Score, in an average risk population is gonna sub-stratify their risk as it would in an average risk person. But yeah, that true negative emotional component, I think is very powerful.

 

0:46:12.6 DS: Yeah, and it's similar in a way to even multi-gene panel testing for those individuals where... I was always trained as... You do point mutation testing if it's a known mutation in the family, there's still clearly plenty of recommendations floating around in that regard, however, the field... Some individuals do still like getting a multi-gene panel on these folks just to make sure that... Yeah, even if you test negative for the point mutation that's floating around the family, like we're discussing here, there's clearly other whole set of genes coming in from the other parent, and making sure there's sometimes not a concomitant check to mutation floating around on the other side of the family or whatever it may be.

 

0:47:00.5 DS: And PRS is kind of the similar argument in that regard, where... Yeah, just making sure that there's kind of using all the genomic information you can essentially to give a good, accurate risk prediction. I don't wanna belabor the conversation with the chemo prevention paper, so I'm gonna put it in the chat here, but it just came out, Cancer Prevention Research, and it's just looking at... It just took women that had Polygenic Risk Score and looked at their willingness to undergo chemo prevention, and essentially it just shows that yeah, if you had a high Polygenic Risk Score, you were just a little bit more kind of motivated to do chemo prevention.

 

0:47:43.3 LG: I didn't wanna point out in the chat, Shelly did share a really interesting paper. I'm just looking at on my other screen here by Yanes, just talking about women's responses to understanding PRS information, and I wasn't sure if Dr. Pederson, you could maybe share your experience in clinic with how patients receive the information, positive, negative, and how that's been? You're muted.

 

[pause]

 

0:48:14.6 DP: You really hit on something that's incredibly important and that's the communication of risk information, and that's something that we all do everyday with highly penetrant genes and moderately penetrant genes, but I think as we moved forward, particularly with OlympiA and with ASPRS recommending that surgeons test all patients, we're going to need to not only outline guidelines for providers who are counseling patients, but help providers in their communication of this information to patients. And I think that that's a topic in and of itself that I'm actually working on with our Head of Psychology at Cleveland Clinic, to try to look into that field of communication of risk information, because I think that we're gonna need to help providers across the board do that. It's something that we refine over time, those of us who do it everyday, but a lot more people are gonna be doing this, and so I think that there can be tools that can be helpful to help people communicate.

 

0:49:46.7 DS: Yeah, absolutely.

 

0:49:48.5 LG: Yeah, I would say it's definitely a challenge, and I hope that you do some research and have a publication because it was something... It's something I think that we would definitely share, I at least would share with others because there is this hesitancy, and I think at first, some providers assume the role of the patient and say, "Well, they're anxious, they don't know how to deal with the information." But I do agree, it's the way that it's presented and something's not presented in a certain way or confidently, then that's transferred to the patient. And there's a lot of work to be done, I think, with a lot of different provider types, it's not just one. Of course, it doesn't help that NCCN and other bodies have not been hugely supportive of PRSs, so it kind of muddies the water a little bit. Would be helpful, I think, for a lot of people to have something to lean on and say, "Well, NCCN says X Y Z and this is why we say X Y Z." But I don't think that that's gonna happen for a little bit or maybe...

 

0:50:50.4 DP: Well, you know what? I think because of OlympiA, I think it's gonna happen by next week. I think that there will be...

 

0:50:58.3 DS: Are you saying for BRCA1 and BRCA2 there or...

 

0:51:01.8 DP: So, for early stage ER-positive and HER2-negative breast cancer, I think that medical oncologists, just because of the... It would overwhelm the genetic counselors of America instantly if they all counseled all of those patients in terms of the ability to take Olaparib, and so...

 

0:51:30.5 DS: Yeah. We probably should just... I don't know if any... A lot of people probably haven't heard of that study so I can happily give a...

 

0:51:36.5 DP: Yeah, go ahead and review it, TJ.

 

0:51:40.4 DS: Yeah. Just for people that haven't heard, so it's... Definitely look into it. It was just presented at ASCO. It's called OlympiA with a capital A at the end, and it was just published in... Gosh, I can't remember.

 

0:51:53.6 DP: New England.

 

0:51:54.4 DS: New England Journal, yes. There's also a tumor paper that's gonna be coming out as well, looking at just the germline at the tumor status, but essentially it was looking at well over a thousand BRCA1 and BRCA2 carriers, and then you got your standard treatment of your breast cancer, adjuvant chemotherapy, and then the only difference was you either went on placebo or you went on Olaparib for a year, and then it looked at the overall outcomes and the much better survival... And in the Olaparib arm just looked much better having being disease-free, so it was a very positive study overall showing that, yeah, if you have a BRCA1 or BRCA2 mutation, you probably do get massive benefit from a PARP inhibitor even after you're presumably treated with your first line chemotherapy, so it's really using Olaparib in this case in the maintenance setting. And these were women with mostly stage two and three breast cancer, I should also throw that in and all HER2 negative.

 

0:53:06.3 DP: So adjuvant as opposed to metastatic, and that was really that the distinction, and so many women are gonna wanna know up front, and so I think that providing the ways in which we can help the medical oncology community can communicate that to those patients will help everybody in the end, and I think it's gonna be a slam dunk by necessity.

 

0:53:43.2 DS: Yeah, at least for HER2 negative, I would think. And at bare minimum for people that meet OlympiA inclusion criteria, I would think so...

 

0:53:51.8 DP: I mean women just the the necessity to help providers with that communication, that's what I mean.

 

0:54:00.5 DS: Yeah, absolutely, yes. Yeah, well, great. We're getting near time. Any other questions? 

 

0:54:08.1 DP: Are you gonna leave the chat up or how do you get... How do you access the chat? 

 

0:54:14.4 DS: Yeah, great question...

 

0:54:16.7 DP: 'Cause I haven't been clicking on the papers.

 

0:54:19.4 DS: Yeah. Well, I...

 

0:54:22.2 LG: I will send the the follow up, if you want TJ, I mean I can, we have access to the chat, we can click the links that are in here and we can send a follow-up to any body whose interested.

 

0:54:34.7 DP: Okay.

 

0:54:35.3 DS: Yeah, this was a very paper heavy Myriad Oncology Live today, I actually just cut and pasted the chat, which is... I'll shoot you an email, Holly, but yeah, it looks like anybody can cut and paste the chat, so there's about 30 papers in there, so if any one wants to just spend their weekend reading about Polygenic Risk Scores and OlympiA, there you go. [laughter] Well thanks again, Michelle, I see, I love PRS and so excited about it. Thanks, Michelle. Well, I just wanna say thank you to Holly so much for coming on. That was excellent discussion today. We went through a lot of material, you see that a lot of this material is literally months old, weeks old, we showed a paper that came out yesterday, so this is a very fast moving field Polygenic Risk Score is on fire right now. From a research standpoint, from figuring out how to get this into clinical utility, and going back to what I showed in the beginning from Shelly, it's not just breast cancer, this is happening in colon, prostate beyond cancers, people are looking at cardiovascular disease, neuro diseases, diabetes even. So, the world of genetics is moving very rapidly into Polygenic Risk Score for a lot of these multi-factorial condition, so I'm just proud to be part of it. And Holly, thank you for doing your good work, and an amazing...

 

0:56:06.8 DP: Well and I think that the NIH committing 38 million to studying PRS really speaks to its importance right now as well, and thank you for having me.

 

0:56:19.5 DS: Yeah, yeah thanks everybody and yeah come on next week we're gonna have a really good discussion on cancer survivorship so I look forward to seeing people.

 

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