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.
0:00:11.5 Dr. Thomas Slavin: Welcome. This episode of Inside The GENOME is a recent recording of Myriad Oncology Live, a webinar hosted by me, Dr. Thomas Slavin, Senior Vice President of Medical Affairs at Myriad Oncology. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, please visit Myriad Oncology for a list of dates, times, and subjects. I look forward to exploring the world of genetics with you all. Hello, everyone. Welcome to Myriad Oncology Live. Thank you so much for coming on, and as always, we'll start with a little housekeeping, so yes, here we are. So today, we're talking about pros and cons of germline genetic testing for all breast cancer patients. So we have two special guests. We have Dr. Paul Baron and Dr. Mark Robson. As always, we have Shelly running the chat and we'll do some introductions in a minute or so. And then we have a little break. The summer has been a little light. People are [chuckle] getting back into their, hopefully, pre-COVID routines, unless you live in Los Angeles where I live, where things are going the opposite way. And I know a lot of states are having COVID problems, so hopefully we can continue to keep things under control and we don't take a step backwards.
0:01:40.1 DS: But a lot of people are opening up, and so I'm spacing the webinars a little bit but also with the summer break and a lot of people getting their kids back up to school, vacations, and everything else, we've been giving a little space. So then, July is a big travel time, so we put a little space there. And so after today, we're really not gonna regroup until mid-August, and Holly Pederson will be on from the Cleveland Clinic and we're gonna be talking about polygenic risk scores for all ancestries. This was sought-after a little bit. We did an ASCO presentation. I think people just wanna learn a little bit more about it. And we can just talk in general about where the field's at with polygenic risk scores and bring people up to speed. So if you're looking for something, definitely, that will be a good one to put on your calendar. And if you click on the link, you can register and it'll pre-populate your calendar all the time. And then I'll build more out after that as we get closer.
0:02:44.0 DS: And then I did wanna point people to the podcast because we are now... For those that can't attend, we are keeping at least just audio of these so people can listen to them on the back end. And it's getting a little convoluted, I still need to work through this a little bit, but anything that says Myriad Live on the Inside the GENOME podcast, that is one of these webinars, so we're just putting them up. And then if you see something like this, like a look at breast cancer gene expression assays with Dr. Adam Brufsky or the psychosocial aspects of hereditary cancer, if it doesn't say Myriad Oncology Live in front of it, then it's a regular 15-minute, 20-minute podcast where I'll sit down with somebody, then we'll go through any key finding in the field or aspect of the field. So without further ado, let me do more of a formal introduction. I'm gonna stop sharing and also, I should have mentioned, so Shelly is running the chat if you have questions and again, the whole purpose of this is just to be able to ask questions. It's for education. Anything is fair game. You can bring up whatever you want, you're not gonna offend anybody on here, and we try to keep them theme-based.
0:04:10.6 DS: Today, we're really talking about hereditary breast cancer genetic testing and the present nature of the field but hey, if you have a colon cancer PMS2 question and it's burning, and you gotta get it off your chest, [chuckle] then feel free to ask that as well. If you wanna unmute an ask a question, I think it's always the most... Then we can have a rich dialogue. If you're uncomfortable coming off mute, that's fine too. You could just send whatever question you have to Shelly and she will make sure they get answered or you could just put it in the chat and we're always coming in the chat and making sure everything gets addressed. So, yes, Dr. Robson and Dr. Baron, thank you both for coming on. And we can do quick introductions. Both of you are very well nationally known and even internationally. Dr. Baron, do you want to tell people what you do at Northwell and your interest in genetics, I guess, in general?
0:05:14.3 Dr. Paul Baron: Genetics, it's a fun subject. I'm the chief of breast surgery here and director of the breast program. I have a major interest in high-risk patients, and so thank you for inviting me.
0:05:28.8 DS: Yeah, no, thank you for coming on. And Dr. Robson, do you wanna let people know what you do at Memorial Sloan Kettering? Your role is changing.
0:05:36.4 Dr. Mark Robson: Yeah. It's always changing. So I'm Mark Robson. I am the Chief of the Breast Medicine Service here at Memorial. Prior to that, I was the Clinic Director for the Clinical Genetic Service here.
0:05:49.6 DS: Yeah, thank... Go ahead.
0:05:52.1 DR: That's good. [chuckle]
0:05:54.2 DS: Well, thank you both for coming on. And so I have some things on my agenda to work through, but again, if questions arise as we're going through this, let's address them. I think, first, I wanted to just talk about a new paper that came out that people may not be familiar with, let me share my screen, and that is the OlympiA trial. Here we go. Hopefully, people can see that. Geez, I have no idea what people see, I have multiple screens. Is that normal to everyone or is that horrible?
0:06:30.5 DB: It's good.
0:06:31.1 DS: Oh, okay.
0:06:31.7 DR: We're seeing your Adobe Reader.
0:06:34.7 DS: Okay, yeah, that works. Yeah, so this was a study recently published in the New England Journal of Medicine. So if people haven't seen this, it's a good one to look over and it's looking at olaparib specifically for BRCA1 and 2 mutation carriers and more of the frontline settings. So after chemotherapy, should you just watch someone, give them an endocrine therapy or you also add in PARP inhibitor? And so it was a very well done study. You see here a very large study, 1836 patients, I'll go through down here, there are some survival curves here. So essentially, it's showing, with disease-free survival, that people are faring better if you put them on olaparib versus placebo. And so this is, I would say, has been fairly practice-changing, at least from a treatment standpoint, and we have recent emergent ASCO updated guidelines, also the NCCN for breast treatment. Unbeknownst to me, actually, I just saw it yesterday, they'd also just released updated guidelines on how to take care of patients then after initial chemotherapy if you have triple-negative or HER2-negative cancer. And I should phrase that this is a HER2-negative disease.
0:08:15.3 DS: So yeah, I wanted just to get some of our experts' opinion of how do you think this is gonna change the field because it seems like, right now, there's a lack of guidance on who are we testing for breast cancer from a germline standpoint. And this seems like a fairly practice-changing trial but there's still an absence of clarity beyond the American Society of Breast Surgeons who in 2018 said, "Yeah, we should be testing everyone or consider at least testing everyone." And I just wanted to get opinions. Maybe we could start with Mark. I don't know, you're pretty intimate to all this and you're even a co-author on that American Society of Breast Surgeon paper.
0:09:01.5 DR: Yeah, actually, to be clear, I'm not.
0:09:03.8 DS: Oh, I thought you were.
0:09:05.0 DR: I was part of the panel but I did not actually [laughter] sign on to the final work.
0:09:12.9 DB: Weren't you even part of the authorship?
0:09:16.1 DR: I know.
0:09:17.6 DS: Did you support the concepts, I guess? [laughter]
0:09:20.0 DR: I supported part of them but not all of them and I think that's why I sort of threaded the needle, and we'll undoubtedly get into how I felt about that at some point along the line. So this is a major, major paper. I think a couple of things to be clear about are that this actually is not all patients who have germline BRCA mutations. This is explicitly a group of patients who have relatively high-risk disease and there's a particular set of complicated definitions of that but ultimately, nearly 80% of the patients on this trial wound up being triple-negative patients who either had residual disease after neoadjuvant therapy or who had a T2 or greater and one or greater cancer, so decent-sized cancers and/or node-positive cancers, and there was a subset of hormone receptor-positive cancers that were also pretty high-risk, a lot of residual disease after neo or four or more positive nodes. So this is not all BRCA carriers...
0:10:26.9 DS: Yeah, that's a good point. It's a HER2-negative high-risk.
0:10:31.4 DR: HER2-negative high-risk and...
0:10:34.6 DS: But non-metastatic, yeah.
0:10:36.1 DR: Non-metastatic early stage. So in the United States, there are already criteria for allowing or supporting the testing of, basically, everybody with triple-negative disease under the age of 60 and a pretty reasonable proportion of people with hormone receptor-positive disease. And then you've got a number of other kind of pieces of data that feed in, you have Fergus Couch's data with [0:11:06.7] ____ showing that the sensitivity of just an age cut off of 65 accounts for more than 98% of the BRCA carriers. And remember, in the United States, 40% of breast cancer is diagnosed after the age of 65. So I think that, yeah, this does give another reason to expand testing criteria in the younger patient population, and I don't know that sort of waiting until somebody meets high-risk criteria is necessarily pragmatic, but I do think that there's a step between that and saying, "Automatically do this as a biomarker for everybody," because the cost-benefit payout over the age of 65 is pretty limited.
0:12:05.9 DS: Yeah, we had Fergus on last week, actually, but we should brought up the... Those were good studies. I would like to hear his thought there too. What do you think of then about the American Society of Breast Surgeon guidelines that you are not an author, for full disclosure?
0:12:24.0 DR: That I assisted with the development of and actually [0:12:28.1] ____.
0:12:28.7 DS: Because those made a big splash. I was at City of Hope when those came out and it was like, "Oh yeah." The day they came out, everybody was talking about it and would it actually change the field, and yeah, I don't know, I think when those came out, it seems like... And I'd like to hear your opinion, Mark, and then I'd like to hear how that maybe has changed Paul's view too on genetic testing.
0:12:57.2 DR: So my view is that if the question was, should we test every breast cancer patient for BRCA1 and BRCA2? And maybe toss in PALB2. I don't necessarily know that I'd have a huge amount of hard burn with that. I think the pay-off over age 65 and the cost effectiveness over age 65 as a system level question is pretty poor, but just if that was all that we were talking about, that would be fine. But that's not all we're talking about because nobody does BRCA1 and BRCA2 testing nowadays, they do multitude panel testing, and I think my view is that we still have not come down to a comprehensive way to make sure that people who have moderate penetrance variants get the right care. Those were things that we're trying to do. You guys have got at least some PRS in some patients and add some of this in the group we're building out models, but when we're winding up with papers, touting, finding large numbers of just whatever, MUTYH alterations as being improvements of diagnostic yield, I think that those not only overstate benefit, but also neglect the potential for harm in the prompt experience.
0:14:46.5 DR: We have people who undergo prophylactic oophorectomy. We're putting together our prophylactic mastectomy experience and our contralateral prophylactic mastectomy experience, and it's frightening. People do things that they shouldn't be doing on the basis of risk, and we also know even the unaffected setting from the polygenic risk work that there's a substantial number of these people who actually are not even at increased risk. So, if I could leave all that out and just do BRCA1, BRCA2, I probably would be a little bit more supportive.
0:15:22.1 DS: Yeah, and one of the perplexing things in particular is PALB2 where we're seeing it... It certainly is separating a bit from ATM and CHEK2, and it's looking more between BRCA2 and those genes, and then Fergus did bring out last week, which we're seeing the same in a paper with Mary Daly and Allison Kurian that we're putting together right now, that PALB2 doesn't seem to have... You can't really use that 65 or 45 age cut-off. It does seem like it has a persistent increased risk for breast cancer even out well past 65. So, we still have to sort out how that fits into all this, and that's important as well because there's some growing literature showing that a partner and localized or BRCA2, PALB2, it's an HRD gene and it looks like similarly to BRCA1 and 2, it is very responsive when it's driving a cancer to PARP inhibitors.
0:16:24.3 DR: Yeah. TBCRC48 is exciting for the 11 patients who were on it. [chuckle] We'll have to see what happens as that gets kicked out a little bit, and whether or not that degree of efficacy stands up and then whether or not it's durable.
0:16:39.6 DS: I don't even know about that. So, what is that?
0:16:42.7 DR: What do you mean?
0:16:43.5 DS: Is it a trial?
0:16:44.9 DR: Yeah. So TBCRC48, it was published by Nadine Tung.
0:16:50.9 DS: Oh, that's the Nadine and Judy Garber, yeah.
0:16:54.9 DR: Yeah. There's a lot.
0:16:55.6 DS: Yeah, yeah, a lot of people. [laughter] Yeah, a lot of folks.
0:16:58.1 DR: But yeah, looking at patients who had non-BRCA alterations and finding it, but anyway. So, I think you have to separate, I wanna just reflect on a comment that you made, is that you have to separate out the question of whether or not there is risk associated with the gene out past X age. BRCA1 and BRCA2 have risks out past age 65 clearly, and what is the diagnostic yield of testing that population, right? Because yeah, okay, you may have an increased risk that extends out past age 65, but still the yield among all people who have breast cancer over age 65, what proportion number due to PALB2 is gonna potentially be a lot lower?
0:17:48.6 DS: Yeah, yeah, agreed.
0:17:49.5 DR: Anyway, PALB2 is still not driving care. We don't know what contralateral cancer risks are in PALB2 for instance. Whether or not that should be driving prophylactic contralateral mastectomy data. I'm curious to know what Dr. Baron thinks about that.
0:18:03.7 DS: Yeah. What do you think, Dr. Baron, about all this? Has your practice changed over the last few years from your patient population and how you're managing?
0:18:15.5 DB: Well, I think there's two aspects. We're mainly focusing on the patients themselves and their mutation. I think also it's important to emphasize that when we find these mutations and there's always first-degree relatives who are at risk for having the same mutations and their cancer risk. So as a surgeon, one of the things I've always been struck by is that these days, a lot of times what drives patients' interest in getting tested is not only for themselves, but also about their daughters or their sisters or granddaughters, and I think that's an important piece of this also, not to be mentioned. [chuckle]
0:18:55.6 DS: Oh, yeah.
0:18:57.8 DB: So, I can't give you specifics on PALB2, but I will say that. You know, certainly, you guys probably have more breadth of knowledge on that, but certainly the patients who we do find pathogenic mutations on, neuro-pathogenic mutations on, the BRCA1 and 2, PALB2, and opt for mastectomy, usually want contralateral mastectomy in that setting. And certainly, yeah, we talk about the pros and cons of mastectomy versus a breast conservation, and I would follow them closely. And a lot of these patients, when you go through all the risks and stuff, they do have an elevated risk for subsequent cancers, and they are worried about frequent mammograms, frequent MRIs, low thresholds by radiologists recommending biopsies in these patients, and it can be very stressful to a lot of patients. And so I think it's very valuable to know if they do have a significant mutation, significant high-risk mutation. And so I do have a fairly low threshold for recommending testing for those. And I certainly hear everything you said, Mark, about the low-risk genes that are included in some of these panels, and the risk is pretty negligible, but if you do find on these high-risk genes, it can really be life altering and family altering.
0:20:26.1 DS: Yeah, no, excellent, excellent feedback. And so, in your practice, how are you clinically thinking through these? Are you recommending mastectomies, leaving it to the patient, leaving it in a consider realm. Are you bringing in age or using models?
0:20:52.1 DB: Well, whole bunch of things. Yeah, you bring in their risks of subsequent cancers, you bring in their... I think I have a few reference to the Ostomy software, which I think is very helpful, where I'll pull out their history and pull up the graphs and I'll show them what their risk is for developing a cancer or a second cancer if they've already had one. And again, it gives comfort to a lot of these people, like I've personally heard Mark speak a number of times, and he emphasizes the importance of age in a lot of these cancers. For example, the risk of certain cancers like ovarian cancer, BRCA2 is older than younger, so that may be less urgency to consider uterectomy in a BRCA2 patient than a BRCA1. And I've seen you also show that data for other of these murderous genes too, as far as modifying age of testing based on what gene mutation we find in a family.
0:22:00.3 DS: Yeah. Yeah.
0:22:01.6 DR: Yeah, surveillance.
0:22:04.0 DS: Yeah, Mark, are you using Ostomy in your practice? What do you think about it as a tool?
0:22:14.4 DR: So I think it's challenging because... I like Kevin a lot and I appreciate everything that he and his group do, I think that the problem is that, particularly for moderate penetrance genes, it's very clear that it's a much more modifiable factor than BRCA1 and BRCA2. So I fear that there is a suggestion of precision which is unwarranted. It would be just based upon largely, a single risk estimate from a single study. So, I don't actually use it, and I think particularly for ATM, CHEK2, which have significant ER positive components that are likely to be modified, I think it really risks either underestimating or over-estimating what the individual's risk happens to be. And we don't have any data for contralateral risk estimation, actually, for any of the moderate penetrance... You have some for CHEK2, but there's...
0:23:36.0 DS: That was your paper a few years ago. You were the first author on it, yeah.
0:23:39.6 DR: Yeah. You have a little bit for CHEK2, but it's not great. ATM, pathogenic mutations actually don't have any contralateral risk, and we care. So, I think moderate penetrance genes, I always conceptualize them as risk factors that interact with other risk factors to produce some global risk. And we are not incorporating the whole range of potential modifiers into these estimates at this point, so I find them very hard to use. And a substantial, like I said earlier, a substantial number of women who have moderate penetrance variants will actually not have a greater than 20% lifetime risk.
0:24:27.8 DS: Yeah. Yeah, no, yeah, doing it off age is definitely the way to go as a starting point, so no question. And we clearly need better tools. I can tell you from being in practice with and learning from Jeff Lightsall, Yeah, we would just archaically, do back of the napkin calculations for using 1.5% chance per year for a BRCA1 or 2 carrier. We kinda made up numbers for moderate risk genes ranging from 0.75-1%, and it's just kind of loosely grounded in the current data that's out there. Paul, so you stick, it sounds like, pretty... Do you give patients the read out when you run Ostomy? Or Do you kind of give patients like, "Well, this is the general range, or this is what we would expect." Do you just see patients eyes get bigger at certain numbers? What are you seeing on the breast surgeon clinical side?
0:25:35.4 DB: Yeah. Actually it tends to go the other way. It tends to be more comforting because... And most of those curves are slowly sloping upwards, a few exceptions. But most of them, if they show that their risk of cancer really doesn't get up there until over 20%, until they're like 70, it's hard to get too excited or worried about that. And certainly if we're following pretty closely. The risk is in a much younger age than... Or if they already have cancer, then I do find that their patients, particularly I think follow NCCN guidelines it's easier to consider prophylactic mastectomies. A lot of the patients opt for that. I do have many patients though that I tell them, "Look, we can follow you also in MRI on an annual basis, alternating with a 3D mammogram every six months between those." So every six months getting one or the other. Some patients that's what they do, they choose to follow the course and that's totally fine. I do think there's some geographic variations with that too. While I was looking at the South, a lot of patients feel more comfortable with prophylactic mastectomies, and I think in the north east and north west they're more comfortable with just being followed.
0:26:50.9 DS: Yeah, what are you seeing your surgeon friends across the country practice? How are you seeing them practice differently? Are you noticing these pockets that you've just described? Is there some that are really recommending?
0:27:07.5 DB: I think certainly with BRCA1 and 2, it will be frequently recommending, if you say that we can do a mastectomy, because in their age, if their risk is 20% getting a second cancer in the next five to 10 years, some of those women opt for prophylactic surgery rather than having to be followed. Certainly if the risk is less than that then they are fine to be followed.
0:27:31.4 DS: Yeah, yeah. We do have a question here from... I'm trying to come. I know, Shelly, fell off. You said, so I don't know if you can see the template?
0:27:39.7 Shelly Cummings: I'm here, I'm here. So we have a couple of questions from Robin Palmer. So since we're on this topic of genetic testing and BRCA1 and 2. She would want some clarity around if BRCA1 is considered a melanoma gene, if so, what's the magnitude of risk for somebody that has a variant in the BRCA1? What's the magnitude or risk of melanoma with BRCA2? And do either BRCA1 and 2, have a clear risk for stomach cancer and if so, what's that magnitude of risk in BRCA1 and 2? She has more questions, we're gonna pause at those four five there. So Dr. Baron and Robson can give their opinion?
0:28:28.1 DS: Yeah, Thanks, Robin. Yeah. I don't know if either one of you have a good handle on melanoma and gastric cancer for these?
0:28:34.3 DB: A melanoma is slightly elevated BRCA2. I don't know if there's risk with BRCA1.
0:28:40.1 DS: Yeah. I'm trying to think. I thought there was just... Yeah, there was a JNCI oncology paper actually that just came out looking at gastric cancer, at least. That came out last week, from actually Memorial Sloan Kettering, now that I think about it. Were you on that paper, Mark? Or he was using your data?
0:29:02.7 DR: They've been using impact.
0:29:04.3 DS: Yeah, it was using the impact data. I'm trying to remember who the first doctor was. But, oh, Elaine...
0:29:14.7 DR: O'Reilly?
0:29:16.8 DS: That's Stoffer.
0:29:17.7 DR: It would not have been her.
0:29:21.9 DS: I can think of it in a second. But that looked at gastric cancer versus esophageal and mutation rates that were different using the MSK-IMPACT germline data. And of the top of my head, I can probably find that paper honestly. We have melanoma in it too.
0:29:43.0 DR: Sofia did it with Joanna.
0:29:45.3 DS: Yeah, Sofia, yes. That's a good paper to look at. Shelly, I know we spoke about it at some point last week too.
0:30:00.9 SC: I'll put the link in the chat in a second.
0:30:02.1 DS: Yeah, because that at least showed gastric cancer has a higher rate of high penetrance and moderate penetrate mutations. It was like 11% versus 5% for esophageal, and it had the confidence intervals in there for the range. And BRCA2, if I remember, was a bit high, I think it was like 2.4% or something. I need to find the paper. But for gastric, at least, I don't remember if it had melanoma listed. But that may be a good reference, Oh, 'cause they've actually went in melanoma, 'cause it was just gastric versus esophageal. Melanoma I can't really think of any Sentinel studies. We know that Uveal melanoma may be up in BRCA2. Melanoma risk in general. I really can't point to a great source. Oftentime I had the NCCN is kind of long lines of raising awareness, but I don't think there's any recommended screening at the moment for a BRCA2 carrier.
0:31:04.4 DR: This all goes back to the old registry studies. There are some very old studies looking at cancer risk in these families, and the BRCA2 families. There are some JNCI stuff that came from the old breast cancer linkage consortium groups, and the challenge is that... So what happens is, that they look at the incidents of these particular malignancies in the families, and then they sort of compare them to standard incidence rates in the population and say, "Okay, you know the incidence ratio is X, Y or Z." But you have sort of a lot of potential biases in there, and so yeah, you do sometimes see a little bit of increased risk of gastric, you see a little bit of increased risk of cholangio, you see a little bit of increased risk of plain old melanoma, but I agree with you that none of them kinda raise to the level of requiring any specific screening. And interestingly, most of them are BRCA2, I mean, BRCA1 is pretty much breast and ovary, pancreas, and there's been a couple of suggestions of maybe prostate but that's about it. The one study suggesting colon risk was kinda little iffy 'cause it included patients on that study as being BRCA-related colon cancer when they were like anal cancers, which are clearly different.
0:32:41.8 DR: Also melanoma, a lot of these people who have the BRCA mutations in the original families were Europeans, and some of them were kind of perhaps a little pale, and maybe there was another melanoma risk associated with that. It was just correlation, not causation. Telling people to check their skin once a year is not a bad idea, but I don't think you need to tell them to do anything else.
0:33:03.5 DS: Yeah, yeah, personally, I would put in kinda do a general review of systems if I were in my high risk clinic, just to make sure they're not noticing anything unusual, and kinda talk about the ABCDEs of melanoma and leave it somewhat at that. I think it's interesting where the future may be going with this, and Mark you've brought it up about, there's just a background, that's the way I kind of see it, there's kind of a general background elevation of risk for a multitude of cancers when you have disruptions and these oncogenic pathways like MGUS recombination, and really tumor suppressor pathways, I should say to be accurate. It seems like it's leading towards... Even though one thing by itself may not hit a threshold for screening, taken together there may be some rationale one day to do something. And you see the field of early detection, you just had Grail launching, there's a lot of companies now racing towards early detection. I could see over time, not any time soon, 'cause it's gotta even be figured out from a baseline and how that's gonna adapt to the general population and everything, but I can see over time that being a nice tool for people at high risk for a lot of cancers that taken together in aggregate, do equal 3% lifetime risk or 5% lifetime risk, because at that point you're talking either... You'd have to have some sort of strategy like that or go to a whole body imaging type strategy, which is probably not gonna be realistic.
0:34:39.3 DR: Well sure, paying cancer ctDNA screening would be wonderful, right? Yeah, that would be great. And obviously, it's the holy, no pun intended, grail, and lots of people are working towards it but we're not there yet, and so the question then becomes absent kind of a paying cancer screening tool. What are the thresholds at which it's worthwhile putting people through multi-system screening and basically turning their life into a very expensive series of screening visits? You think about cancer risk in the general population, let's just say pancreas cancer for instance, because this is a place where there's a lot of discussion right now, should we be doing pancreas cancer screening. Even for BRCA2, pancreas cancer risk is like 4% or 5%, it's not enormous. Pancreas cancer is a terrible disease, and I'm not trying to mitigate that, but on the other hand, pancreas cancer is also the number four cancer in the United States, and probably before long will be number two, and yet we're not proposing population screening. And of course, there's no evidence of efficacy of pancreatic cancer screening.
0:36:00.7 DR: So the challenge is, we generate these numbers, we tell people you're at increased risk without necessarily being very good about quantifying it, and then in this kind of circular reasoning say, therefore you have to undergo all these additional tests, which themselves have both financial and potentially medical consequences, and by the way, are not available to large segments of our population who are either underserved or underinsured or just have geographic limitations, so it becomes in a way unfair doing that.
0:36:39.1 SC: I think that was part of Robin's question, that series of questions when you look at the personal and family history of melanoma or stomach cancer, understanding what the management is, but then when some of these patients are self-pay and they don't have the means, is it, should you do the genetic testing and then you're stuck with a quandary of not being able to follow through on what those recommendations might be, given the uncertainty of the strength of the risk?
0:37:09.8 DS: Yeah, yeah.
0:37:11.9 DR: But for BRCA1 or BRCA2, you have hardcore interventions. If nothing else, there's oophorectomy.
0:37:19.9 DS: Until you get into the cancers like yeah, right, until you get into things like gastric cancer yeah, right.
0:37:22.9 SC: Melanoma and stomach. Yeah.
0:37:28.0 DR: Upon those who create the screening guidelines to have a relatively higher degree of confidence in the clinical validity of the association before making recommendations. Because of these equity issues, otherwise, because of lots of things, but these equity issues are not small.
0:37:50.1 DS: Yeah, yeah, absolutely, I wanted to switch... Oh, go ahead...
0:37:54.2 SC: I was just gonna ask if we could switch gears to CHEK2 for a moment?
0:37:57.1 DS: Sure, yeah.
0:38:01.6 SC: So, this is a Robin question again.
0:38:07.4 DS: Thank you, Robin.
0:38:08.3 SC: Yeah, she always has great questions. She wanted to hear from you, Dr. Robson and Dr. Baron about the magnitude of risk of prostate cancer with CHEK2. Is it considered a prostate gene for all prostate cancer? She goes on to share that some providers seem to do genetic testing for any prostate cancer, and the literature suggests to her that in the presence of a CHEK2 gene, there maybe, it could be more aggressive, but she's less inclined to offer genetic testing to any personal family history of prostate cancer. She also shared that Ostomy quotes risk for thyroid and renal cancer with CHEK2, and she's not super confident about those risks or certain, so we'd love any insight you could shed on that.
0:39:06.0 DR: I've been talking a lot, I'll let Dr. Baron take care of it.
0:39:09.8 DB: Oh yeah, 'cause this is my area of expertise.
0:39:11.1 DR: I know. [chuckle] He's a breast surgeon. Yeah. [chuckle]
0:39:12.7 DS: Oh yeah, I don't wanna, I don't wanna over...
0:39:14.8 DR: I can weigh in a little bit here, where at least in my mind, the BRCA2 literature in prostate actually looks decent, that it may increase, and in the sense of if you have a guy and he's found to have a low-risk prostate cancer and you're trying to sort out active surveillance or treatment, yeah, you'd probably wanna know the BRCA2 status, that's supported by the Philadelphia consensus guidelines. I would not be shocked if that continues to get perpetuated in different guidelines. I think I'm a little less sold on BRCA1, ATM, there's a bit of data too about aggressiveness. CHEK2, I actually am not really that familiar with it all, I know it's reported here and there. We just have to realize there's a high background risk, just in the general unselected population of European folks for CHEK2 mutation, so we always have to make sure that studies are done well. I do suspect that there's probably a background rate for anything that's mucking up a homologous recombination deficiency pathway or a tumor suppressor pathway, and it's just hard to tease out...
0:40:35.4 DR: Okay, so getting back to what Dr. Robson was talking about where similar to gastric cancer it's like, okay, even if there's a little bit of increased risk, let's say your chance for prostate cancer as a male, I still don't even know what the chance for prostate cancer in a male is, to be honest, I don't know if anyone on the line does, but I'm always perplexed when I look at the data, but let's say it's, let's call it 15%. [chuckle] And if it raises your risk to 16%, is that actionable? What if it dialed it down instead of 50 to a median age of 49, is that actionable, or from 60 to, let's say, like 54 or something, is that gonna change your screening where we recommend everybody by the age of 50 get screened anyways with annual DREs plus or minus PSAs? So yeah, I think we have a lot to learn on the relevance of some of these genes in particular and in prostate, but we're getting data, there's a lot of studies ongoing right now.
0:41:38.2 DS: Do either of you think that there's a BRCA3 out there? Do you think there's some other impactful gene out there that we have to find?
0:41:46.1 DR: No, I don't think so.
0:41:47.2 DB: OB2 is probably the closest to that, at least from a somewhat prevalent in the population, looking like it causes risks higher than ATM and CHEK2, but yet not quite as high as...
0:42:02.0 DS: OB2?
0:42:03.6 DB: BRCA1 and BRCA2.
0:42:07.6 DR: I would say sort of lower end of BRCA2 risks and with strong family history modification it's probably up in there, but no, I don't think there's another single high penetrance allele that's floated around out there that we haven't found.
0:42:20.8 DB: Yeah.
0:42:21.1 DR: And it's just that...
0:42:22.1 DB: Fergus said the same last week, he thinks we're pretty done, there could be some discrete families here and there, but yeah, he didn't think there was anything we're really missing at this point across global populations.
0:42:32.6 DR: Just too many exomes have been sequenced, I think at this point it's unlikely, but...
0:42:37.8 DS: So, our biggest challenge then is to find patients who have the BRCA1 and 2 before they get breast cancer? That's a big challenge.
0:42:47.5 DR: Yeah, I think so. I think if there's gonna be a place where there's an impact, I think this idea of screening, and then it becomes this fascinating question of how does that actually work? And it is true that starting with the effecteds, if you had effective cascading, you would... Ken and I had published a paper about this a while ago, you get to saturation, if you will, much more quickly through cascade testing than you do through population screening, unless you have basically a newborn population screening program that's mandated, which I think is gonna be untenable for a variety of reasons. So, if you do have aggressive cascading, and the problem is cascading doesn't work that well. You identify your carriers, but unfortunately, the family uptake is not what you would think it would be. You think everybody would pile on, but they don't. Yeah, excuse the pun, but there's a lot of genetic testing skepticism that well predates our vaccine skepticism. [chuckle]
0:44:10.8 DS: Yeah, yeah.
0:44:10.9 DB: Same thing.
0:44:10.8 DS: Yeah, but you make a good point. I mean, BRCA1 and 2, yeah, there's some data in Ashkenazi Jewish populations, there was a paper published, I don't know, a year or two ago. Sorry, Shelly, I think it was in JAMA Oncology again, I thought, I can't remember the authors at all, just make it more fun, but you don't have to find it, but it was looking at overall survival, if you knew your BRCA1 and 2 status prior to being diagnosed with breast cancer, and it showed that yeah, you had an improved overall survival, and it was thought that it was a lot of just lead time bias because you were picking up... I spoke with with Allison Kurian about this too, that yeah, you picked up... If you were identified with BRCA1 or 2 mutation, the screening did what it was supposed to do, which was you went into a higher risk screening program and then you were identified earlier with a breast cancer at a lower stage and had better overall survival. So, that's the only paper I really know in the space that has made an impact.
0:45:14.7 DR: That makes a lot of assumptions that are not necessarily supportable in our healthcare system. Right?
0:45:20.5 DS: Yeah.
0:45:21.7 DR: That may be great for folks in a highly insured, or like Northwell, a comprehensive health system, but that unfortunately does not represent a whole bunch of people in the US. So, the implications for that are that if you did, and we kind of touched on this a little bit earlier, if you did have some approach of essentially treating BRCA testing like a biomarker, and doing it like ER/PR, HER2, and BRCA, then yeah, you would identify all the families, but would you actually really necessarily impact, or move the needle, because of all the people who couldn't get testing, who couldn't get care, who couldn't get screening?
0:46:08.7 DS: Yeah.
0:46:11.8 DR: And that's worrisome. Then you're stuck with this huge pool of people who are now theoretically at high risk, but you're not doing anything for them.
0:46:19.6 DB: I would think that if you knew you were high risk and there's gotta be some insurers who can crunch the numbers. If you find the cancer earlier it's gonna be less costly than finding the cancers later on.
0:46:35.8 DR: Yeah, but breast MRI is probably not on most of the Affordable Care Act catastrophic programs, right?
0:46:44.5 DS: Mm-hmm. Yeah.
0:46:46.6 DB: That's a good point. But there are new technologies coming down the pipe, they're like Short MRIs and just screening ultrasounds. Some of those tests may play a role in these populations. If you can truly identify a high-risk population and follow them more closely.
0:47:04.8 DS: Yeah. What percentage are you seeing in your practice, Dr. Baron, that are unaffected? You said in the beginning, you do some high-risk screening too.
0:47:17.2 DB: What was the first part of the question?
0:47:19.3 DS: How much high risk screening do you do in your practice?
0:47:22.5 DB: A fair amount. We see a lot of patients who have strong family histories and the only tools we have are, other than just regular exams is, do they qualify for genetic testing and do they benefit from an MRI? All these patients do Tyrer-Cuzick, and all these people and determine their lifetime risk of breast cancer. If they're over 20%, they usually get an MRI. And certainly, if they meet NCCN criteria for testing, then we recommend that. And certainly, there are patients who don't meet NCCN criteria, but they're willing to pay out of pocket for less expensive genetic tests to see if they have it. And, you counsel them on the pros and cons of that, but that's really an option for them.
0:48:12.5 DS: Yeah. I do wanna address a question from Barbara Correy, thank you. And we have about 10 minutes left, or not even five minutes if we wanna be nice to people. [chuckle] She brought up, "Where do you see the future going in all this?" I think that would be good to close out on as a good question. In the sense of PARP inhibitors, it also makes me think of tumor normal testing. Yeah, even though we're not there yet, maybe as a biomarker from the germline side, I don't know, Dr. Baron, are you seeing more in your practice or with your colleagues, are you seeing people do more tumor normal testing, as a work-up of breast cancer? It seems like PARPS are gonna come in more.
0:49:00.9 DB: Oh yeah. I think it's gonna change. The data is so new, that I haven't really seen it yet, but I think the data is pretty impressive. It's gonna change testing. And again, as Mark pointed out, we're talking about the high risk HER2 negative cancers. I was intrigued by that data, that, maybe I read this wrong, it seemed like the placebo group had more triple-negative patients than the other group. Is that the case, do you really know?
0:49:32.0 DR: It was pretty well balanced in my opinion. There might have been a percentage point or so off, but they were pretty straight. I think it was like 78% versus 76%. I mean, it was pretty close.
0:49:47.6 DS: Yeah, and Dr. Robson, I know you're involved with a lot of this research and where PARPS are going. I would say even the paper we first spoke of, OlympiA in the beginning, is really that moving forward in treatment extension from a paper you were first author on, which was Olympiad. I don't know, so, Olympiad was looking at...
0:50:11.2 DB: Looking at the other names we can use for this stuff [0:50:14.7] ____.
0:50:14.8 SC: What?
0:50:14.1 DB: Very confusing.
0:50:16.2 DS: Yeah, I know. I know. I don't know why. Yeah, why was the name [0:50:21.3] ____.
0:50:21.4 DR: I don't remember, Olympiad was just one of those cute names, and then once you had Olympiad, it made sense to do OlympiA. The next one is actually gonna be Olympian, which is gonna be a Neoadjuvant study. So, it's kind of cute. Yeah, I have no idea where Olympiad came from. I think.
0:50:40.5 DS: So, is that where you do see... I don't know, is Olympian an actual... Did you make that up or is that an actual study in progress?
0:50:47.9 DR: It will be a study. It's in development right now. So it will be a study. So, I think Neo is a place... You know, Jennifer Litton did NEOTALA, which was Neoadjuvant talazoparib. And if you do neoadjuvant therapy for the BRCA carriers, you have about the same PCR rate as you do with conventional chemotherapy, so in theory, that would work, I don't think anybody is likely to clinically feel very comfortable in a high-risk population just de-escalating all the way to PARP inhibitor alone, at least yet. So, I think what's likely to happen is you might wind up with some, I don't know, we'll see how it goes, we'll see what the trial design actually winds up being and how well it accrues, there's a lot of work using PARP inhibitors in combination with checkpoint inhibitors because coffee and donuts they're two big things and put them together. So, there are two other places where I think you could look at PARP. One is in actually de-escalation in low-risk patients, so, in other words, if you took the patients who had small BRCA associated cancers and then just tried to use PARP inhibitor in that setting, because particularly in a triple-negative space in young patients, we're still giving a lot of chemo for one centimeter, or one and a half centimeter tumors, and if you could potentially treat them with PARP inhibitor alone, that might be beneficial, you could argue, but at least that's one approach.
0:52:26.7 DR: And the other question is gonna be prevention, right? In OlympiA, it is too early to tell whether or not there's gonna be a decreased rate of second cancers, and most of the patients underwent mastectomy, so, I'm not sure how many contralateral breasts are gonna be at risk in that study, but there is already some hint, at least numerically, of a decreased risk of second cancers. And if that plays out, and at the same time you don't have any increase in AML MDS, then you may well be able to start thinking about a prevention trial, and you run into all kinds of questions about dosing and toxicity because PARP inhibitors aren't that much fun to take. But nonetheless, it's at least a question that could be asked, so, I think that those are kinda where they're gonna go in addition to expansion into other disease, other genes like OB2.
0:53:26.7 DS: Yeah.
0:53:27.2 SC: So, I have one last question, and this is my question. Do you think that we will get to a point where all women that have breast cancer, regardless of stage, biomarkers will have genetic testing? Well, it'll be standard of care?
0:53:50.6 DS: Yeah. [chuckle] Yeah, and again, it gets back to that American... There is a guideline body right now suggesting that. But I would say, yeah, the overall pick up across the United States, at least from what I've seen, and I don't have the data, but I don't know how much that moved the needle in this country towards that.
0:54:10.3 DB: Yeah, it definitely did. I will say for a newly diagnosed cancer patient, I will talk to them about genetic testing in a 100% of them, and there are some that go through it, even if they don't meet NCCN guidelines, 'cause they're over 65 and etcetera, etcetera, they sometimes will want it anyway and...
0:54:34.7 DS: So you are talking to everybody about it then?
0:54:36.4 DB: Yes.
0:54:36.7 DS: Like even a 70-year-old woman that comes in and you at least bring it up, and yeah.
0:54:40.0 DB: Well, that's why we're at the cascade testing because frankly, the 70-year woman is more concerned about her grandchildren than she is about herself or anyway.
0:54:52.5 DS: Yeah, yeah. No good.
0:54:55.7 DR: I think you can make a case, and a case probably will be made for at least BRCA1 and BRCA2 testing in everybody at 65 or younger. I don't think that that's particularly problematic, I think that there are, as we said earlier, I think there are issues about once you move above that, you're now more into the questions of population screening than you necessarily are the questions of diagnostic testing, if you will, right? And they're slightly different considerations, and if we continue to have to do broad panel testing without having a way to handle on the back end the consequences of that, because Shelly's here, one of the things we haven't talked about in this entire hour is the issue of how do you support this and how do you support the patients from the standpoint of counseling, because BRCA1, BRCA2 in a newly diagnosed breast cancer patient that that is perfectly within the purview of the breast surgeon to discuss the clinical implications of that, and then medical oncology can perfectly well discuss what the implications are for medical onc.
0:56:14.1 DR: But who's gonna actually take care of the family members, and if we get actually past BRCA1, BRCA2 into these much more complicated genes, then who's gonna help educate people about that, and if we're doing population screening in older patients, does that require a different kind of consent than if you're doing diagnostic testing when there's actually a clear medical implication? And I don't think we've wrestled with those questions well.
0:56:50.9 DS: Yeah, a lot to be answered. Well, thank you so much, Dr. Baron, Dr. Robson, this was great discussion. Thank you for those, Barbara, Robin, folks chiming in on the chat, Shelly for running the chat. No, this was great discussion. I hope everyone learned something. I did. I didn't know about Olympian, so, I'll be on the look out for Neoadjuvant moving...
0:57:15.2 DB: Still in development.
0:57:16.4 DS: Yeah, exciting.
0:57:18.2 DB: In development.
0:57:18.8 DS: So yeah, much to come, yeah, so. Well, thanks everybody and make sure, yeah, August, mid-August, put on your calendar, we'll get into the PRS if anyone is interested with Dr. Peterson as the next one, and we'll build out the schedule from there. Thanks, everyone. Have a great rest of your day.
0:57:38.3 SC: Thank you.
0:57:38.8 DR: Bye now, thank you.