Inside the Issue: Current and Future Management of ER-Positive Metastatic Breast Cancer After Disease Progression on a CDK4/6 Inhibitor (Webinar Video Proceedings)
Inside the Issue: Current and Future Management of ER-Positive Metastatic Breast Cancer After Disease Progression on a CDK4/6 Inhibitor
Aditya Bardia, MD, MPH Erika Hamilton, MD Featuring perspectives from Dr Adiyta Bardia and Dr Erika Hamilton. Published August 23, 2023
Introduction: Biopharmacology and Endocrinology of Breast Cancer DR LOVE: Good afternoon, everyone. I’m Neil Love from Research to Practice and welcome to Inside the Issue, as today we talk about the current and future management of ER-positive metastatic breast cancer after disease progression on a CDK4/6 inhibitor. We have a great faculty today, Dr Aditya Bardia from the Massachusetts General Hospital in Boston and Dr Erika Hamilton from the Sarah Cannon Research Institute and Tennessee Oncology in Nashville. We have some additional faculty members who took a survey that we’re going to show you before the end of this program. As always, if you have any questions or cases you’d like to run by us, just type them into the chat room and we’ll talk about as many of these as we have time. We put together a 1-minute pre- and post-meeting survey for you to take. If you do that, we’ll get a — learn a little bit about you and you’ll get a lot more out of this meeting. We do webinars all the time. Next week, we’ll continue our soft tissue sarcoma series. And then later on in the week on Thursday, we’ll be talking about hepatocellular cancer and all the controversy about first-line therapy, adjuvant therapy of HCC. On July 31st, we’ll be doing a program on localized high-risk hormone sensitive nonmetastatic prostate cancer. The EMBARK study and many more new trials coming out in that disease. Then on August 2nd, we’ll do a program on bispecific antibodies in the management of non-Hodgkin lymphoma. We just did a program earlier this week on bispecifics in multiple myeloma. Then on August 8th, we’ll be doing a program on metastatic pancreatic cancer. And on August 10th, a program on the management of melanoma. We’ll have a bunch of video cases being presented for that one. We know a lot of people end up listening to our webinars. If you’re into audio podcasts, check out our Oncology Today series including a recent program with Professor Curigliano. Today, we’re here to talk about breast cancer and one specific focus of it where there’s so much going on. As in other programs in this Inside the Issue series, I met with both faculty members in the last couple weeks to record a PowerPoint presentation that goes through many, many papers and a bunch of cases. And this is really the third part of this program where we’re going to pull some of the slides from the presentations and kind of take it to the next level. Here are some of the papers that are being — that are reviewed in these 2 presentations. I really recommend you check them out. They’re in the chat room if you want to look at them now. Here’s where we’re heading today. We’re going to start out chatting a little bit about the biopharmacology of breast cancer and the endocrinology. Then, we’ll go through some of the things that Dr Bardia talked about in his talk and his cases. Then, Dr Hamilton’s talk. And then, we’re going to finish out with a very interesting clinical investigator survey, as always. Always interesting to see what our faculty members are doing in their practice. So, Erika, when we talked, I was mentioning to you that we actually launched Research To Practice with a program about hormonal therapy. And this is our animation that we used on the hormonal therapy from the 1980s. I think we’ve come a little far — a little ways since that time in trying to understand the biology. But I’ve got to say, a lot of times, I see some of the kind of complex graphics, for example, some of the things in your talks like this slide which I’m going to ask you about in a second. And for me, I kind of get a little bit confused. I just want to take a step back before we sort of dive into this to just ask you how you explain, forget the slides for a second, Erika. You’re on rounds, you’ve got a fellow there, maybe a med student and they say, well how does hormonal therapy work? Why do you give an AI? Why do you use tamoxifen? What’s your vision, you know, maybe 40 years later after that animation, really how hormonal therapy actually works, Erika? DR HAMILTON: Yeah, I actually explain it to my patients a lot of times in these simple terms, right? So an aromatase inhibitor, once the ovaries stop making estrogen, it’s preventing the conversion of steroids into estrogen. So an aromatase inhibitor works by getting rid of estrogen. A SERD, on the other hand, that Dr Bardia is going to talk about, doesn’t care about how much estrogen is floating around. It’s binding the estrogen receptor on the cancer cell, and I say, chewing it up and spitting it out. And so that’s really important in terms of ESR1 mutations where I describe it as a light switch turned on that may be signaling even if that estrogen molecule is not around. And so if we’re chewing it up and spitting it out, that’s how we’re continuing to get activity. DR LOVE: So actually, I kind of maybe wasn’t that clear about what actually ESR1 actually is and the fact that actually, it’s a sign of endocrine sensitivity, Aditya. Can you talk a little bit about what we know about when we see ESR1 and your vision of what’s going on molecularly? DR BARDIA: Yeah, absolutely. You’re exactly correct. So when the tumor acquires a mutation in the estrogen receptor, which would be ESR1 mutations, it becomes resistant to approaches that would lower estrogen like aromatase inhibitors. So the tumor is estrogen independent. It’s still driven by the estrogen receptor, so it’s still ER dependent. So drugs that would bind directly to estrogen receptor like oral SERDs would still work in that setting. So I find ESR1 mutations to be helpful in the second-line+ setting because it provides a very broad surrogate marker that the tumor is still ER dependent. It’s not perfect. There could still be tumors that have this mutation that are not that ER dependent and vice versa. But overall, it gives us some insight that it’s likely that in this setting, the tumor is ER dependent and drugs that directly bind to ER could potentially be effective. DR LOVE: Going back to that same graphic, Erika. You see there, the PIK3 and AKT, we’re going to talk about that later. Again, to me, all I see is upstream and downstream. But what’s your vision of what’s actually going on here? DR HAMILTON: Yeah. It’s another pathway that certainly can cause cells to get the signal to grow and divide. I think the tricky thing about the PI3/AKT/mTOR pathway is that some of these, it matters if you have a mutations and other ones, it matter — it doesn’t really matter if you have a mutation. So for example, everolimus, right? We don’t have to test for mTOR. That’s a drug for all patients that have ER-positive disease. And then, we got alpelisib which very much matters whether you have a PI3 alteration. And then the most recent data with capivasertib is, maybe a little bit grayer, looks like it’s probably more along the mTOR lines, but a little bit increased magnitude of benefit if there was an AKT alteration. So it seems complicated because it is complicated. DR LOVE: Well that’s good to know. And here’s another slide that you showed in your talk and discussed about ESR1. I don’t know if you want to add anything to what you said before, Aditya. But also, the idea of trying to assess “endocrine sensitivity clinically”. For example, we’ll see this later with some of the data, how long were they on the CDK inhibitor before they progressed? Even in the adjuvant setting, patients who progress while they’re on an AI as opposed to after they’ve completed AI therapy. Do you kind of look at these clinical variables, Aditya, when you think through therapy? DR BARDIA: Absolutely. Because at the end of the day, we’re trying to find the best therapeutic option for our patients. In the past, we had limited options. But now, you have a number of options. So you’re trying to select the best therapy which could either be based on genomics or looking at patient’s history. Someone who has disease recurrence on, say, adjuvant endocrine plus a CDK4/6 inhibitor is very different from a patient who completes adjuvant aromatase inhibitor and then 2 or 3 years later has disease recurrence. So those factors do help understand what’s happening from a biology perspective in therapy selection. DR LOVE: So I was just waiting. Usually, Dr Kumar from the FCS is always asking great questions in the chat room. Here he is. Erika, you probably know him from FCS. He’s got a HER2-positive patient actually, but the thing that’s interesting about his case is ER 0 PR 60%. So not so much the issue of being HER2-positive, Erika, but do you use hormonal therapy in a patient who got ER 0 PR 60%? And what kind of other sort of ways do you look at those numbers? DR HAMILTON: Yeah, the more common HER2 pattern is ER-positive with PR loss and being HER2-positive. But this whole PR-positive in the absence of ER, it’s unusual. We see it. I typically don’t think about those patients being very endocrine sensitive. Progesterone receptor tends to signal with ER. And if you don’t have the ER, that PR signaling is not really going anywhere, is kind of how I think about it. But I’m curious to see what Aditya thinks. DR BARDIA: I fully agree. Some actually feel that tumors that are ER-negative PR-positive, that’s more of a lab artifact because biologically, you do need ER along with PR for signaling. So I fully agree, I would not use endocrine therapy for that patient. DR LOVE: Interesting. So I’ve got to say, of all the slides the 2 of you went through, this is the one that really got my attention more than anything else, Erika. I had not even heard about this idea of sort of the spectrum between SERD and SERM activity. Can you explain this, Erika? DR HAMILTON: Well this is my favorite slide too. And I feel a little bit guilty because it’s not really mine. It’s Dr McDonnell’s slide from Duke. And he has a lot of fantastic research in terms of the estrogen receptor. And so this is all kind of endocrine agents. And you see compounds on here that have since been discontinued. We see oldies, but goodies that we know about like tamoxifen all the way over on the right, fulvestrant all the way over on the left. And you can see that these compounds are really kind of a mix between estrogen degraders and selective estrogen receptor modulators or tamoxifen. And so what I find really interesting is that most of the SERDs are in this drop-down box you see, the black box kind of on the left side of the screen. And so they have more SERD activity than they do SERM, but it’s a little bit of a balance. I think it’s really interesting that out of all of the SERDs, elacestrant is actually the most SERM. So I hear a lot of people, oh my gosh, we just need 2 endocrine agents. Why do we need all of these drugs? They’re all the same anyway. And so I think it’s important to remember that they’re not all the same. And so based on an individual patient’s mutational profile, all these other pathways like PI3 and AKT and ESR1 that may be active, there may be certain of these drugs that are better for one patient than another. And this is part of the reason that I think profiling is so helpful because if we don’t look at it, we’re never going to learn. DR LOVE: Any comments, Aditya? And Erika gave her sort of vision of how AIs and fulvestrant work. What’s your vision of how SERD — SERMs actually work? Is it mainly from the direct effect in the nucleus? DR BARDIA: That’s what it looks like. So SERDs would degrade the estrogen receptor. SERMs would block the estrogen receptor, but not necessarily degrade it. And an interesting property of SERM is it’s tissue dependent. In some tissues, it can actually block signaling of ER. And in other tissues, it can actually increase signaling of ER like with tamoxifen, we see blood clots or we see improvement in osteoporosis because in the bone and vascular tissue, it actually increases ER signaling. Current Strategies for Previously Treated ER-Positive Metastatic Breast Cancer (mBC) — Dr Bardia DR LOVE: All right. Well let’s get on to Aditya’s talk. And, Erika, I want you to respond to his first case here of a 65-year-old woman. Aditya, can you present that case to us and what your question is about it? And we’ll see what Erika has to say. DR BARDIA: Yeah. This is a common scenario we see in clinic. This is a 65-year-old female who had ER-positive disease, got adjuvant endocrine therapy with exemestane and then stopped treatment. And a few years later, had disease recurrence. And because it was a few years after exemestane, got treated with letrozole plus a CDK4/6 inhibitor which worked for 2 years. And now, the patient has disease progression just in the bone. No visceral metastases. And the question is, what therapy would you consider in the second-line setting? Fulvestrant? Would you do fulvestrant/CDK4/6 inhibitor? Exemestane/everolimus? Or you would want more information before deciding what to do next? DR HAMILTON: I phone a friend. DR LOVE: And, Erika — DR HAMILTON: I need more information. I want to know whether the patient has a PI3 alteration. I want to know if they have an ESR1 mutation, as we now have approved therapy for that. So I want to know what this patient’s cancer looks like a little bit more. DR LOVE: It’s interesting. As you say, this really is a common scenario and yet the answer to the question really is different than it was probably 2 years ago, very recently. And we’ll see later in the survey that, again, there’s unanimity that both, as you said, PIK3 and ESR1 are really mandatory to make a decision in this case. One of the things you brought up as a possibility was the use of continuing CDK, using CDK after CDK. Again, when we asked the faculty, we hear sometimes people do it. Erika, what’s your take on this question? And in what situations will you use a CDK? Maybe a patient even got it adjuvantly, has been disease free. Would you use it again in metastatic disease? DR HAMILTON: Yeah, we haven’t really encountered those patients yet that received it adjuvantly and then had a long interval and had cancer come back. I probably would reuse it there, kind of treat it like we would trastuzumab and pertuzumab for HER2. As long as you’d had a treatment free interval for a while, you’d consider that patient’s cancer still sensitive to it. In terms of in the metastatic setting, I typically don’t use CDK after CDK outside of a trial. There are certainly good trials. I have equipoise in ordering that. But there’s a lot out there in terms of novel endocrine backbones and we’ve had some trials that have looked positive like MAINTAIN, some that haven’t been an encouraging. So I’m really waiting on bigger trial data to tell me about CDK after CDK. DR LOVE: So this patient actually did have an ESR1 mutation and didn’t have PIK3 and got put on elacestrant, doing well. Aditya, anything you want to say about what we know about this as the first approved oral SERD that we have available in terms of the supporting data? DR BARDIA: It comes from the Phase III trial, the EMERALD trial which looked at elacestrant versus standard of care endocrine therapy. Majority of patients got fulvestrant. So in a way, it was elacestrant versus fulvestrant in two-thirds of patients and showed improvement in progression free survival. So overall, the trial did meet its primary endpoint and the signal was stronger in patients who had detectable ESR1 mutations. And this led to the FDA approval. But another interesting thing in this study which received a lot of attention was if you look at the curves, you see this drop in both the arms and then separation. So median PFS is not a good marker in this setting. And PFS rate at 6 and 12 months is a better metric. But it also highlights, and this has been seen consistently in other studies in the second-line setting as well, can we identify endocrine resistant versus endocrine sensitive patients? So we need better biomarkers to identify that. DR LOVE: And, Erika, this is kind of what we were just talking about before, the idea of endocrine sensitivity. And if you think about this patient, she relapsed after she had the adjuvant AI, so maybe more endocrine sensitive than somebody who would have relapsed while getting it. But anything you want to say about these data showing greater benefit from the agent the longer the patient had previously been on CDK, Erika? DR HAMILTON: Yeah, I think this is beautiful data. It shouldn’t be surprising to us, right? Somebody that only got 6 months duration on a CDK4/6 inhibitor, something’s wrong with that, right? The median progression free survival should be almost 2 years. So that tells me off the bat, this patient probably isn’t as endocrine sensitive as we think. I think the reason we see patients like this on trials is that the physician is worried about them and knows they have aggressive disease and wants to put them on a trial. So I think that sometimes, this is the reason in the real world we see even longer PFS when a drug actually gets approved than on the trial because there’s not this selection bias of being like, uh oh, this is bad, this patient is in trouble, right? DR LOVE: And we’ll talk in a second about some of the SERDs that are being studied. As I mentioned, this patient is doing well, elacestrant. Before we get to the next case, just kind of curious. Any tolerability issues with elacestrant with this patient, Aditya? And have you seen any tolerability issues in general with this agent? DR BARDIA: Yeah, the number 1 side effect is nausea with elacestrant, but majority of patients don’t need antinausea medication. So it’s more something that is, that they notice. It usually is better when you give it with food. Some patients have noticed upper GI symptoms as well, so you can use a proton pump inhibitor if needed. But generally, you don’t need an antiemetic. Besides that, the side effects are similar to what you would see with endocrine therapy, like hot flashes. DR LOVE: So, of course, chemotherapy is an important part of the management of metastatic ER-positive disease as well. And Aditya has an interesting case that kind of will lead us into that discussion. Can you talk about this 55-year-old lady? DR BARDIA: Yeah. So this is a younger patient, 55-year-old female with metastatic hormone receptor-positive metastatic breast cancer. HER2 IHC 0. I think it’s important for us to review that, especially in this setting. This patient had received various endocrine-based options and most recently, capecitabine and paclitaxel. Performance status of 1. No organ dysfunction. Ha germline BRCA testing done which was negative. Tumor genotyping done. PIK3CA and ESR1 wild type. And back to the question of, what therapy would you consider next for this patient? Eribulin? Vinorelbine? Sacituzumab govitecan? Or trastuzumab deruxtecan? Again, HER2 IGC 0. DR HAMILTON: I’d be thinking about — DR LOVE: So, Erika, what are your thoughts about this? DR HAMILTON: Yeah, I’d be thinking about sacituzumab for this patient. She’s exhausted her endocrine therapy. She’s already had chemotherapy. And we know this is the spot where sacituzumab outperforms other single agent chemos. DR LOVE: And, of course, one of the important variables here is the IHC of 0, but we’ll get into how you would think through therapy if it was HER2-low. Can you comment a little bit about sacituzumab? It’s been around for a few years now, Aditya. What have we learned about it and what’s been your experience with it in your own practice? DR BARDIA: Yeah, 3 quick things related to sacituzumab govitecan. First, it’s an antibody drug conjugate that targets TROP2. And the antibody is linked to SN-38 which is the active metabolite of irinotecan. So it’s a way of giving higher doses of SN-38 than you could with irinotecan. Second, in terms of activity. It has shown activity in ER-positive breast cancer as well as triple-negative because TROP2 is overexpressed in all the different breast cancer subtypes. And third, in terms of side effects. The side effect profile is what we would expect with irinotecan, so myelosuppression, diarrhea, alopecia. Those are the common side effects that are seen. Side effects that we generally do not see with sacituzumab govitecan include neuropathy, cardiomyopathy as well as pneumonitis. So not all ADCs are the same, and we’ll come back to this point later on as well. It’s like chemotherapy. We cannot say that all chemotherapies have the same side effect. So it’s important to consider sacituzumab govitecan different from other ADCs. DR LOVE: And here’s some data comparing its efficacy in various HER2 including HER2-low which it seems to be effective and a hazard rate of 0.58. And, Erika, you were saying before we got started, there’s data of saci in the neoadjuvant setting. What do we know about that and where’s that heading? DR HAMILTON: Yeah. Certainly, I think the challenge is that we’re seeing such encouraging data with these antibody drug conjugates, honestly, whether we’re talking about sacituzumab or trastuzumab deruxtecan. There’s a big impetus to get them earlier-line, not wait for third-line disease, and even in the curative settings. So there are trials kind of looking at sacituzumab even in combination with immunotherapy, sacituzumab for residual disease that doesn’t respond well to chemo. And ultimately, I think these trials are likely to be positive. DR LOVE: Any thoughts about the neoadjuvant setting using saci, Aditya? And also, combining it with IO? DR BARDIA: These agents appear to be superior to chemotherapy, and that’s why there’s interest in moving them to early breast cancer like the neoadjuvant setting. And we have some data from a trial called NEOSTAR where sacituzumab govitecan as a single agent was evaluated with a pCR rate of 30% which in general is more than, say, taxanes as single agent which have a pCR of 20%. Now in the neoadjuvant setting, we use combination therapy. And that’s the next step, looking at these ADCs in combination with or without chemotherapy, and also in combination with IO. For a patient with localized triple-negative breast cancer, we use chemotherapy plus pembrolizumab. So there’s interest in combining these ADCs with IO as well. DR LOVE: Yeah, we know chemo plus IO is effective in lung cancer, for example. Actually, in bladder cancer, we had recently the approval of ADC plus IO, so enfortumab plus pembro approved first-line in metastatic bladder cancer. A couple questions from the chat room, Erika, before we get to the next case which is really a variation of the next one. Nicholas wants to know, what are the reasons or do you ever dose reduce elacestrant? And Padima wants to know, suppose you have both ESR1 and PIK3? DR HAMILTON: Yeah, I wouldn’t dose reduce elacestrant out of the gate, certainly. I think somebody that ended up needing a dose reduction maybe for GI toxicity, et cetera. I don’t think it’s a drug that we really think about needing to reduce frequently like abemaciclib or alpelisib, et cetera. In terms of what to do when you really could use either fulvestrant and alpelisib or elacestrant, I think that’s a tough question. I think that really depends on the patient. On one hand, the PFS is longer with alpelisib. So I think the magnitude of benefit there is longer. Even if we look at the BELIEVE study specifically for patients that have already seen CDK, our PFS is a little bit longer. On the other hand, I think elacestrant is much easier to tolerate. And so I think most patients might kind of roll the dice at elacestrant. I completely agree with Dr Bardia that the PFS is a little bit misleading because half of patients just came off at their first scan. So that really dilutes the benefit. I think there’s a lot of patients on elacestrant that really are having a long tail. And I think a lot of people are kind of willing to roll the dice hoping they’re one of those patients. DR LOVE: So, Aditya, another, more stuff coming into the chat room. I knew this was going to happen. Interesting question from Yu. Do you ever use endocrine therapy plus an ADC or sacituzumab plus endocrine therapy? Any thoughts about that, Aditya? DR BARDIA: It’s a good question. On one hand, we do combine antibodies with endocrine therapy like trastuzumab or pertuzumab plus endocrine therapy. But on the other hand, antibody drug conjugates are also like chemotherapy and, in general, we do not combine chemotherapy plus endocrine therapy. There are ongoing studies looking at combination of antibody drug conjugates with endocrine therapy. We have seen some data with trastuzumab deruxtecan in the neoadjuvant setting with endocrine therapy, and at least in the neoadjuvant setting, did not show activity that was higher than what you would expect with ADC alone. But I expect over the next year or so, we’ll have much more clarity about the role of endocrine therapy with ADCs. DR LOVE: So, Erika, another question from Dr Kumar who has a patient. He must have patients with everything. No matter what type of webinar we do, he’s got great cases. So anyhow. A patient who is not very compliant, on an AI and CDK. Responds well for 2 years and then stops. And comes back a year later and now has an ESR1 mutation. Do you go back to the AI or do you switch over? It kind of reminds me of the study, I think it’s with cami, where they’re going to bring in cami earlier in people who flip to ESR1. Any thoughts about this case and about this idea of watching — DR HAMILTON: Exactly. DR LOVE: Yeah. DR HAMILTON: I think the moral of the story is that I don’t really consider that patient resistant to their CDK, right? They stopped and their cancer came back. That’s expected. But now, we have this ESR1 mutation. So that’s probably a patient that I would think about switching the backbone to fulvestrant and giving CDK again. DR LOVE: Any thoughts — DR HAMILTON: And I think the moral of the story is Dr Kumar is busy. DR LOVE: Everybody is busy, I think. Any thoughts about this case, Aditya? And any thoughts about this strategy of switching therapy when you see the ESR1 mutation? It’s being studied in a trial. What about clinically? Is that something you would ever think of doing or you want to wait for the data? DR BARDIA: No, I do. If there is an ESR1 mutation that’s known, in general, I do not use aromatase inhibitors because biologically, it would not work. So I would use an ER-directed therapy, be it fulvestrant or elacestrant or one of the novel SERDs in a clinical trial. DR LOVE: So, Erika, here’s a question I’ve been enjoying asking for the last couple of years. Same exact case that we talked about before, but now we’re saying the patient is HER2-low. So are we still saying sacituzumab, Erika, or T-DXd? Maybe it depends on how sick the patient is or other factors. But in general, what are you thinking in that situation, Erika? DR HAMILTON: Yeah, in general, I’m probably going to use trastuzumab deruxtecan first just for the magnitude of benefit being so much larger. DR LOVE: And we’ll get to this later, Erika, but what about hormone receptor-negative HER2-low? What comes first, T-DXd or — we’ll see what the faculty said. I can’t even remember right now. I think they said saci. But what do you do in that situation, triple-negative? Well — DR HAMILTON: I have more equipoise here. In the trial, the majority of patients were hormone receptor-positive. The number of triple-negative patients was actually very small, double digits as opposed to 400+ that had hormone receptor-positive disease. So I do think the data is a little bit stronger there. So on the other hand, those triple-negative patients seem to do just as well. So I really think that either is reasonable. I think that the sacituzumab data may be a little bit stronger there. DR LOVE: So, Aditya, one of the things you talked about in your talk was HER2-low disease. Anything you want to say about sort of the definition of it and particularly whether or not you have any patients that are HER2 0? If you look hard enough, can you find enough HER2 to call it HER2-low? DR BARDIA: That is what it looks like, that essentially this HER2-low classification is being challenged. So the current definition of HER2-low refers to tumors that are IHC 1+ or 2+. And if it’s 2+, FISH negative. So something that would not qualify as HER2-positive, but there is some HER2 expression. And given the use of trastuzumab deruxtecan which has a bystander effect, as long as there is some HER2 present, it would work in that setting. But if you look at the definition of HER2 0, it’s really not 0. There is some HER2 even in HER2 0. And so that’s why some people have questioned this classification of HER2-low. We’ll have results from DESTINY-Breast06 trial which is looking at trastuzumab deruxtecan in HER2 IHC 0. At this time, until we get the results of that study, I do not use trastuzumab deruxtecan in HER2 IHC 0. Having said that, usually, if you talk to pathologists, the line between 1+ and 0 is quite thin. And often, if either you talk to the pathologist or you get multiple biopsies, you can have a biopsy that’s IHC 1+ and then you can use trastuzumab deruxtecan. DR LOVE: Any thoughts about HER2-low outside of breast cancer, Erika? I know you’re very involved with the gynecologic cancers. I feel like I’ve seen HER2-low data with T-DXd. I think it was biliary tract cancer. Do you think — and we’re seeing T-DXd being used now in multiple different cancers. Do you think HER2-low is going to follow T-DXd into these other cancers? DR HAMILTON: Yeah, I do actually. I think this, it comes back to the mechanism of action being so different than what we typically call HER2-targeted drugs, right? Typically, with a tyrosine kinase inhibitor or trastuzumab, we’re banking on blocking downstream signaling of HER2 and that cell needs to be really dependent on HER2 signaling. And that’s the reason that outside of breast and other tumor types, it’s just been what I call kind of a passenger alteration and maybe not the driver and it hasn’t worked as well. But I think of antibody drug conjugates a little bit differently. The HER2 is a honing mechanism. We’re not really blocking a bunch of downstream signaling, we’re just getting a chemotherapy drug to the right cell and then it’s acting like a chemotherapy. So I do think it has potential there. DR LOVE: So, Aditya, this is another slide from your talk. And I’m hearing these kinds of things, again, with ADCs outside of breast cancer, trying to figure out sequencing of ADCs. I was talking about bladder cancer. They have 2 approved ADCs in metastatic bladder cancer right now. And one of the things that you talked about is trying to look at, when you talk about sequencing, what was the target of the prior ADC and what’s the payload? Can you kind of talk a little bit more about that and where you see that heading? DR BARDIA: This comes up because right now, there are 2 ADCs and there might be additional ADCs in the future including ADCs that have similar antibodies as well as similar payloads. Example being Datopotamab deruxtecan which is a TROP2-directed ADC, but has deruxtecan as the payload. So in a way, it’s like a cross of sacituzumab govitecan and trastuzumab deruxtecan in the sense you have a TROP2 antibody and you have deruxtecan payload. And so if a patient has received trastuzumab deruxtecan and has disease progression and say you have the option of using both sacituzumab govitecan and Datopotamab deruxtecan, which one would you use? Would you switch the payload or would you switch the antibody? I think these are questions we’ll likely grapple with in the future. So we looked at this question based on clinical studies we had done with different ADCs and found that for some patients, there’s cross resistance based on antibody and in other patients, the cross resistance is because of payload. So we need more data, but those are the kind of questions we’ll be asking over the next couple of years. Future Directions in the Management of ER-Positive mBC — Dr Hamilton DR LOVE: Really interesting. Well let’s get into your talk looking at the future including unapproved agents. We talked about the one approved oral SERD and you — I thought this was kind of a cool concept in terms of how you view these SERDs in general. Can you comment on that, Erika? DR HAMILTON: Yeah. So certainly, fulvestrant is a SERD. It has a lot of challenges in terms of the fact that it’s intramuscularly administered and has some PK challenges. So the advantage of these oral SERDs really is the fact that they’re pills the patients can take at home. They work better than fulvestrant does. And specifically that they have activity in ESR1 mutations and have activity post-CDK4/6. So I think that’s really the selling points. DR LOVE: Anything you want to say about — DR HAMILTON: This slide goes through — DR LOVE: Go ahead. DR HAMILTON: Sorry, go ahead. DR LOVE: No, you go ahead. DR HAMILTON: This slide goes through a couple of the different oral SERDs. And so you see elacestrant on the left, camizestrant, giredestrant, imlunestrant. And it goes through side effects. And you’ll see here kind of in this middle where you see red and blue that a lot of the side effects are similar. All of them, to a degree, have some GI toxicity. It’s really hard comparing these Phase I trials and even later-phase trials apples to apples when some of the patient population is really oranges. But I think some have a little bit worse GI toxicity than others, in my opinion. And then, we get these kind of bonus side effects that are a little bit more unusual. We can see bradycardia with a couple of the SERDs as well as actually one of the other compounds, a SERCA. And then, we also see this visual disturbance. I like to call this the movie theater phenomenon. It does not affect reading or driving or constant vision, but it’s when light changes. When you flip on the light or when you flip off the light, you have a little waffle at the edge of your vision for a couple minutes and it goes away. So people describe it as turning the nightstand off at night or walking into the bathroom in the morning and turning the light on. Haven’t had anyone have real issues for that. And then, across the board, all of these drugs are going to work in ESR1 mutations. So I think it’s just encouraging that we have multiple of these out there. You certainly can see that they’re at different doses, but really different compounds. DR LOVE: So, Aditya, any comment on your experience in terms of tolerability of these agents? I was telling Erika that the visual thing sort of reminds me of what I hear from our pulmonary colleagues that you see with crizotinib. I know it’s different, but it kind of reminded me a little bit of that. What’s your experience with these agents in terms of tolerability, Aditya? DR BARDIA: It’s fairly similar. So all of them have some degree of GI side effects. Some have more nausea than diarrhea. And then have unique side effects like visual disturbance or bradycardia. Giredestrant, an oral SERD also, is associated with bradycardia, but at higher doses, 100 mg. So the development dose moving forward is 30 mg. And at that dose, usually we don’t see bradycardia. DR LOVE: And my understanding, the bradycardia is not that profound. It’s kind of a little bit of a drop. Is that what you see? DR BARDIA: That’s correct. It’s usually Grade 1 and it’s something that you see on EKG rather than the patient reporting any symptoms. DR LOVE: So the other agent that we actually see mentioned a lot in our survey is camizestrant. And I’m thinking back to your SERD/SERM diagram too, Erika. Can you talk a little bit about this SERENA-2 study, what was seen there and, again, what your experience is with this agent? DR HAMILTON: Yeah. So as opposed to elacestrant, this is the other trial where we have randomized data now. This wasn’t a registrational trial, but it looked at fulvestrant and then 2 different doses of camizestrant, 75 mg as well as 150 mg. All of these patients had had endocrine therapy. And so it was kind of a second-line setting trial. Some had CDK and some didn’t based on the country they were in, et cetera. And so what we saw was that camizestrant beat fulvestrant at both doses. PFS somewhere in the 7 months compared to a progression free survival of less than 4 months with fulvestrant. And then if you look over on the right, you see how this behaves if we have ESR1 mutations. And not surprising, just like we saw with elacestrant, for patients that have ESR1 mutations, they’re a little more likely to be endocrine sensitive and a little more likely to get even longer benefit out of the camizestrant. DR LOVE: And I was curious when you said some of these people didn’t have CDK, Aditya. And in the beginning, we were talking about your vision of how things work. And I’m curious what your vision is about how CDK works and whether or not it makes any sense to add CDK to a SERD in somebody who hadn’t had CDK. DR BARDIA: It does. I view that CDK4/6 inhibitors are complimentary to endocrine-based therapy. They have a different mechanism of action, so it’s like a punch and a kick against the tumor. Different mechanism of action, but very complimentary. And SERDs in principle would work with CDK4/6 inhibitors as well. And in fact, there are ongoing trials looking at SERD plus CDK4/6 inhibitor versus AI plus CDK4/6 inhibitor in the first-line setting. DR LOVE: And here’s, we already talked about side effects, but I really like the way Erika put this slide together. And here is the study, just as you said, cami plus palbo as first-line therapy. Really interesting. We’ll see how that plays out. Anything you want to say, Erika, about imlunestrant? DR HAMILTON: Yeah, I think the interesting thing about this trial is you’ll see this bonus third arm at the bottom looking at imlunestrant with abemaciclib. So this trial is kind of asking 2 questions at the same time. So patients that have progressed on AI and CDK4/6, is imlunestrant better than fulvestrant or exemestane? But does continuing a CDK improve imlunestrant beyond endocrine therapy alone? DR LOVE: That will be very interesting. This is the study we were talking about before, SERENA-6, where they’re randomizing it to switching when you see the ESR1 mutation. I’m just kind of curious, Aditya, when you put people on AI/CDK, if they’re doing well, are you actually measuring — looking for ESR1? Or if they’re doing okay, no? DR BARDIA: In general, no. So if the therapy is working well, the patients are tolerating the drug well and the scans look good, in my clinical practice, I don’t do serial ctDNA testing. And that’s why this is an interesting study because if positive, it could potentially change practice. DR LOVE: So interesting. And so many other new agents. PROTACs, I’ve been hearing that from the prostate people as well. There’s a lot of analogies between prostate and — I was talking about the EMBARK study. I could go on about that. But anyhow. What are PROTACs? And what’s the future of these agents in your view, Erika? DR HAMILTON: Yeah. So PROTAC just stands for proteolysis targeting chimera. And how it works is it’s the little rainbow molecule. And when it binds its target of interest, which here is the green estrogen receptor, it causes a confirmational change that recruits in this E3 ligase. And what E3 ligase does is it ubiquitinates the estrogen receptor which is essentially a signal for the cell, hey, I’m a foreign invader, chew me up, get rid of me, spit me out. So it’s just a different way of really kind of degrading the estrogen receptor. And so we had this in a Phase I clinical trial, tolerated quite well. Patients were very heavily pretreated here. So you can see, everyone had had CDK, 30% had had fulvestrant, half the patients had had chemotherapy, and we saw good activity. So clinical benefit rate is right around 40%. It looks more right at 40 if you’re looking for all-comers. You can boost that up to about 50 if you’re looking for patients that have ESR1 mutations. And, again, you see this study, a real big push at the FDA to make sure we’ve got the right dose. So just like the camizestrant, they also looked at 200 as well as 500. DR LOVE: And, Aditya, any comments in terms of this strategy, tolerability of these agents? I’m going to guess that maybe they’re going to combine this with other stuff, maybe combine it with a SERD. Any thoughts about all this, Aditya? DR BARDIA: You’re exactly right. ARV-471 is a very exciting molecule. Different mechanism of action in terms of targeting ER, but the results look quite impressive in this heavily pretreated setting. And clinically using this agent, it appears to be well tolerated in terms of side effects. And it is being combined with CDK4/6 inhibitor. There’s a planned Phase I — Phase III trial combining ARV-471 with a CDK4/6 inhibitor versus AI/CDK4/6 inhibitor. So it’s a similar theme to the oral SERDs. DR LOVE: So, audience, we’re just going to go deeper and deeper into this. Complete ER antagonist. Again, prostate has ADT that’s either antagonist or agonist. Any thoughts, can you comment a little bit about what these CERANs are, Erika? DR HAMILTON: Yeah. So our typical endocrine agents act at the estrogen receptor and they block activation function-2. And so that really kind of allows activation function-1 to continue to signal. You can kind of think about this as mTOR1 and mTOR2. But essentially, why it’s called a complete estrogen receptor antagonist is that it can block both AF1 and AF2, so really shut off the signaling. And, again, this is a molecule that we anticipate having activity regardless of ESR1 mutation. So this was the Phase I trial. And you see on the left, monotherapy, on the right, combination with palbociclib. And very similar numbers. Heavily pretreated population. Clinical benefit rates look around 40% again. DR LOVE: So flipping over to AKT inhibition. It’s amazing. Like 3 or 4 years ago, there was like nothing to talk about with endocrine therapy. Now, we’re barely going to get through this in an hour. Let’s talk a little bit about the pathway. We were talking about it earlier. Anything you want to add to that, Erika? And can you comment a little bit about this pathway, capivasertib and also where everolimus fits in? DR HAMILTON: Yeah. So you can see that everolimus is over on the left. That’s mTOR in the red, right? PI3 is the big square in the middle that’s orange. And then AKT is downstream of both in blue at the bottom of our slide. And so what really got us excited about AKT was the FACTION trial. It was fulvestrant with capivasertib and really showed an impressive progression free survival benefit. So you’ve got here the New England Journal article. DR LOVE: Do you want to talk a little bit about what was — DR HAMILTON: So this is CAPI — DR LOVE: Go ahead. DR HAMILTON: Yeah, CAPItello-291. This was patients that had already seen endocrine therapy and they were not required to have CDK, but a good percentage of patients did, about two-thirds did. And they received fulvestrant or fulvestrant with AKT. And what we saw was that fulvestrant with AKT gave us a progression free survival of 7.2 months and this classic less than 4 months number with fulvestrant. The 2 differences on the slides here is whether we’re talking about all-comers or those that have AKT mutations. And so what we see is that AKT, altered or not, with capivasertib tend to do equally well really, right over 7 months. But those that had an AKT alteration did even worse on just fulvestrant alone, 3 months. So this is where we kind of get into the debate. I think the benefit here is probably for all-comers, more like everolimus and an mTOR inhibitor. Also, overall survival. You can see, very encouraging here. Really looking to start to separate which I think is encouraging to see. Sometimes, we don’t see this with smaller advantages in PFS. DR LOVE: A little bit better benefit there with the AKT. This is where we’re getting a lot of questions, Aditya, about tolerability. We already have Kamal in the chat room earlier said, what’s your experience with the tolerability of alpelisib? So I’m curious what you have to say about that, but particularly in comparison to capi. Which I guess one of the things there is the — that it’s not continuous dosing, so I’m not sure how that affects tolerability. But globally, what have you seen with alpelisib, Aditya? And how would you compare it to what you’ve seen with capi? DR BARDIA: With alpelisib, the 3 most common side effects are hyperglycemia, rash and diarrhea. And a lot of interest in capivasertib is also because the side effect profile appears to be better than alpelisib. So there’s less hyperglycemia. There’s less rash. You do see diarrhea which is the #1 side effect with capivasertib. And the thought is that if this agent does get FDA approved, it’ll provide another option to alpelisib in this setting. DR LOVE: So, Erika, Priya in the chat room wants to know, can you use capi after elacestrant? And also, maybe you can talk about your experience with capi in terms of tolerability. DR HAMILTON: Yeah. I think it is better tolerated than alpelisib in my opinion. The problem with alpelisib is you kind of don’t know what side effects you’re going to get, right? Rash can be problematic. The blood sugar can be problematic. The diarrhea can be problematic. Capivasertib is a little cleaner in terms of I’m worried about diarrhea and that’s what I’m managing, but that’s pretty much all I have to manage. So it just makes it a little bit more straightforward. We don’t have information about whether we would use fulvestrant, capiva after elacestrant. They’re kind of both being looked at in the same line now. But maybe eventually, we’ll have some of that data. DR LOVE: So we’ve been talking about ADCs but also, there are some new ones coming along. And, Erika, we’ve heard about this agent in non-small cell lung cancer where interestingly, one of the areas we’re looking at is people who progress on osimertinib interestingly enough. But anyhow. What is HER3 and what is patritumab? And what do we know about it in breast cancer? DR HAMILTON: Yeah. So HER3-DXd is a very similar molecule to Dato-DXd or trastuzumab deruxtecan. It has the same linker, the same exatecan payload except the antibody on the front instead of being HER2 or TROP2 targeting, it’s HER3 targeting. And if we move to the next slide, one of the big questions about this was, well what tumor types is it going to have activity in? And do we need to be looking at HER3 expression? Sacituzumab, we don’t look at TROP2 expression. Right now with trastuzumab deruxtecan, we do although I think we could debate whether we should be with DAISY trial and kind of the question of how low we can go. But this was actually data from Ian Krop at ASCO 2022. And you see yellow hormone receptor-positive, orange triple-negative, and blue HER2-positive, all really showing great activity with this antibody drug conjugate. So this was ICARUS-Breast01. It was presented at ESMO Breast in May of this year. And this was all single agent patritumab deruxtecan, HER3-DXd. And you see the clinical benefit rate upwards of 43%, and these are for patients that have had up to 3 lines of chemo for triple-negative. This was data I presented at ASCO looking at ER-positive or triple-negative disease. And on the left, you see that HER3 is highly expressed on breast cancer. So most patients actually have high, greater than 75%, expression. That’s about two-thirds. Pretty much the remaining one-quarter have low expression, 25 to 74%. And only 4 patients out of this sample of 60 had less than 25. And if you look over on the right side, whether we’re looking at hormone receptor-positive disease or triple-negative disease, we see some meaningful shrinkage. DR LOVE: Any comments on this interesting ADC, Aditya, in terms of — and also, in terms of tolerability, when I see DXd, I start thinking about pneumonitis, but you tell me. What do you see tolerability here? DR BARDIA: It’s an interesting agent because it targets HER3 which is different from the other ADCs we’ve seen, so it’s a novel target from that perspective. And we do know that HER3 is involved in endocrine resistance, some chemo resistance in the HER2-positive setting as well. So it’s good to have an agent that targets HER3. In terms of tolerability, generally well tolerated, some myelosuppression. Correct me if I’m wrong, Erika, but in general, the pneumonitis rate is much lower than what we would expect with T-DXd. DR HAMILTON: Yeah, you’re absolutely right. It is about half what we would expect with T-DXd. DR LOVE: So one more ADC — DR HAMILTON: This is Datopotamab deruxtecan. DR LOVE: Right. DR HAMILTON: It’s a cousin. So we talked about trastuzumab deruxtecan, HER2, and now we’ve talked about patritumab deruxtecan, HER3, this is Datopotamab deruxtecan so this is TROP2 targeting. So you can think about it as a different payload, but kind of a sacituzumab-like molecule, and very similar data. TROPION-Breast01 has complete accrual. We anticipate, this was what I was hinting at we should be seeing in the next year for sure. And this will be Datopotamab deruxtecan head-to-head against chemo. DR LOVE: It’ll be kind of a race between breast and lung cancer to see which one gets, if it gets — maybe it’s going to be approved in both. But certainly, there’s a lot of excitement about this agent. DR HAMILTON: Yeah, they beat us on immunotherapy. We’ve got to beat them on ADCs. DR LOVE: Well we’ll see. Hopefully, you’ll both get there. Clinical Investigator Survey DR LOVE: All right, let’s talk a little bit about this clinical investigator survey. And if we don’t get through all of these, I invite the audience to look through these. So just to sort of as a preface, I thought it’d be interesting to see where people are in terms of choice of CDK. Erika, we’ve been hearing more and more people talk about ribo because of the survival data. Almost a consensus. Dr Burstein has to be a little bit different. Any thoughts though, Erika, about why you see this? Do you think it’s the way the trials were done or do you think there’s something about the ribo molecule that’s maybe more effective? DR HAMILTON: Yeah, I don’t know. Progression free survival with palbo, those trials were so equivalent it was kind of creepy, the hazard ratio of 0.55. And then did not see overall survival. I don’t know why. But the reality is we have 3 approved agents and I have a hard time sitting in front of a patient telling them I feel so strongly that palbo, that they should take palbo over a different one. And so I think that’s why you see most physicians switching. DR LOVE: All right. Now, let’s get into what we’ve just been talking about. And as you can see, it kind of seems like if you’re going to say we need both of these variables that you’re going to potentially have 4 different subsets based on ESR1 and PIK3 positivity. So, Aditya, this is kind of a typical situation. A 65-year-old woman, but she progresses while on adjuvant anastrozole, so interesting. Then, she gets a CDK inhibitor, but then progresses 18 months later. So first of all, before we get into how people sort of sort this through based on biomarkers, Aditya, how would you see this patient clinically in terms of, at this point, in terms of hormone sensitivity? It seems like she relapsed while she was on an AI, but was on the CDK for 18 months. DR BARDIA: It looks like, so this could be a patient who has an ESR1 mutant tumor, so the tumor is still ER dependent and that’s why had disease recurrence on anastrozole, but did well on fulvestrant which is a direct ER-targeting agent with a CDK4/6 inhibitor. DR LOVE: So there’s a lot of data on this, but let’s just focus on Erika. And maybe you can just go from left to right, Erika, and talk about why you make, you think you would make the choice — it’s interesting, even at this point, you’re saying elacestrant or cami. Anyhow. How do you — can you kind of talk about why you would take these different courses? Particularly, I’m interested about your third answer there, ESR1 negative, PIK3 positive where you would go alpelisib. DR HAMILTON: Yeah, I always struggle with your questions when you say regulatory and reimbursement issues aside because these are not the decisions that we unfortunately have the option to make in clinic often. So that’s why I included camizestrant. We’re assuming that I can order any of these. And so I’m thinking about a SERD is pretty much the answer if we have an ESR1-positive tumor. Really, regardless of PI3 because I think that the SERDs are better tolerated than alpelisib. If we go into the third column, now we don’t have an ESR1 mutation but we know the patient has a PI3 alteration. That’s where I’m still thinking about alpelisib and a potential benefit there. And then in the absence of a PI3 alteration, I’m typically thinking about exemestane/everolimus or one of these targeted agents that works despite a mutation. Honestly, capivasertib could be another option as well if it’s approved. DR LOVE: So, Aditya, it’s interesting, we were talking before about, let’s say, double-positive, you know, ESR1 and PIK3. Most people go with the SERD although Dr Goetz wants to try alpelisib in that situation. What’s your thinking about that situation, Aditya? DR BARDIA: In general, I tend to consider elacestrant although you can always use fulvestrant/alpelisib also. But it’s largely because of tolerability and better side effect profile. And in the metastatic setting, it’s a matter of using drugs in sequence. So if you start with elacestrant then after that, you can use fulvestrant/alpelisib or vice versa. DR LOVE: So another question we asked, we were talking before about CDK inhibitors. This way, we get a little bit more of a spectrum of responses. But it looks like people are kind of in agreement that this is a strategy that in some situations would be reasonable to pursue. We talked about that before. We also talked about what, to me, I’ll call a new standard in terms of biomarker workup on patients in the scenario we’re talking about tonight to get both of these biomarkers. Aditya, we were talking before about using trastuzumab deruxtecan in IHC 0. There’s kind of a split here. Some people have done it, or at least Dr Burstein has done it. Others haven’t, but would in the right situation. But also, the question of the patient who has a HER2 mutation. Of course, in lung cancer, that’s actually where they’re using it. I don’t know how often you see HER2 mutant disease, Aditya. Any comments? DR BARDIA: HER2 mutation in metastatic ER-positive breast cancer can be seen. I think the frequency is around 5 to 7%. And it could be a marker of endocrine resistance. So the use of trastuzumab deruxtecan in this setting would be extrapolation from other diseases including lung cancer. So if you’re running out of options, you want to use an antibody drug conjugate, you could use T-DXd. DR LOVE: So we were talking before about sequencing and first-line therapy. We presented a case of a patient who goes through endocrine therapies and then gets chemotherapy. Most people say sacituzumab, and as we talked about before, even earlier. Here’s the way people are thinking through the use of sacituzumab, Erika. Basically, both triple-negative and ER-positive after 1 line of chemo. Can you comment? DR HAMILTON: Yeah, I think that people across the board are just encouraged that the antibody drug conjugates are beating chemo. And so I think we want to use these earlier instead of using kind of naked chemo that’s not getting us as much bang for our buck. And I agree, we spent so much time subsetting patients by mutation and ER-positive and triple-negative. And now, with antibody drug conjugates, it seems that we’re mushing everybody back into one bucket again. DR LOVE: So, Aditya, we also asked the faculty if camizestrant were to become available, in what situations would people use it or prioritize its use? Actually, your — most people say ESR1 mutant disease, but you like to put the patient on the first-line SERENA trial. Any thoughts? DR BARDIA: Yeah, I mentioned first-line because that’s where camizestrant would likely get approved because those are the studies which are looking at this agent in the first-line setting. So if those studies are positive and the gets approved, that’s where I would use it. DR LOVE: What about capivasertib, Erika? Where are you thinking that’s going to fit in if and when it becomes approved? It seems like it certainly has very good data. DR HAMILTON: Yeah, we’re — DR LOVE: So you say fulvestrant naïve — go ahead. DR HAMILTON: Yeah, it seems really everybody is answering the same way. It’s just we’re writing it in different. The disadvantage of free text. So I think we’re all thinking about it second-line or wanting to give it with fulvestrant, the combination that we know of, so we’re wanting the patient to be naïve. And then a lot of people are picking something to make them think that the patient is still endocrine sensitive whether they had prior benefit on CDK, whether they have an ESR1 mutation, something like that. DR LOVE: So we also asked where people think Dato is going to fit in, but also patritumab. Any thoughts, Aditya? Where do you see — would you like to be using these 2 agents right now based on the data that you’ve seen? Do you want to see more data? And where do you think they’re going to fit in? DR BARDIA: I think we need to see the results of the Phase III trial given that we have 2 ADCs, SG and T-DXd. But these drugs have shown impressive Phase I/Phase II results so I would want to use them provided that the results of the Phase III trial look good. DR LOVE: So we asked a whole bunch of questions I’m not going to show because we’re going to actually close out here in a second. But let you, just let you know the data is in there. Very interesting the variability you see also in terms — we asked this question for like 12 different drugs if you want to check it out. This is elacestrant. And Dr Burstein seems to hold medicine more than other people. But we asked this for like 12 different drugs if you want to check it out. In any event, I want to thank Erika and Aditya for working with us on this project. I thank the audience for attending as well. Come on back next week and we’ll hear what Dr Riedel has to say about soft tissue sarcoma and desmoid tumors. Be safe, stay well and have a great night. Thanks so much, Erika. Thanks, Aditya. DR HAMILTON: Thank you, guys. DR BARDIA: Thank you. |