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In this exclusive roundtable video from 口袋女优, three expert leaders in the field of breast cancer discuss the latest emerging and potentially practice-changing data from the San Antonio Breast Cancer Symposium.

Moderator , is joined by , and , in this first of four episodes, in which they discuss updates in the treatment of HER2-positive breast cancer.

Following is a transcript of their remarks:

Rugo: Hello, I'm Hope Rugo from the University of California San Francisco's Comprehensive Cancer Center. I'm here at San Antonio Breast Cancer Conference 2022 with my colleagues, Dr. Joyce O'Shaughnessy and Dr. Jennifer Litton. And we are going to have a roundtable and discuss some of the really exciting new developments and updates on certain studies that were presented here at the meeting. And we hope that you enjoy our discussion.

Joyce, you want to tell us a little bit about yourself?

O'Shaughnessy: Sure. Hi, Hope. I'm a breast medical oncologist at Baylor University Medical Center, Texas Oncology, and U.S. Oncology in Dallas, Texas.

Rugo: Great.

Litton: Hi, I'm Jennifer Litton and I am a breast oncologist at the University of Texas MD Anderson Cancer Center in Houston.

Rugo: Wonderful. So it's really exciting to talk to you about these new developments. I mean, this year, San Antonio, I think, was one of the most packed and interesting in a while, although I think our memories are short, but we had a lot of new data and one of the things I think that's really made a huge splash is antibody-drug conjugates in pretty much all aspects of breast cancer care. And, Joyce, there was some new updates in HER2-positive disease. What did you think about DESTINY-Breast02 and -03? Tell us a little bit about that.

O'Shaughnessy: So, DESTINY-Breast03, of course, we had seen the data before and it's approved -- T-DXd, trastuzumab deruxtecan [Enhertu], is approved in the second-line post-trastuzumab chemotherapy first-line versus -- it was looked at in DB03 [DESTINY-Breast03] versus T-DM1 [trastuzumab emtansine; Kadcyla]. And we saw mature survival data here at San Antonio this year, and it's very positive for survival. We weren't too surprised that its survival curves were already trending beautifully. We saw updated PFS [progression-free survival] and that was enormous, I think it's 0.35, but that's one with the 20 zeros before it got to the 1, you know? And it's still miles and miles apart on PFS, but now we have survival as well.

And so that had already become our standard of care for second line. So I don't think these data change anything, but it's just great to see that it is having a really positive impact on survival. So that's DB03.

DB02 [DESTINY-Breast02] was also for HER2-positive patients -- T-DXd again versus post-T-DM1. It was a choice of one of two standards of care, capecitabine-lapatinib [Tykerb], which we don't really use very much anymore, or capecitabine and trastuzumab. And that was also very positive for both progression-free survival and overall survival. But I think that's not going to be too relevant to us because we're using it in the second line now, so we're not waiting to use a post-T-DM1.

Rugo: Yeah, I think actually DB02 has a bigger role maybe in some countries where you can't access the drug until later or there's a cost issue. It's an interesting question, but I think it's certainly nice to have the supportive data. Was there anything that concerned you about those trials?

Litton: So, I think, again, they confirmed, it doesn't surprise me as we're getting longer follow-up, I think the thing that we need to think about for this drug, which I absolutely think is just an incredible drug, that in the last couple meetings is of course the lung disease.

I thought where we saw the toxicity was what we expected, although we didn't see it in DB03. And I thought Sara Hurvitz [MD, of the David Geffen School of Medicine at UCLA] made a really important comment that I think really needs to be highlighted, which is that they were really watching and keeping every 6 weeks with CT scans. And as we think about how we're going to monitor these patients, I really think that as people do well, and it may be several months -- because that's the survival curves we're seeing -- is that we need to continue to be really diligent in getting those CT scans at every 6 months. I thought that was such a good point.

And really just a low suspicion for anything that you see any ground-glass opacities and to really manage that aggressively and quickly. And I think that's going to improve the toxicity. Because a lot of people did drop out of these studies because of the adverse effects and despite that ... survival benefit. So if we could keep them on ...

Rugo: I know. It is interesting, I mean, I don't know that we'll keep all of them on, but I think that in clinical practice we have to stratify a little bit. And so I've generally recommended if people are at higher risk for ILD [interstitial lung disease], and we know a lot of the factors that put people at risk -- having lung disease already, certainly hypoxia, but abnormal renal function, and living in Asia, which we're not going to be treating people in Asia, living in Asia right now -- and there are probably other risk factors that will come up that will identify previous history of any ILD now, which wasn't allowed in the study, we should probably be scanning every 6 weeks. But in patients at lower risk, probably 9 weeks is a reasonable interval for a clinical practice, I think.

And then the idea of re-treatment, if you have grade 1, you ... skip a dose, give steroids at a half mg/kg, and if they get better you can re-treat them. And my experience has been very good using that approach.

O'Shaughnessy: Yeah, the DB03, the initial rate of ILD was 10%, and with longer follow-up and just longer treatment it went to 15%, but still no depth in the earlier line. So the later line patients get, the higher the risk. So it's good that we're using it second line.

Rugo: Although I don't know, I mean now it's 15% for DB03 and that was second line.

O'Shaughnessy: Right.

Rugo: That's identical to the pooled analysis risk. So I think that may be sort of where it is, no matter where you treat patients. I mean, it'll be interesting to see when we get to the neoadjuvant and adjuvant setting if we see a lot less. But it is interesting. And we have seen now, of course, data with trastuzumab deruxtecan in HER2-low disease, the striking data from DESTINY-Breast04. And there was a huge session talking about what HER2-low is, and is it a separate entity?

And we heard from three people, David Rimm [MD, PhD, of Yale School of Medicine], talking about the pathologist's perspective, which was kind of an interesting talk. And then we heard from Giuseppe Curigliano [MD, PhD, of the University of Milan] who was a pro -- yes, it's a separate entity, but all I got out of it was that he argued it wasn't. And then Sara Tolaney [MD, MPH, of Dana-Farber Cancer Institute] who argued that it wasn't. So basically we got from all three of them, it's not a separate entity.

But I was interested in your thoughts about testing and what you do, because one thing Sara recommended was that if you had a positive test any time, that that would be good enough. Is that how you would think about it too?

Litton: I think it's really interesting because we all know there's really a problem with concordance on HER2-0, HER2-1, and the central testing. I thought that was very interesting. I think Sara made a really good point. I think that giving the patient the benefit of the doubt, the way the studies were doing, if I had someone with HER2-1+, 2+, I would definitely try it.

O'Shaughnessy: And there were data on DESTINY-Breast04, it was a poster spotlight, I think. So they looked at DB04 and of course everything had to be centrally done to be HER2-low for 1 or 2+. And the investigators mainly sent in what they thought was going to be HER2-low. And there was 78% concordance, so 22% were discordant. The vast majority were zero. There were a few that actually were HER2-positive, but there was mostly zeros. So that was one thing, 78% concordance between local and central. But then if you look at what the local had called 1 and 2, about a third of the time it went the other way. So if it was a 2+ locally, it was a 1+, or if it was a 1+, it was a 2+.

But still, that's okay, but then there were zeros, there were about 45 zeros -- 46 zeros. And of the zeros that came in, because we'll just try, we'll get the central review, we'll see what they say -- 23 were HER2-low. So that's the big issue, is that they're being called zero out there.

But the other thing that was interesting is that, to the point about primary versus metastatic biopsy, because the primary could be a long time ago, and if the primary was positive, who knows what the metastatic is. The patients got the same benefit as if the metastatic biopsy was positive.

So, I must say, having said that, if I have a 1+ from 15 years ago primary and I'm getting a liver biopsy on somebody with serious liver disease, and it's zero? Do I treat her on the basis of the primary 15 years ago if she's got a zero right now? And we know it's heterogeneous in there and I'm only getting this much, but ...

Rugo: You don't want to use sacituzumab [Trodelvy] for that situation. But then of course it brings up the question of sequential ADCs [antibody-drug conjugates], which I think are really interesting. Also, there's interesting quantitative testing of HER2, which David Rimm talked a lot about, and that might help us a little bit in the future.

But I think it's important for our listeners to understand that there's actually now quite a lot of data and there were a lot of very interesting posters at the meeting that talked about the fact that HER2-0, 1+, 2+ is quite a variable finding. And so it's sort of continuously in motion as far as we could tell, like going from neoadjuvant to surgery and the metastatic primary to metastatic, even over the course of treatment, it really varies a lot. So that means that we do have to make some difficult decisions that we don't totally understand. So I think right now we're just giving the drug the best we can.

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