Breast Cancer Takeaways from ASCO

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I am happy to be joined by Dr. Megan Cruz, a Medical Oncologist and Director of the Clinical Breast Cancer Research Program here at Cleveland Clinic. She was previously on this podcast to discuss the differences in management of invasive lobular breast cancer and invasive ductal breast cancer. And that episode is still available for you to listen to. She's here today to discuss highlights of the research on metastatic breast cancer discussed at the 2025 ASCO Conference. So welcome back Megan.

Megan Kruse, MD: Thank you for having me.

Dale Shepard, MD, PhD: So remind us what you do here at Cleveland Clinic.

Megan Kruse, MD: So I am a breast medical oncologist, so I spend about half of my time seeing breast cancer patients across the clinical continuum in the office, so early stage disease, metastatic disease. And then the other half of my time is spent running our clinical research program. So developing our portfolio of trials that we feel covers our patient's best interests and needs, as well as developing new trials for the next advances coming down the road.

Dale Shepard, MD, PhD: Excellent. And speaking of advances, you just weathered the storm with 45,000 of your favorite people at ASCO and there were some interesting studies and we're going to talk about three of those.

Megan Kruse, MD: Sounds great. It was a tremendous meeting for breast cancer. I don't recall a meeting that had this many potentially immediately practice changing implications. So it certainly makes your head spin but pretty exciting.

Dale Shepard, MD, PhD: Yeah, that's fantastic for patients. So I guess the first one let's talk about was one that was actually presented at the plenary session. It was a trial called the SERENA-6 trial. So give us a little bit of an idea what that trial was about.

Megan Kruse, MD: So SERENA-6 was really interesting. I've not seen a plenary involving breast cancer that had this much controversy around it. And so I think that breast medical oncologists really believe in the idea behind SERENA-6, but knowing how to implement it is a whole nother beast. So the idea behind this trial really started a few years back when there was a trial called PADA-1 that came out and this was taking the idea that we can predict which patients in the first line metastatic hormone receptor positive HER2 negative treatment setting will develop resistance to standard of care therapy with an aromatase inhibitor and targeted therapy with the CDK4/6 inhibitor. Because we know that the most common mechanism of resistance in that situation is development of an ESR1 mutation, and this really renders the estrogen receptor active. So it doesn't matter if you block the production of estrogen any longer, it's as though the body has estrogen around all the time. And we know patients with this mutation are no longer sensitive to aromatase inhibitors.

And so the idea initially behind PADA-1 and then ultimately behind SERENA-6 was if you identify that mechanism of resistance early through blood-based circulating tumor DNA rather than waiting for disease progression on scans as we typically do, does that actually allow patients to have a longer ultimately disease control period with a CDK4/6 inhibitor by switching off of the aromatase inhibitor and onto an estrogen receptor blocker. In PADA-1, that was Fulvestrant. Here in SERENA-6, it's a novel oral SERD called Camizestrant. And so the trials were pretty similar with the foundational idea of looking for this sort of molecular progression, detecting the ESR1 mutation in the blood before you have radiographic progression on scans. And so, not surprisingly, PADA-1 showed that the strategy worked in terms of progression-free survival, but the criticism back then was is this just lead time?

Are we finding something and acting on it early when ultimately a patient's overall disease outcomes wouldn't be any different by changing therapy early? And SERENA-6, the trial took a bigger approach to this, taking patients again in the first line hormone receptor positive, HER2 negative metastatic setting that were already on aromatase inhibitor and CDK4/6 inhibitor. As long as they had had disease control for six months, then doing standard ctDNA monitoring usually along with scans every two to three months looking for this ESR1 mutation.

And so the top line results or the study of it in SERENA-6, those patients who did have a switch in medical therapy over to the oral SERD Camizestrant versus staying on AI along with their CDK did seem to have better cancer control outcomes measured by PFS. I think the concern about that is we don't really know how the patients did in the control arm once they did switch over therapy to an oral SERD. And actually most of them didn't go on to get a SERD of any kind, whether it was the new oral drugs or regular old intramuscular Faslodex, only 10% of the patients in the control arm ultimately went on to get a SERD.

Most of them actually went on to get chemotherapy. So while this was a positive trial, and I think it's very thought-provoking, it doesn't necessarily fit who our patients are in reality and what they receive for second line therapy.

Dale Shepard, MD, PhD: And we think about these things like the ctDNA testing, is this something that's being done really, and I guess I ask because I don't treat breast cancer, is this being done as standard of care universally or is this part of a research construct?

Megan Kruse, MD: Yeah, the way it was done in this trial is entirely research-based. I think we can do this. We typically get a lot of ctDNA. It's been a big win for our patients because so many of our breast cancer metastases are hard to biopsy. If they're in the bone, may be hard to reach and then we worry that the results may be impacted by the technical ability to get the DNA out of the bone. So I think ctDNA in general has been really great for breast cancer, but we tend to do it at times of clear radiographic progression when we're looking to see what the next targeted treatment option may be. And there are a whole bunch of those targeted treatment options that exist in the second line. So I think what's different about SERENA-6 is we're not waiting till radiographic progression. So we're not looking for mutations other than just ESR1. If we were making the traditional treatment change in the second line, we'd be looking for ESR1 as well as things like PIK3CA, PTEN alterations. So that whole panel of information is important.

And typically we don't do it at the cadence that was done here in SERENA-6. Every two to three months is really quite a bit. And I think that's where a lot of the strife and conflict about this trial comes in is what is the impact of that on patients and providers and office practices. It's a lot of testing, it's a lot to keep track of. It's a huge financial burden for the system.

And I think we don't really have great quality of life data from the study quite yet. There was one piece of data that talked about global quality of life, which included a lot of physical symptoms and it seemed to be in favor of the switching strategy to Camizestrant for patients. But I think a lot of us wonder what is the impact psychologically of having all this testing, waiting for results to come back. And if you know that you have progression molecularly but you feel fine in your scans look fine, what is the implication on overall quality of life? So it is a version of what we do in practice, but certainly a much more extensive testing strategy.

Dale Shepard, MD, PhD: And at this point too early to have overall survival information. Is that-

Megan Kruse, MD: That's right.

Dale Shepard, MD, PhD: ... anticipated? Because I guess what comes to mind is a plenary about 10 years ago in ovarian cancer looking at CA 125 as a marker. And certainly quality of life was lower in people that had the testing information and they got more chemo and changed therapies more often. Much like we're looking at here, but ultimately the overall survival is equivalent.

Megan Kruse, MD: Exactly. And I think that's the concern is we've had situations like this in breast before as imaging has gotten better and as the tumor markers have gotten better where we've tried to look for progression early and it ultimately just doesn't seem to matter in the long run. And so overall survival of this trial will take a long time because these patients do generally well for years. But it will be important to see, and I think a lot has been made about seeing PFS-2 data from this trial, which is going to be hard to honestly make a lot of because the PFS-2 really isn't the same between the intervention arm and the control arm. The control arm is almost on PFS-3 by the time you measure "PFS-2", whereas the control arm is at true PFS-2. And knowing that so many of the patients in the control arm didn't go on to get oral SERD, which really would be the pattern in the U.S., further presentations of this data will need to be taken with a grain of salt for sure.

Dale Shepard, MD, PhD: And PFS-2 was at 24 months, is that correct?

Megan Kruse, MD: Right. So I think that's the other thing that's interesting about this is if you look at the typical duration of control for patients on first-line therapy with an AI and a CDK4/6 inhibitor, you're expecting that to be around 24 to 28 months. And so you are waiting a long time. And patients who were on the control arm, even when we knew they had an ESR1 mutation and stayed on standard therapy, which you would predict wouldn't work, they were still on it for about nine months before they switched to their true second-line therapy. So it's really interesting what's happening within that nine months. Are you just developing more resistant clones? Is there a little bit of change on scans but it's not considered clinically meaningful or meaningful per the clinical trial? And you just wonder that if you switch patients early, are they really losing that nine months in which the control arm was stable, taking apart the whole idea of testing and all the implications of that as well.

So I think it brings up a lot of questions. When I look at this, the improvement in quality of life, I wonder if that is just the difference between aromatase inhibitor, which tends to have a lot more arthralgias and joint stiffness and these SERDs which don't seem to have that. So I could see where there might be a tangible physical improvement on one endocrine therapy versus the other, but that doesn't necessarily mean it has anything to do with cancer progression and cancer control. It may just be we have more tolerable agents. So there's a whole new wave of these studies looking at use of the oral SERDs in the first line that are coming. And that may actually end up being the better strategy. You're treating more patients for whatever resistance mechanisms they may have earlier on with the more tolerable drug. So I wonder if the implications of SERENA-6 are only going to be a snapshot in time until we're using oral SERDs more universally and then some of this concern goes away.

Dale Shepard, MD, PhD: So certainly it's going to be interesting to see how this gets shaken out over time, and it's certainly thought-provoking. So let's switch gears. How about triple-negative breast cancer and the ASCENT-04 trial?

Megan Kruse, MD: Yeah, so triple-negative breast cancer, it's really nice to see a study that's positive in the metastatic triple-negative space because we know that these patients really need new treatment options. And we just talked about the patients in the first line hormone receptor positive space. They're getting upwards of three years of control on their first line therapy, whereas these metastatic triple-negative patients, we're lucky if we get a year of control.

And typically, once you get through that first line therapy for triple-negative patients, there's really a steep drop-off of patients that either don't reach second line therapy or have very, very short disease control on second line therapy. So here, maximizing first line therapy is really of key importance and that's actually what ASCENT-04 looked at. It was a trial for metastatic triple-negative breast cancer, specifically those that were PD-L one positive. Where the standard of care right now is chemotherapy plus immunotherapy typically in the form of pembrolizumab in combination with either a taxane or a platinum Gemcitabine combination.

And so in this trial, those standard of care therapies were compared to antibody drug conjugate therapy in the form of sacituzumab govitecan or TRODELVY along with pembrolizumab . And what was found was that there was about a three-month improvement in progression-free survival in favor of the TRODELVY + pembrolizumab arm. And I think we expected that to be the case. Sacituzumab govitecan is a drug that we use a lot in the later line setting for triple-negative disease. And actually in practicality, we've used it in first line for patients who are getting earlier stage treatment with chemotherapy immunotherapy and may have seen all the typical drugs by the time they have a metastatic recurrence.

And so we have a lot of faith in the drug, a lot of experience using it. And so I would say it wasn't a surprise that this was a positive trial, but I think it's a nice step forward because it hopefully will give us another treatment option for patients that really come to their metastatic diagnosis pretty heavily pretreated already. I think that this is actually data that we can apply right away. It's not yet a labeled indication and it's not yet in the guidelines, but sacituzumab govitecan we use all the time and so for the right patient, I think it'd be reasonable to apply this now.

Dale Shepard, MD, PhD: So that's good. So like you say, this is one that frequently comes up is one, we're looking for novel therapies. So good to see that something that quite honestly we're already utilizing. We see a lot of trials with current therapies being rearranged and they don't necessarily work so well. So good to see a success here.

Megan Kruse, MD: Yeah, it is. And actually I really applaud the sacituzumab govitecan investigators because when they originally got this drug approved, they intentionally looked at later line treatment patients. So the original ASCENT study was in patients who had had up to three prior lines of therapy. And so when you look at those results, sometimes they don't look as impressive, but you realize when you move it up to an earlier treatment setting, it does work and it works very, very well. And there were no new toxicity concerns identified, which I think is equally important because we know that sacituzumab can be tough on the GI tract and of course, pembrolizumab can have GI toxicities as will. But thankfully, the combination was pretty well tolerated, no serious issues identified.

Dale Shepard, MD, PhD: And so I guess let's then turn our attention to HER2 therapies, and ADC therapies and HER2 positive disease, and that would be the DESTINY-Breast09 trial.

Megan Kruse, MD: Yeah, DESTINY-Breast09, another blockbuster, but a little bit controversial a trial.

Dale Shepard, MD, PhD: Seems like that was a theme, controversy.

Megan Kruse, MD: That was a theme. I would say this is one of the first conferences where we have clearly positive studies that got a very large platform where we're individually deciding how to use them in practice. So I normally think about, say a plenary session with SERENA-6 or this late breaking Destiny-09 being immediately practice changing. And while they are, I think they are with a little caveat, right? How are we actually going to use them?

Dale Shepard, MD, PhD: We're a tough crowd, aren't we? We're like, we need a positive trial. And then we get one and you're like, wow.

Megan Kruse, MD: Exactly right. The standards have been raised, they're going higher and higher every time. And again, like the theme from ASCENT-04 where we expect an antibody-drug conjugate therapy to best chemotherapy, that's really what we saw in DESTINY-Breast09 where trastuzumab deruxtecan took on and actually was more active than our standard first line therapy for HER2 positive disease, which is taxane, trastuzumab, and pertuzumab, or the Cleopatra regimen as we like to refer to it. And that's really been the hallmark regimen for the better part of a decade for these patients and partially because it's very tolerable, but also because it works extremely well. Again, progression-free survival in the first line for these patients being on the order of closer to two years. So we knew that it was going to be a high bar for trastuzumab deruxtecan to meet, but trastuzumab deruxtecan has been great in every trial we've seen it in so far.

Now, I will say that one of the key things to keep in mind about DESTINY-Breast09 is it was actually a three-arm trial where the Cleopatra regimen was compared to trastuzumab deruxtecan alone and the combination of trastuzumab deruxtecan + pertuzumab. And what we saw at ASCO 2025 was the trastuzumab deruxtecan + pertuzumab arm. So we've yet to see what the activity of trastuzumab deruxtecan as a single agent will do, and hopefully we'll be seeing those results later on in the year. But there was actually about a 14-month improvement in progression-free survival in favor of the trastuzumab deruxtecan + Pertuzumab arm. And the devil is in the details as per usual with trial design. The big difference between this and our typical standard of care is that when you use the taxane, trastuzumab, pertuzumab, cleopatra regimen, that's six to eight cycles of induction type chemotherapy plus targeted therapy followed by often a very prolonged period of just targeted therapy alone.

Whereas in this trial it was trastuzumab deruxtecan + pertuzumab or the single agent essentially until progression. And so you don't get that clear maintenance phase that is so important for our patients where they're growing their hair back, they're not having GI toxicity, their counts are a little bit better. And most importantly, I think their energy levels are better on targeted therapy alone. And so this progression-free survival advantage is very striking. But you wonder what would happen if you did trastuzumab deruxtecan + pertuzumab in the more induction way for a set number of cycles or until best disease response and then follow it up with just that maintenance trastuzumab, pertuzumab. And that's what we really, I think as clinicians want to see. So we won't see that data. I think that's going to probably come from real world application of this. So I'm very, very curious to see what individual practitioners and practices do with this data moving forward.

Dale Shepard, MD, PhD: And I guess one of the big things, patients tend to really, really try to avoid chemo psychologically from a side effect standpoint of taxane therapy. So what kind of impact might that have in terms of being able to sort of eliminate that taxane?

Megan Kruse, MD: Yeah, I think it's huge because if you come into this knowing that it's going to be tough in the beginning, getting the taxane for six or eight cycles, but you have that finish line in sight, right? You're not going to do that for three years, four years, five years. So the psychological impact of being on antibody-drug conjugate fundamentally chemotherapy for whoever knows, it could be many, many years, I think that's really hard. And there was also a poster at ASCO showing that out of the group from Dana Farber, that scalp cooling, which we actually use a lot for women receiving the taxane-based combination for first-line HER2 positive disease, where it's really effective in preventing hair loss, that same technology doesn't work as well for the antibody-drug conjugates. And so when you're going from a situation where outwardly a patient, you wouldn't be able to tell they're going through this at all and then they're on maintenance therapy after six or eight months and really living their lives pretty normally.

That maintenance therapy now in the form of PHESGO can be given as a subcutaneous injection. So that's really great for quality of life. And then contrast that to the antibody drug conjugate IV every three weeks with everything that comes along with sustained chemotherapy. And trastuzumab deruxtecan, it's a much more tolerable drug than I think we all thought it was going to be when it first came out, but it's still chemo and it still has a long-term risk of what can be fatal interstitial lung disease. And so I think we are going to find out more of how we balance this and a lot of the information about who developed ILD and who's at risk for that. There were actually two deaths on the Destiny-Brest09 study related to drug associated interstitial lung disease. So all of this efficacy comes with a cost for sure.

And then we have to balance it with a study we saw earlier in the year where for those patients with hormone positive, HER2 positive metastatic breast cancer in the PATINA study, that the addition of palbociclib in that maintenance phase actually had an outstanding improvement in progression-free survival over two years. And so you're mixing and matching trials to get your patient the best outcome, but there are more tolerable options out there other than trastuzumab deruxtecan. So I think it's going to come down to patient selection and we're going to get a feel for this. And the data certainly has a place, but this is why it makes me stop and think and why it's not just so immediately practice changing for every single patient with HER2 positive metastatic breast cancer we see.

Dale Shepard, MD, PhD: So it sounds like a good outcome, but one of the big questions is can you minimize treatment?

Megan Kruse, MD: Yeah. And now that these patients have such great overall survival, there are certainly some of these patients that we may actually be curing, especially those with de novo, HER2 positive metastatic disease, do they really need this intensity of treatment for that long? There is actually a smaller single-arm study looking at, I think what the clinically appropriate question is going to be. It's called the DEMETHER study, and this is going to be that induction T-DXd or trastuzumab deruxtecan followed by maintenance versus doing the antibody drug conjugate long-term. And I think that, we'll be able to compare a little bit with the study that has been done, DESTINY-Breast09, to get a sense of what we might actually be doing in clinical practice or what our temptation to do in clinical practice would be.

Dale Shepard, MD, PhD: Well, it certainly looks like it was a great year of data at ASCO, controversial but great. Hormone positive, triple-negative, HER2 positive. A lot of good data being presented and appreciate you coming to summarize it for us today.

Megan Kruse, MD: Absolutely. Thanks for having me. It's rare that we get a conference where we practice changing trials across all the breast cancer disease states. So again, raising the bar, but it's certainly fun and I think it allows us to use our brains and really individualize treatment options for patients.

Dale Shepard, MD, PhD: Yeah, the controversy with great results is a good problem to have, right?

Megan Kruse, MD: Absolutely.

Dale Shepard, MD, PhD: All right. Well, thanks for being with us.

Megan Kruse, MD: Thank you.

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