Listen to Aditya Bardia, MD, MPH, FASCO, and Ruta Rao, MD, as they discuss multidisciplinary care of patients with HER2-negative/ultralow/low metastatic breast cancer, with a focus on ADCs.
In this podcast episode, Aditya Bardia, MD, MPH, FASCO, and Ruta Rao, MD, discuss ADCs for HER2-negative/ultralow/low metastatic breast cancer, including:
Presenters:
Aditya Bardia, MD, MPH, FASCO
Professor of Medicine
Geffen School of Medicine
University of California
Los Angeles, California
Ruta Rao, MD
Medical Director, Rush University Cancer Center
Professor of Medicine
Rush University Medical Center
Chicago, Illinois
Content based on an online CME program supported by educational grants from AstraZeneca and Daiichi Sankyo, Inc.
Link to full program:
https://bit.ly/47JLtBt
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Experts Discuss ADCs for HER2-Negative/Ultralow/Low MBC
Dr. Aditya Bardia (University of California): Hello, everyone. I am Aditya Bardia, Medical Oncologist at UCLA and look forward to the discussion today.
Dr. Ruta Rao (Rush University Medical Center): I am Ruta Rao, a Breast Medical Oncologist at Rush University Medical Center in Chicago, and I am pleased to be here with you all today.
Dr. Bardia: Excellent. Thanks, Dr. Rao. Let me set the stage. Why do not we talk about HER-low, HER2-ultralow, and what does HER2 expression essentially mean in metastatic breast cancer in 2026?
Dr. Rao: Yes, it is a great question. This is a definition that has really evolved over the last few years. Previously, we used to think of HER2 classification in a very binary way. It was either HER2-positive or patient was HER2-negative.
Today, we have these classifications of HER2-ultralow and HER2-low. Today, we have newer classifications. We know that our patients who are traditionally thought to be HER2-negative can be reclassified as HER2-low, HER2-ultralow, or HER2-null, which is truly zero. This is really important for us to know about a patient's tumor because it can make them eligible for treatments, specifically for trastuzumab deruxtecan, which is now approved in the setting of HER2-low and HER2-ultralow ER+ metastatic breast cancer.
Dr. Bardia: Yes, absolutely. It has been a game changer because previously we were looking at HER2-positive and negative for trastuzumab. But HER2-negative does not necessarily mean that there is no expression of HER2.
If we go back and look at our classification for HER2, HER2-positive was defined as immunohistochemistry 3+ or 2+ along with FISH amplification, but 1+, which means that there is HER2 expression was classified as HER2-negative, but now we have this new category of HER2-low.
Even HER2-zero technically was tumor cells that have either no expression or 0% to 10% of tumor cells having some HER2 expression was classified as HER2 IHC 0, but zero is not necessarily 0%, and that is this new classification of HER2-ultralow, where 1% to 10% of tumor cells have some HER2 expression. So it has really been a game changer.
Dr. Rao, have you had pushback from oncologists or pathologists in terms of if there is a tumor that is, say, HER2 IHC 0 or HER2 IHC 1+ trying to reclassify that as ultralow or HER2-low?
Dr. Rao: We really, in clinical practice, have not had that pushback. We did have to make an effort to discuss and educate our pathologists about trying to define, especially the category of HER2-ultralow, the patients who are zero, but have this, as you mentioned, 1% to less than 10% expression of HER2. Because otherwise these were patients who were classified as HER2-zero.
To ask them to go back or now in our pathology specimens that they report out now, we are asking them to report zero or zero-plus. Once we had this discussion with them, it was pretty straightforward, but I think it was a matter of educating them. They are always trying to help us out in terms of finding new treatments for patients, so they were more than willing to do it. It was just letting them know why it makes a difference to us clinically.
Dr. Bardia: That is a great point. That is education so that the team is aware that this is a new category and it is important because that is actionable. That is a message for practitioners, providers, oncologists that if there is a patient who has HER2-negative disease or you see a prior specimen that is HER2 IHC 0, zero does not mean 0%, and it is important to evaluate and see if that could be ultralow because that is potentially actionable with newer therapies, particularly trastuzumab deruxtecan.
Any final thoughts related to this topic, Dr. Rao, before we move on?
Dr. Rao: Yes. One other thing I think about when I am seeing these patients with metastatic breast cancer is that we do have some heterogeneity in their different tumor samples. Oftentimes you might have a patient who had a biopsy that has some HER2 defined on it, a mastectomy or lumpectomy specimen, and then a specimen from their metastatic disease diagnosis.
I would like to identify any patient who is eligible for this. In my practice, I will look at any of these specimens to see if there is any HER2-low or HER2-ultralow expression in any of them, and then consider the patient eligible.
Dr. Bardia: Great point.
Dr. Rao: Great. Let us move on, Dr. Bardia. I would love to get your thoughts about antibody drug conjugates. We have seen these really take over in terms of treatment of our metastatic breast cancer patients. Maybe we can start by talking about antibody drug conjugates in the ER+ metastatic breast cancer space.
Dr. Bardia: Absolutely. These are slowly replacing chemotherapy. If you look at management of ER+ metastatic breast cancer, usually we use endocrine-based therapy, CDK4/6 inhibitors, oral SERDs if a patient has ESR1 mutant disease, PI3 kinase AKT inhibitors for patients who have alterations in the PI3 kinase pathway in the tumor.
But then after a patient has disease progression on endocrine-based therapy, we usually go to chemotherapy, and that is where antibody drug conjugates come in. The current ADCs we have are essentially targeted chemotherapy. They have an antibody that binds to an antigen that is overexpressed in tumor and then deliver the payload which is a chemotherapy agent.
There are three that are FDA-approved at this time:
In terms of these different agents, it is important to know about HER2-low and ultralow because that is actionable with trastuzumab deruxtecan. Pivotal studies, DESTINY-Breast04 and DESTINY-Breast06, essentially showed that trastuzumab deruxtecan or T-DXd is superior to standard chemotherapy, be it eribulin, navelbine, or even oral capecitabine.
The progression-free survival was much higher with T-DXd as opposed to these standard chemo agents. Essentially that has replaced standard chemotherapy. In these trials, patients with HER2-low and ultralow disease were included. That is why it is important to look at this.
In these trials, any prior specimen that had HER2-low or ultralow was considered eligible for the trial. So it need not be the last biopsy. It could be the primary breast cancer specimen or a prior archival specimen.
The other agents target TROP-2. So both sacituzumab govitecan and datopotamab deruxtecan target TROP-2. The HER2 expression in a way does not matter because the drug targets TROP-2. These are drugs that are approved both for HER2-low, ultralow disease, as well as the small category of HER2 IHC null or completely zero.
In terms of how to use these agents, these are all options to consider. Generally, given the significant results we have seen with T-DXd and significant magnitude of overall survival improvement, generally T-DXd is prioritized first. Then after that, one has an option of using Dato-DXd or SG.
I am curious to hear from you as well, Dr. Rao, given that we have these three agents, how do you use them? How do you sequence these drugs for patients with ER+ metastatic breast cancer?
Dr. Rao: Yes. Having them available has really been, like you said, a game changer for our patients with metastatic breast cancer. The issue we face in clinic is that we do not really have any data on how to sequence them. I would agree with what you said that, in general, if a patient has HER2-ultralow or HER2-low expression, then trastuzumab deruxtecan is my first choice of ADC. If a patient is truly HER2-null, then we really have our choice between Dato-DXd and SG.
In subsequent lines of therapy, what we have seen from some real-world analyses is that sometimes there is some efficacy with a second ADC after a first one. But in general, we get the biggest bang for our buck from the first ADC that a patient receives.
Dr. Bardia: Yes. Makes sense, and partly speaks to potential cross-resistance between these drugs, because all the three FDA-approved ADCs in this space, Dato-DXd, SG and T-DXd have similar payloads. It is identical with Dato-DXd and T-DXd which is deruxtecan and even sacituzumab govitecan. Govitecan and deruxtecan, both are TOP-1 inhibitors. So there is definitely some cross resistance because of similar payloads. It is an open question at this time in terms of how to sequence these drugs.
Dr. Rao: Right. And one of the things is when a patient progresses on one, we are not quite sure if they have become resistant to the antibody or to the target. We know that trastuzumab deruxtecan and Dato-DXd have the same payload, and Dato-DXd and SG have the same antibody, the anti-TROP-2. That is yet another thing to think about when we are sequencing these.
Dr. Bardia: That is a great point. Absolutely. We need more research in terms of trying to understand resistance related to these ADCs and how to sequence them.
I guess at this time, then the question becomes how do we select? Say, a patient receives T-DXd and then has disease progression, how do we select between SG and Dato-DXd?
I can talk about my practice. Often it boils down to the adverse effect profile. These drugs have different AEs, so both SG and Dato-DXd are TROP-2 ADCs with similar payloads, but the side effect profile is quite different. SG or sacituzumab govitecan, the three most common AEs are neutropenia, including grade 3, grade 4 neutropenia rate of more than 50%. So one in two patients will have an ANC that is significant that would need some intervention.
The second is diarrhea. And the third is alopecia. Nausea, vomiting is also seen but often can be managed with three-drug antiemetic regimen.
In contrast with Dato-DXd, it is mucositis. That is the number one side effect. Usually, you need a steroid mouthwash for primary as well as secondary prophylaxis, can also cause keratitis, and very rarely 1% or less can cause significant pneumonitis as well.
The schedule is also different. Sacituzumab govitecan is day one, day eight every 21 days and Dato-DXd is every three weeks. So you would have to choose between SG and Dato-DXd. Given that efficacy looks similar, it is often this schedule as well as side effect profile that helps me discuss this with the patient and then select one option.
How about your practice Dr. Rao?
Dr. Rao: I would agree with you 100%. One of the things to think about with did Dato-DXd, like you mentioned, it is really nice to have something that patients are only coming in once every three weeks for. But to prevent the stomatitis, we do recommend using a steroid mouthwash four times a day. Sometimes that can be really burdensome for patients.
If they develop stomatitis, we know that that can be a severe side effect. Similarly, there is the ophthalmic side effects with Dato-DXd, for which it is recommended to use eye drops multiple times a day. Again, we have to make sure we have patients who will comply with these preventative measures so that they do not get severe side effects from this.
Dr. Rao: Dr. Bardia, can you talk to us about using these antibody drug conjugates in first-line triple-negative breast cancer? I think we have seen some recent data presentations in these settings.
Dr. Bardia: Yes, absolutely. Sacituzumab govitecan, based on the ASCENT study, previously was approved for second-line and beyond metastatic TNBC. But ASCENT 03 and 04 evaluated SG with or without immunotherapy in the first-line setting. Then TROPION-Breast02 evaluated Dato-DXd in the first-line setting for patients with metastatic TNBC. All of these trials were positive and essentially have moved these TROP-2 ADCs in the first-line setting, SG with or without immunotherapy for patients with metastatic TNBC. Then Dato-DXd as first-line for patients with metastatic TNBC as well.
The question is how to choose between SG versus Dato-DXd? As we were saying for ER+ disease, it is similar based on side effects as well as the schedule, day one day eight with SG versus every three weeks with Dato-DXd.
Dr. Bardia: Continuing on this theme in terms of patient counselling. Dr. Rao, the team did a survey where they asked in terms of unmet need and what patients and patient advocates would like to hear about. A common theme was, how do we, as oncologists, as providers discuss treatment options with patients and how do we counsel them on side effects? What is your opinion or your own clinical practice in terms of discussing side effects with patients and counselling patients?
Dr. Rao: It is really important to be upfront with them about the side effects that they may experience. I try to go through it with the patients, but this is also a team effort. I involve my clinical pharmacist as well as our nurses to talk to the patients about the side effects that they can expect, what supportive care measures to use, what preventative measures to use.
It is the more education that we can give them and the more that we can encourage them to be in contact with us when these side effects develop so that the side effects do not get very severe and we can step in and help them with management of the side effects. It is really just important to provide that education before they start the treatment.
Dr. Bardia: That is a great point. Often if you spend a lot of time in the first visit, it saves time during subsequent visits. It is also a good clinical practice to let patients know about potential AEs and potential mitigation strategies. For example, we were talking about neutropenia. When we talk about neutropenia, mentioning that there is a medication, G-CSF, pegfilgrastim or filgrastim one could use. Similarly, when we talk about diarrhea mentioning that there is loperamide, one can use. Talk about mucositis, talking about steroid mouthwash.
Whenever you are talking about AEs, also talking about the potential mitigating strategy is in general quite helpful.
The other point to make is that this is not just one time. The key is follow-up. Often when you start a new medication, it is good to have a date follow-up just to check in. That could be with the nurse practitioner or the pharmacist, someone from the healthcare team. So just check in how the patient is doing. It could be a virtual visit as well. It could be a phone call, but just when you start a new medication, having a short-term follow-up often can then help on maintaining compliance and adherence to these therapies.
Because if you are able to manage the AEs, often patients would remain on the drug. But if they have significant AEs, that is where you have to discontinue and compliance could be an issue.
Your thoughts, Dr. Rao, in terms of compliance and adherence with these drugs?
Dr. Rao: You are absolutely right. The main way we can get our patients to continue to be compliant and take these drugs again, every three weeks or two weeks on, one week off, is to help them manage and mitigate the side effects, just like you mentioned.
Dr. Bardia: Fantastic. Well, this was a great discussion. We talked about the new HER2 classification. We talked about newer therapies, ADCs. We talked about their side effects, how to select different ADCs and how to counsel patients and help with adherence. I really enjoyed the discussion, Dr. Rao. Thanks for joining.
Dr. Rao: Yes. Thank you. Me too. Thank you so much.