This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Kathy D. Miller, MD: Hi. I am Dr Kathy Miller. Welcome to the Medscape InDiscussion podcast series on breast cancer and HER2. Today, we'll be talking about all the toxicities that don't involve the heart or lungs. We'll mention those briefly, but we have separate episodes on cardiac toxicity and interstitial lung disease. We'll take a deeper dive into those toxicities, but you all recognize that those are not the most common things our patients experience.
Today we're going to be talking with my guest, Dr Alexandra Thomas. Dr Thomas is a professor of medicine and the Associate Director of Translational Research at the Duke Cancer Institute, about those more common toxicities. Dr Thomas, welcome to the Medscape InDiscussion breast cancer and HER2 podcast.
Alexandra Thomas, MD, FACP: Always a pleasure to be with you, Dr Miller. This is a great topic, something we face in the clinic frequently.
Miller: I think particularly because when trastuzumab and the first HER2-targeted agents became available, they were compared to chemotherapy, and that almost gave people the impression that they didn't have toxicity other than the cardiac toxicity, which we worried about, but it is uncommon. Toxicity was not a thing here, and over time, we've realized they are generally well tolerated, but there are definitely things that patients notice that can be troublesome. When you talk to patients, what are the most common toxicities that you hear about?
Thomas: I think we've also seen an evolution in HER2-directed therapies. We started with just trastuzumab. And you're right, relative to chemotherapy, we thought it was less toxic, but as you know, I see a lot of premenopausal patients, so I certainly think about pregnancy and future pregnancy. Something we don't talk about frequently is that trastuzumab is absolutely contraindicated in pregnancy, associated with oligohydramnios. One thing I really wasn't aware of that I would love to highlight is when a patient completes trastuzumab, because it takes a long time to clear the drug, you want to wait 7 months until after they see their last trastuzumab before starting to consider conception. That's something we don't talk a lot about in the clinic, but it's important to remember.
Miller: I think it's something that we need to think about with many of our antibody therapies. I am old enough to remember when trastuzumab was given once a week. That was really a misunderstanding of the pharmacokinetics and the long half-life, especially after patients have been on chronic therapy. The bad news, perhaps for our patients, is that if they're experiencing toxicity, missing one dose may not make much of a difference for them and for future pregnancies; it means they need to wait a much longer period of time for the drug to clear than what we usually think about.
Thomas: It is something we don't think about as much. And now that we've seen this plethora of other HER2-directed therapies with another wide range of side effects, there are similar thoughts about conception, but also that they have a broader range of side effects than HER2-directed antibodies by themselves.
Miller: Let's take them one by one and think about what's unique and different about them. Pertuzumab is very commonly used in combination, and I think that the GI toxicity of pertuzumab was initially underrecognized. Can we talk about diarrhea?
Thomas: Absolutely. I may not be old enough to remember when trastuzumab was regularly given weekly, but I'm old enough to remember when we first unveiled pertuzumab, and I thought everybody was going to be admitted with diarrhea. I am shocked at how frequently we admit young, healthy patients — receiving pertuzumab as part of their regimen — with diarrhea.
My strategy on that is to tell patients about it and send the significant other to make sure they're stocked with the prophylactic options we have, often over-the-counter but sometimes going to prescription. This is an "act early," not "call once it's happening" symptom. I think early intervention and prevention are so key to success. You can often deliver this drug pretty well if you're able to stop the problem before it happens.
Miller: The other one that we didn't fully anticipate with pertuzumab was the skin rashes and itching. We had seen many more skin rash issues with some TKIs (tyrosine kinase inhibitors) that clearly had EGFR (epidermal growth factor receptor) inhibition as well. But I don't think the potential skin toxicities were as well recognized with pertuzumab when it was the new thing on the block.
Thomas: I think that's absolutely true. All across the HER2 spectrum, snuggle up with your dermatologist for a range of severities. But pertuzumab is one we didn't think of as much, and, actually, you're right: relative to the TKIs, it's less frequent and more moderate, but certainly worth keeping in mind on your differential when someone shows up with these.
Miller: The other thing we saw with pertuzumab, which is even less common, is itching without a visible rash — most classically on the upper trunk, shoulders, and upper back — that, for reasons I certainly don't understand, seemed to improve for many patients with minocycline. That was seen in the very early pertuzumab trials. But I think it is a toxicity and a trick for managing that many people haven't heard of.
Thomas: Yes. All of these are almost anecdotal, but they are important things we need to share with our community. And again, one that you're absolutely right, we learned of it early, and then as we've been so focused on some of the newer agents, we really haven't spoken of that that much. This is particularly important, coming on the heels of ESMO (European Society for Medical Oncology), where we had so much new information in the HER2-positive space. We'll be using these agents in new and different ways in the coming years.
Miller: That's going to make our understanding of the toxicity — managing them, and educating patients about the toxicity — even more important. Before we move to some of the newer agents in the antibody-drug conjugates, I want to talk to you about the different ways trastuzumab and pertuzumab can be given.
We started with IV infusions; there are now subcutaneous injections. I suspect that some, but not all, of our listeners have experience with the subcutaneous formulations. What's good about them, and are there some unique toxicities?
Thomas: I'm so glad you brought that up, because while we don't classically think of this as an adverse effect, it definitely impacts our patient experience. I would additionally add that these have been available, and you'll hear from the companies that sell them that patients prefer them. I think that's probably true. The injections are shorter chair time, so there are probably some financial implications in terms of efficiency of clinical operations. But there are differences between the IV formulations and the injections.
There are reported to be more reactions with the IV formulations. Do not forget, you can have serious reactions from the injections. I've experienced one of my most serious reactions from the injection formulation. Just remember, it can happen, I would argue. As for pain at the injection site, they're thought to be similar in terms of safety and efficacy, and that's what I tell patients, though there's a little bit more neutropenia and a little bit more side effects with the injection. I am surprised that patients prefer the injection. It seems relatively painful. There's probably some individualization in that as well.
Miller: I think it's always hard to know what to make of those patient preferences, particularly if you're talking to patients who've had the IV formulation and they've done well with it. I wouldn't be surprised if they said this is working for me. And the same for the injections. If patients have had a good experience, there are some time advantages both for clinic operations and for patients. I certainly have had patients have some injection site pain and reactions. We've also had some challenges in some patients getting insurance approval for the injections, so it has not always been quite as simple to take advantage.
Thomas: This is often a payer-directed decision, which may evolve. I suspect that's going to evolve with time as well.
Miller: Where I think it's been really helpful, even with all those caveats, is for some of our patients who have struggled with vascular access, who may need ongoing therapy, may be near completing a course of adjuvant therapy. Their access device gets clogged or they get an infection and it needs to be removed and everybody groans and rolls their eyes at the idea of, "Do I have to get another one?" The potential to switch to a subcutaneous injection to be able to complete the course has been a really nice option for some of my patients.
Thomas: And to know that, with regard to safety and efficacy, you're not making a compromise can be very valuable in that setting. Exactly.
Miller: Let's shift to some of the newer antibody-drug conjugates (ADCs). These do contain a cytotoxic moiety, so we have to think about more typical cytotoxic toxicities. What do we know about nausea with the three available ADCs?
Thomas: I remember the first patient I treated with trastuzumab deruxtecan (T-DXd). I thought it would be just like trastuzumab emtansine, no big deal. I learned pretty quickly. There was pretty significant nausea — striking nausea — which can be managed. And now that I've done it a lot. I've not used Dato-DXd (datopotamab deruxtecan) very much yet. I've used it on study, and the stomatitis was striking.
Miller: I haven't used it either because the toxicity sounds horrible. With potential ocular toxicity, the Dato-DXd is clearly an active agent, so I sometimes feel a little bit bad about not using it. But we have so many other options. I struggle with the lack of data on efficacy from one ADC to another. It will come up in my clinic at some point, I'm sure. I just have not done so yet.
Thomas: I've used it on study. It's active, it works great. It's hard to deliver. It was the stomatitis and then the concern about the ocular toxicities.
Miller: Stomatitis has been an issue with several of our agents. What do we know about using steroid mouthwash prophylactically or in those who struggle with stomatitis? Does it respond similarly?
Thomas: It has. When I had it on study, when it was aggressive, mouthwashes did help. But patients don't always want to do that, and they'll describe it as glue paste or terrible. It sounds easy, but it's harder to do in practice.
Miller: It almost feels like it adds a different toxicity. Glue paste and an icky taste are not the equivalent of grade 3 stomatitis. I'm not suggesting that. I sometimes worry if we're adding other issues by trying to chase side effects of drugs and adding more things to prevent side effects.
Thomas: I think that's so important. Also, I think when we start to talk about antibody-drug conjugates, some people will describe them as "chemo-light." That makes me nervous. I think they're far closer to chemotherapy than endocrine therapy, which has its own body of side effects. And then, as we think about things like 14 cycles of T-DXd, that is not nothing in somebody for curative intent. These are a serious set of side effects. And for T-DXd, nausea is a predominant thing that can be managed. Our patients feel these drugs. It is far closer to chemotherapy. I'll just use endocrine therapy as the other extreme, which is not side-effect-free.
Miller: Since these do include chemotherapy, what about some of the other chemotherapy-associated toxicities? Are there many issues with alopecia?
Thomas: I was going to bring up alopecia. I was hoping you'd bring that up because I think that's what our patients care about. I've been very pleased when we first got trastuzumab emtansine. That was, relative to chemotherapy, relatively minor when you saw low-grade alopecia, not frequent.
And then we got sacituzumab govitecan, where you had to try to change gears and tell patients with the TROP 2-directed therapies you are going to see more alopecia and possibly of a higher grade. With trastuzumab deruxtecan, a little bit more [alopecia] than trastuzumab emtansine in my experience, but not nearly as much as sacituzumab govitecan.
Miller: The other thing that comes up with chemotherapy sometimes is LFT (liver function test) abnormalities, which are not common but unpredictable. They seem to just come out of the blue with no warning. How common is that? Are there any management strategies?
Thomas: Yes, in large part because of the associated chemotherapy, but with trastuzumab emtansine, I see it with some frequency, generally grade 1 and 2. But I have managed with dose reduction and careful monitoring. I've definitely seen patients getting trastuzumab emtansine in the adjuvant setting, where you've had to stop therapy and actually revert back to trastuzumab if it's serious enough. You're right, it's not predictable who it's going to happen to.
I know we're going to switch to the tyrosine kinase inhibitors in a moment, but also with them, you want to think about hepatotoxicity.
Miller: It's a perfect time to switch to the tyrosine kinase inhibitors. But before we do that, I have to ask you about one last chemotherapy-associated toxicity with the ADC, which is myelosuppression, which I think is a bit different with trastuzumab emtansine than trastuzumab deruxtecan.
Thomas: Absolutely, it's the nausea, but it's so manageable. When we talk about nausea and we talk about myelosuppression, I feel like that and allergic reactions, we as oncologists, those are our wheelhouses. We can manage those typically. So I think that's probably why we’ve become more comfortable with those aspects of the antibody-drug conjugates.
Miller: The other thing I think our listeners need to be aware of is that with really chronic therapy, especially with trastuzumab emtansine, the platelets will take a hit. I certainly have not had issues to the point where people have had bleeding and complications from low platelets. But if your standard is to require platelets to be 100 to get treated, that's going to be a problem with chronic therapy. Usually at about the 9- to 12-month mark, we start to see the platelets starting to drift down. It's not uncommon for many of my patients to have platelets in the 70s and 80s, and to continue treatment, but their platelets are always at a point where they will get flagged.
Thomas: That's absolutely true, and I'm glad you brought that up. It reminded me of another issue related to trastuzumab emtansine that I've seen, which is bleeding with normal platelets. More epistaxis, and then we're all jumping to check the platelets, knowing their platelets are fine, but it's worth warning patients that this can occur.
Miller: I've seen the same thing. A few people who called it their T-DM1 sinus. Just constant congestion, bleeding, platelets were fine, but really, to the point that in a few patients, we reverted back to trastuzumab to give them a break from that.
I do want to talk about the tyrosine kinase inhibitors because they do have some differences in toxicity, including the fact that they come in pills. So patient education, informing them about "with food/without food," what time of day — all of those things become really important. Tucatinib is the one most frequently used now.
Thomas: Although I would say, tucatinib and neratinib have some newer indications — tucatinib not that recently, but neratinib with the HER2-mutated. If you want to use it in the adjuvant setting, where it can be very hard to deliver. Agents that we might be using a little bit more than we had for a few years. The HER2CLIMB regimen is a hard regimen to deliver, but it offers some really unique promise in terms of management of the CNS (central nervous system). I find the three-drug regimen difficult to manage, even for the most reliable patient, due to the different pills at different times.
Miller: I virtually never give people the three-drug regimen. It's too complicated. The GI toxicity is almost impossible to manage for the three drugs together. And if you try to follow strictly — take this one on an empty stomach, and this one with food — one of my patients mapped out; it felt to her like there were about two 30-minute periods a day where she could eat and not be violating something. It didn't seem to fit in the real world.
Thomas: Yes, and since we've had HER2CLIMB, we've had other suggestions of opportunities to improve CNS outcomes. But for a period there, that was our best option for CNS disease. So I did try to push a few patients through it, and it's a complex regimen. Tucatinib has a lot of GI side effects. I would argue that neratinib is even harder to deliver from that perspective. I have two patients who have made it all the way through the adjuvant. I always feel like they're my on-podium patients. And I've admitted the others, like young, healthy patients, as I'm trying to get these therapies on board.
Miller: If you're starting someone on neratinib or tucatinib, do they get the prescription for Imodium in the left hand at the same time that the prescription for their TKI goes in the right hand?
Thomas: It is almost like, take the Imodium before you even think about the neratinib. I know we do this now with some of our CDK inhibitors, in particular abemaciclib, where we slowly dose escalate. I tend to ease the patient into the full dose of neratinib. Now that may or may not be acceptable, but I've had success. I think ultimately the patient's exposure to the drug is better if I escalate them into the optimal dose.
Miller: The other question that I think sometimes comes up, particularly with the HER2CLIMB study because of the capecitabine — but I've gotten this question from community oncologists for the TKIs as well — is for some of their older patients whose GFR (glomerular filtration rate) might not be normal, they don't have symptoms of their kidney disease, but when you measure or calculate their GFR, it's 40 or 45. Is there a need to adjust doses for any of the TKIs for those renal functions?
Thomas: So, I'm fortunate. I work really closely with a pharmacist. I would think first about the bisphosphonate. I'm going to be adjusting that. I'm lucky that I have a pharmacist I work closely with. I am not sure that everybody in the community has that. But especially with a patient who's older, I would be using my calculators and probably trying to start low and go up to optimal dosing, and considering their renal function as I do that.
Miller: I think that's a strategy we've seen with some of the TKIs that we often think about using in ER-positive disease or with things like everolimus or alpelisib with other hormone therapies. We are starting at a lower dose and escalating. It was more successful. It both allowed more patients to get to a stable higher dose and reduced really severe toxicity. Because I think the other challenge is that the patients who really get slammed with toxicity need to stop everything. They need full supportive care to get through this. And then their willingness to give it another go at a lower dose with changes in supportive care is a lot different, as is their treating physician. If I've just hurt somebody really badly with a therapy, I am a little gun-shy of starting it too.
Thomas: Yes, I also try to think about this: Success in the first 2 weeks does not mean I'm going to be successful in the next 12 months. Pushing them to a very high dose that they ultimately can't tolerate could undermine those 12 months of success. We've also seen this with the CDK inhibitors. And it's definitely our practice to start at 50 on the abemaciclib and then increase. So we have that pattern, but it is fairly quickly escalating. We don't hang out at 50 for 6 months.
Miller: We are nearly coming to the end of our time, but I want to ask you about one thing that I've seen in a lot of patients coming to me from the community. Using these agents with radiation. That's going to be particularly important as they move into the adjuvant setting — trastuzumab and pertuzumab now commonly used in the neoadjuvant setting.
Those patients who have a pCR (pathologic complete response) who are going to continue them. In the community, I frequently see all HER2-targeted therapy stopped at surgery and only resumed after radiation. If patients have had complications, they needed a delay, they had had issues or reconstruction; sometimes we've seen a 4- or 5-month gap in the HER2-targeted therapy. So can you push on and just continue using with radiation?
Thomas: This came up in my clinic with the monoclonal antibodies. I tell the patients: We ignore them, and they ignore us. Now the story becomes different when we think about antibody-drug conjugates and CNS radiation. That is a very, very different story. But for curative intent, monoclonal antibodies, these are such important drugs. It makes me sad to hear that they would be withheld when they could almost certainly be delivered safely.
Miller: And we should note that the adjuvant and neoadjuvant trials continued therapy during radiation. So there really is a wealth of data that for breast regional nodal radiation, the antibody-drug conjugates and the antibodies themselves are quite safe.
Thomas: Absolutely. That was pointed out again at ESMO. And especially in terms of lung toxicity with antibody-drug conjugates, they're extra cautious in these studies to watch that, and very reassuring data in that regard.
Miller: Dr Thomas, thank you so much for joining us today. It's been a great pleasure to talk with you about some of the important toxicities for the HER2 targeted therapies. We certainly need to keep in mind that the antibody-drug conjugates have a chemotherapy moiety, so they can have typical chemotherapy toxicities. Also, it is really important to remember GI toxicity with the tyrosine kinase inhibitors. In those cases, perhaps starting slow, escalating doses, and being very intentional about patient education. Proactive management rather than reactive management is going to be key.
We need to remember that while the plain antibodies are really well tolerated, they do have toxicities that patients experience, and we need to be willing to hear those and work with our patients to truly make this tolerable. To our listeners, thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on breast cancer and other Medscape podcast series. Dr Thomas, thank you.
Thomas: Dr Miller, it's always a pleasure and a privilege to be with you.
Miller: This is Dr Kathy Miller for the Medscape InDiscussion podcast.
Listen to additional seasons of this podcast.
Resources
Polyhydramnios and Oligohydramnios
Pruritus Related to Trastuzumab and Pertuzumab in HER2+ Breast Cancer Patients
Toxicity Profile of Antibody-Drug Conjugates in Breast Cancer: Practical Considerations
T-DM1-Induced Thrombocytopenia in Breast Cancer Patients: New Perspectives
Lung Toxicity Induced by Anti-HER2 Antibody-Drug Conjugates for Breast Cancer
Medscape © 2025 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Addressing Common Toxicities for Breast Cancer HER2-Targeted Therapies - Medscape - Nov 25, 2025.
Comments