HER2+ Breast Cancer Treatment Algorithm: Dr. Virginia Kaklamani

2025 was a big year for HER2 positive breast cancer. We saw a lot of data, but let's talk through this, and what it really means for us in our clinic. Hello and welcome back to the Oncology Brothers podcast. I'm Rahul Gossane, here with my brother and co-host, Roy Gossane. All right, today we are continuing our treatment algorithm series in breast cancer. Focus on conversation today is HER2 positive disease. And Rahul, you're right, 2025 was a big year. What we saw was Destiny Breast-09, which recently led to the approval of TDXD in frontline metastatic settings. And SABCS 2025, we saw updates on to cat-need maintenance in this particular space as well. And prior to that at ESMA, what we saw was TDXD move into Neo-Agevent and even test for Agilent Space. So there's a lot to cover to walk us through what we have at hand from current treatment algorithms standpoint. We're excited to welcome back, Dr. Virginia Keklamani from UT Health San Antonio. Virginia, thanks so much for joining us. Thanks for having me. This is going to be exciting conversation. Virginia, welcome. It's always so good to have you. Let's start off with early stage HER2 positive breast cancer, particularly in that less than two centimeter lesion and lymph node negative disease. Your treatment is surgery and then Agilent Tacksaw with one year of Trastosumat based off APT trial. In this settings, we have excellent outcomes, right? With 10-year recurrent free survival over 95%. 10-year invasive disease free survival is over 90%. Here, we're often considering this for that 5-millimeter and above disease. But Virginia, in your clinic, what's your personal threshold of that lower limit in otherwise healthy patient? What about that three, four millimeter lesion? Do you still offer chemo and Trastosumat? So this is what we struggle a little bit. We have some data from the Netherlands and this was a registry. So it was not a clinical trial, but it was a very long-term registry that they looked at patients on an off-trastosumat, showing a benefit even in the T1As, although they did not reach statistical significance because the numbers were small. So I usually show the curves to the patients and I let them decide and I give I have a conversation with them. Now, some patients will say, well, can I just get Trastosumat without chemotherapy? And the answer is no. We have two studies, one from Japan, one from the US. Again, not randomized, not large, but the outcomes with just Trastosumat don't seem to be that great. So this is kind of the issue that we have to give Trastosumat. We want to give it with some sort of chemotherapy and we would give 12 doses of weekly tabletaps. All right, moving along from one struggling scenario to the other struggling scenario. That is in T1C where we are looking at 1.5 or 1.8 centimeter where we usually would go for surgery and then add adjuvant treatment option. However, what is that patient population where you would consider neoadjuvant TCHP in this particular setting or even that neo-carp like approach where we are omitting carboplatin? I usually take these patients to surgery. I've had patients that we thought had a 1.8 centimeter tumor and then we did surgery, it was 0.7. So I think because the benefits and this is a little different from the conversation in triple negative disease where we're more concerned, these tend to be patients that may have a little more aggressive disease. But in her deposit, as you mentioned, the results from the APT trial are just so good. I'm comfortable taking them to surgery. Thanks for covering that Virginia. And to clarify what neo-carp regimen is, which is a phase 3 study, which was just published here in January 2026 in JCO, looking at for going the carboplatin in neoadjuvant setting for selected patient population. And what the conclusion or what we learned here was that THB is non-inferior to TCHB with respect to PATCR rate and also is better tolerable. Virginia, I push in this further. Now, if you have a tumor that is 2 centimeter or more or no positive disease, now the option here is also TCHB neoadjuvant setting, but any role of omitting carboplatin in this particular setting, and which patient population are you? There is another trial called the Helen 006 trial that showed very similar outcomes as well with NAPACLITaxyl HP having exceptionally good PCR rate, I want to say 66%. So I rely on this regimen for my more frail patients that I want to give them neoadjuvant therapy. I don't think they can tolerate TCHB. I will give them single agent taxane. I personally give NAPACLITaxyl together with HB. I think again in the patients that are a little more frail. I think that's very acceptable. You mentioned destiny breast 11, which might change this all together, because we might be giving four cycles of TDXD, followed by THP in these patients, so no carboplatin as well. So this is evolving. I think right now for the majority of patients, the standard of care should be considered TCHB, but the NAPACLITaxyl HP approach is showing really good results as well. Okay, I know you both have brought up destiny breast 11. Let's get there in new adjuvant settings. We're likely going to see TDXD, but we're also going to see TDXD in adjuvant settings based off destiny breast 05. If one they both get approved, Virginia, are you going to use TDXD for all that meat that criteria in new adjuvant settings? Or going to save TDXD for high risk residual disease in adjuvant settings based off destiny breast 05? This is such a tough question, and I don't know that I completely know the answer to it. I don't think anybody does. I think there's a couple things. First of all, the longer outcomes are with destiny breast 05, not with DB 11. So if we want more mature data, we have to think of DB 05. Secondly, there's patients that will not meet criteria for DB 11 and will for DB 05 in the other way around. So we want to keep that in mind as well. Third, the rate of pneumonitis. 4.6% in DB 11 with four cycles of new adjuvant TDXD versus 9.6% with 14 cycles of TDXD and destiny breast 05. So, you know, almost doubling of the rate of iodine. That's something we need to keep in mind. So with all of these caveats, I'd love to be able to give destiny breast 11, but I don't have the mature EFS data yet to do. So until then, I'd be favoring the destiny breast 05 approach, which I've started mostly because patients got TCHP, young, hegg residual disease with positive lymph nodes, and then I talked to them about adjuvant TDXD. Just for completion sake, well, the current standard of care for residual disease is TDM 1 based off of Catherine trial, if Patsy R than HP. Whereas for that high risk population enrolled in DB 05, what we are seeing is three years DFS, which is a longer term data as you stated, Virginia, which is 92.4% with TDXD versus 83.7% with TDM 1. To me, again, adjuvant data is practice changing, though the debate about longer term outcome from new adjuvant TDXD is still due. Okay, moving along into a metastatic space, where TDXD plus partuse map recently got approved based on DB 09 study, which we just covered with Dr. Serra Tulani part of our FDA approval series. So if you've not checked it out, please check it out. Virginia, the option here is TDXD plus partuse map, or THP, followed by HP, or even adding to Katnib based off HER2 climb 05 study. How are you picking your front line treatment option? And if you're picking up TDXD, are you leaning on with some induction cycles, possibly six, and then moving along with maintenance with dual anti-her2? Yeah, I think here things are a little more clear in my mind. I would start with the Destiny Brest 09 approach, especially since this was just approved with TDXD in combination with partuse map, because we have not seen the TDXD only army yet. I would likely give it for several cycles. I think we need to look at data of 15% of patients on the trial achieved complete response. When did they achieve that complete response? Do we need six cycles, eight cycles, 10 cycles? It would be really important to look at that data, because I'd like to give the opportunity to these patients to potentially be cured with metastatic disease, which is huge. So give them some induction therapy. Let's call it eight or 10 cycles, whatever that is. And then try a maintenance strategy. And you have mentioned two of the trials that I love, the patina and the HER2 climb 05, one of them giving palbocyclin and the other trial giving to Katnibb as maintenance therapies. And so that's what I would do, because that would decrease the rate of ILD and also give the opportunity to the patient to recover from, you know, the cytotoxic effects from TDXD that are not not minimal. You know, I'm glad that we're not putting a number here, because there's no magical number. We don't have good data for saying six cycles or eight cycles for every single patient based on their tolerability, based on the response. This is going to look different. And then in our clinic, we'll be making that decision of maintenance therapy. Coming back here, given TDXD has good CNS activity with denoblal brain mats, Virginia, you're still sticking with TDXD and put to some of that. Correct. That's correct. We've seen now a lot of data, including Destiny Breast 12 and a several other series and real world data that clearly shows a good activity in the CNS with TDXD. So I feel very comfortable having said that there's nice data from HER2 climb 05 on to Katnibb. And the fact that it's delaying progression of brain metastasis. So we know this is a great option as well for our patients. Actually, while we're on that topic, do you get brain MRI upfront as part of your staging for metastatic HER2 disease in asymptomatic patients or only consider this as part of your workup if patient has symptoms? I only do it for symptomatic disease. Many of my colleagues will do it. It's all over the place. Some will do it with each progression. Some will do it every six months. It's all arbitrary. If you look at data, we don't have any data to suggest that doing MRIs helps any outcome. We need to generate that data. This is a great question that we need answers. And those answers are very clinically meaningful. Right. Virginia, you just touched on the Patina trial, which was recently again published in any jam. With regards to the triple positive disease, that THP maintenance, PALBO plus endocrine therapy, plus dual heart2, or TDXD with Pertusumab. At what point in time, you're adding endocrine therapy to this? I will typically add the endocrine therapy when I'm done with my cytotoxic therapy. So if I've been giving the clear pathoregimen at the six month mark when I typically stop the patented axle, I'll add endocrine therapy to that. Based on patina, I would try to add palbosyclin as well. Can I push a little with TDXD Pertusumab if you're having that combination? Are you going to add that endocrine therapy and then wait for maintenance phase and then add CDK46 in a better or not add any endocrine therapy while someone's on TDXD? I would typically not add it. I would give it at the six, eight months, whatever mark is when I stop the TDXD, add endocrine therapy, plus palbosyclin at that point. I think you can do either. It's a little unclear what the data and the benefit is of giving endocrine therapy together with cytotoxic therapy. A lot of the data that we've seen doesn't suggest benefit some a little cautious in doing that. Okay, while we're on patina, can I quickly go back to locally advanced disease? We're just posted a poll on this as well, Virginia, in adjuvant settings after TCHP or TDXD. In this triple positive disease, if there's high risk residual disease and patient meets the criteria for natally or monarchy trial, but you're planning to give TDM1 or TDXD because of that residual disease. Would you consider CdK46 in a bitters at all here? I don't. We don't have the data in her depositive adjuvant disease at all. We will. There's ongoing clinical trials. Until then, I really don't. But I will give NARATNib. I think this is important. You have it here in your algorithm as well. We do have data on NARATNib, and I use that in that setting. I know we're going back and forth. Just one other question with locally advanced disease. If the disease was to be BRCA1 or BRCA2 positive, whether that's for HER2 positive or even triple positive, any role of additional PARP inhibitors here. And again, those were patients that were not included in the Olympia, unfortunately or fortunately. And so I stay away from that. I think these are unanswered questions. You would think that since both of these pathways are not really related to HER2, especially the PARP, you would think that you would have a nice benefit from a PARP inhibitor. But we don't have any of the data. All right, coming back to the metastatic space. What we are seeing here is close to 41 months PFS with TDXD plus per 2-sumap upfront. And with Patina, what we are seeing is 44 months PFS. This is incredible and very encouraging. But Virginia, if the disease was to progress, on upfront TDXD, how are you sequencing your left or were options? And what data do we have at hand post TDXD exposure? So let's see, because we don't have a lot of data to oppose TDXD. And this is really one of the issues, my concerns with DB11 going back to the new adjuvant setting. If a patient has residual disease after four cycles of TDXD, do we give them TDM1 in the adjuvant setting? Do we give TDXD for another 10 or so cycles? That's the other limitation of doing the DB11 approach. But going to the metastatic setting, I would probably give my to Katnibe's my second line. I could also give TDM1. I think they would be active, but we don't have data. But it would be just sequencing the other drugs. And again, coming back to Rohe, what you brought up, that significant progression free survival upfront is very meaningful. And now we're in this data free zone. The field has moved so quickly that we're using these active agents earlier and earlier. And that's a good problem to have. We've covered a lot here, but before we close, I do want to quickly touch on some of the common side effects. nausea, hair loss, fatigue, and of course, ILD from TDXD, with to Katnibe, rash, diarrhea, and fatigue or few things that we have to be mindful about. And then, with any of these anti-heritum medications, keeping a close eye on that heart ejection fraction is important. Virginia, anything more to add here in terms of side effects? One thing to consider when we look at trials like Destiny Breast-09, those were trials that were done internationally with many patients being recruited from the rest of the world, where they do not use for anti-amatics for nausea. We know that the NCCN guidelines are categorizing TDXD as highly a metagenic, which means we need to be using a lansapine on top of our three anti-medics. And so I would just urge people to do that, at least for the first cycles. You know, nausea is something that's so preventable. It's really a shame if we don't use the right preventative medications for it. Right. Nausea and other aspects of quality of life are very, very significant. Virginia, this has been an incredibly insightful conversation. And 2025 clearly pushed the field forward in a big way. Thanks so much for taking the time to walk us through your current treatment paradigm. Rahul, let's go over a quick recap from today's discussion. In today's discussion with Dr. Virginia Cachlamani, we walk through the current treatment paradigm for her two positive breast cancer. For early disease, less than two centimeter, APT trial has been guiding our treatment options. That is, adjuvant treatment option post-surgery. And that's exactly what Dr. Cachlamani stressed on as well. For locally advanced disease, where we are utilizing neoadjuvant therapy and the standard of care in the residual disease is TDM1. However, we are seeing impressive results from DBO5, where adjuvant TDXD at three-year mark, DFS is 92.4% with TDXD versus 83.7% with TDM1. Though this is being also tested in neoadjuvant setting with TDXD, but we need to await long-term data before we decide, are we going to utilize this in our clinical practice? Rahul, your thoughts here? Well, very likely we're going to see this approval in neoadjuvant and adjuvant settings. And that right patient who's going to get neoadjuvant versus adjuvant treatment is going to be important keeping all these side effects in mind. We also touched metastatic disease, where TDXD, again, was a hot topic. This recently got approved with Pratuzumab based off Destiny Brest09, where we're seeing significant improvement progression free survival. 41 months with the combination of TDXD versus 27 months, red THP. We also touched on Patina trial, what to do for that triple positive patients. And here, again, we're seeing significantly improved progression free survival. 44 months of PFS versus 29 months of PFS when we're adding that endocrine therapy and Pobbocytlib in that maintenance phase. Patina and Destiny Brest09 are now the new standard of cure treatment options for this particular setting. All right, that's a wrap. But before you leave, on our end, we see your messages every single week. We love what we do, and we love the fact that so many of you in practice have come to us and said that these discussions help you stay afloat and feel empowered by these conversations in order for us to help more people our podcast needs more reviews. Every time we get a review, more people who need this information will see it. And that's why we are here. We'd really appreciate you taking a few minutes to leave us a review on whatever platform you tune in from.