Around the Practice: Updates in HER2+ Breast Cancer - Episode 4
Experts in breast cancer discuss the management of visceral metastases in HER2+ breast cancer, and Vijayakrishna Gadi, MD, PhD, presents the case of a 50-year-old woman with HER+/HR- breast cancer.
Vijayakrishna Gadi, MD, PhD: We talked a little about this. Dr Iyengar, you mentioned this, about the activity in patients with even visceral disease of this regimen. But if a patient, for example, has both brain and visceral disease, I’m hearing that a tucatinib-braced regimen makes some sense. Is there a scenario where you would think, “Hey, there are other agents that might be more active. Maybe I’m going to go there?” Share with me a bit of your thinking about that.
Neil Iyengar, MD: I certainly do think that in terms of systemic disease, we’ve all discussed, we have many agents that are active. But when we’re thinking about that specific patient who has CNS [central nervous system] involvement and visceral involvement, beyond a tucatinib-based regimen, we do have other agents that potentially have activity. We’ve discussed T-DM1 [trastuzumab emtansine] and coupling that with local therapy. We saw an interesting subgroup analysis that I think Dr Isaacs mentioned, from the DESTINY-Breast01 trial, it was 24 patients. The objective response rate in patients who had brain metastases at baseline, I think was around 58%. That’s reassuring, but again, that’s a subgroup analysis of 24 patients in a phase 2, single-arm trial. I’m not quite yet changing my practice, but eagerly await some of the larger phase 3 data. Then we also know that neratinib has some CNS activity. In the neratinib phase 3 registration trial, NALA, there was a lower incidence of intervention for brain metastasis in the neratinib-containing arm, which might suggest that patients are responsive in the CNS to a neratinib-containing regimen. Although I will say that there wasn’t a statistically significant difference in overall survival, as we saw on HER2CLIMB. And so, I think we’re learning a lot about the CNS activity of these agents. We certainly have tucatinib, which has demonstrated clear activity, but there are other options if need be.
Vijayakrishna Gadi, MD, PhD: Perfect. Why don’t we go ahead and move to the next case. Thanks for the robust discussion about brain metastases and how you might prioritize these agents. Let’s go through this case quickly. We have a 50-year-old woman who presents with a 4-cm lump in the left breast. Immunohistochemistry shows HER2-positive, hormone receptor-negative breast cancer, so the so-called HER2-enriched subtype. The neoadjuvant therapy with classic THP [docetaxel, trastuzumab, pertuzumab] for 6 cycles gets her to a lumpectomy and radiation. She actually has a pCR [pathologic complete response], it lasts 32 months. But then she comes to the clinic complaining of fatigue, right-upper-quadrant discomfort, loss of appetite. She gets an abdominal CT, there’s a 5.5-cm nodule on the liver. Immunohistochemistry of that liver biopsy shows that it is HER2+, hormone receptor-negative breast cancer, so a clear recurrence of the original primary. The PET [positron emission tomography]/CT was performed, and we can comment on this, but it was apparently negative for brain metastases. She gets started on trastuzumab emtansine, and then 12 months later a CT shows progression in the liver. I’ll highlight right off the bat, the patient has a pCR that lasts 32 months. How common is this? I thought when people get a pCR, they’re out of the woods? Maybe Dr Isaacs, you can tell me, how often does this actually happen? Why do we have to still keep our radars on high alert on a patient like this?
Claudine Isaacs, MD: It doesn’t happen that often, but it can happen. A lot of the trials haven’t gone out that long, some of these neoadjuvant trials, but they do suggest that the likelihood of that patient having a long-term, at least DFS [disease-free survival], is high. This is an unfortunate case and not what you would expect. I do think this case is unusual, but not unheard of. It’s anywhere from about 10% to 20% of patients who might develop a distant recurrence. This is pretty short for a patient like this, who had hormone receptor-negative, HER2+ disease and had a path [pathologic] CR.
Vijayakrishna Gadi, MD, PhD: I completely agree. I think it’s a little unsettling to see something like this, but it underscores why we all still have to keep our radars up on this particular disease, because this can certainly happen. Now that she has metastatic disease, I’ll keep with you, Dr Isaacs. Obviously, this patient got T-DM1 in this setting. Do you agree with that? How would you have done it? What would have been different had she been walking through your door?
Claudine Isaacs, MD: I think we wonder in patients…the CLEOPATRA trial obviously was done in the absence of patients getting prior neoadjuvant or adjuvant pertuzumab, so it is a different setting. You would wonder whether those data would apply to a patient who had gotten it in the neoadjuvant or adjuvant setting. But I have to say, I think I would have thought about retreating. This lady is 32 months out. My definite “don’t retreat with the same regimen” is 12 months out from completing adjuvant or neoadjuvant therapy. My gray zone is, I don’t know, between a year and 2 years, for where I feel comfortable retreating. But this lady is more than 2 years out, and I think I would have probably retreated her and given her paclitaxel, trastuzumab, pertuzumab. I don’t think T-DM1 is wrong here. But I personally probably would have given her THP [docetaxel, trastuzumab, pertuzumab].
Vijayakrishna Gadi, MD, PhD: I tend to agree. I’m looking at the head nodding from my colleagues here; I think we would all have done that. Certainly, she responded so beautifully to it the first time, you would hope that she could see that kind of response again. Dr Kaklamani, this is a patient with visceral disease only, no brain metastases. And of course, they look for a brain metastasis with a PET/CT scan, which is a little unusual, but we’ll assume they did an MRI too. How would you feel about HER2CLIMB? Let’s say she’s on the T-DM1 now for a little bit and she progresses. Maybe you can describe to me your decision around whether you would invoke the HER2CLIMB regimen here.
Virginia Kaklamani, MD: Because I agree with Dr Isaacs, upon progression, I would put her on THP [docetaxel, trastuzumab, pertuzumab]. Again, we have options, but these patients do well for such a long time, at some point we may run out of options. I’d like to use my first lines, which would be the trastuzumab, pertuzumab, T-DM1, and then move on to the newer agents. Now assuming that we’re done with these, and then the next step is, what are we going to use? Are we going to use a tucatinib-based regimen or T-DXd [trastuzumab deruxtecan]? I don’t routinely do MRIs of the brain unless the patient is symptomatic, so I would probably lean toward the T-DXd regimen. We’re going to have now randomized clinical trial data comparing it to T-DM1, and this may change our second-line regimen altogether. Then I would probably give tucatinib as a third-line option. But this also depends on what toxicities the patient has. When you look at the DESTINY-Breast01 data, we had around a 13% ILD [interstitial lung disease] rate. For somebody who’s otherwise healthy, 50 years old, or 53 at the time of progression and doing great, developing ILD is probably not the best thing for her. If she’s reliable, and she can take oral agents, that might also be a tucatinib win. We don’t have head-to-head data, we probably won’t have head-to-head data. So we all have to decide what would be our “thirdish”-line regimen.
Vijayakrishna Gadi, MD, PhD: Staying on this theme with T-DXd, is there a patient for whom you feel really uncomfortable starting T-DXd? For example, with lung metastases, prior COVID-19? Is there anything that would spook you from using that?
Virginia Kaklamani, MD: Unfortunately, there are lots of things we don’t know about ILD, who’s going to develop it and who’s not. Besides the dosing, which now we know, we have established the 5.4 mg/kg dose. I don’t know that I have a person I would not give T-DXd to, except the rare patient who actually gets ILD with T-DM1. I’ve had 2 patients who were intubated from developing ILD on T-DM1. Those patients would definitely not be on my list to get T-DXd.
Vijayakrishna Gadi, MD, PhD: Thank you. Do either of you, Dr Isaacs and Dr Iyengar, have any concerns around T-DXd and lung toxicity, in terms of patient selection, that kind of thing?
Neil Iyengar, MD: I’m happy to jump in. I think that Dr Kaklamani outlined it perfectly, that we’re still learning a lot. We saw some data that perhaps Asian patients and people who have a prior history of smoking may be at a higher risk for ILD. But that’s neither here nor there. It really depends on the patient. One thing that struck me about this case is, we see a persistent cough. Now, that could be something easy for us to monitor, and it’s not a big deal. But if this is a significant issue, and it’s going to be difficult for the patient to tell us herself if there’s a new cough or a subjective change in the cough, that might give me a bit of pause. I think this is where the art of how we practice comes in, in terms of selection.
Vijayakrishna Gadi, MD, PhD: Nice pickup. I agree with you on that.
Transcript edited for clarity.