Treatment of HER2+ Breast Cancer and Brain Metastases

Vijayakrishna Gadi, MD, PhD; Claudine Isaacs, MD; Virginia Kaklamani, MD; and Neil Iyengar, MD, share their approach to treating patients with HER+ breast cancer who have brain metastases.

Vijayakrishna Gadi, MD, PhD: Why don’t we go ahead and move to the next question. The last question before we get to more discussion is, when you’re treating your patients with visceral disease, do you alter your approach if they also have brain metastases? It looks like I’ve got a single user so far, it’s a 100% yes. We’ll give it a little bit more time for some more answers to come in. We’re now at 6 users; it’s still at 100%. It’s near unanimity here. The presence of brain metastases really matter; that makes sense. We’ll go through some of the data and how my colleagues here go through this. Coming back to some more discussion, I’m going to go with Dr Isaacs for this next one. Maybe you can share with us your approach to patient who has HER2-positive breast cancer and brain metastases. First of all, how do you find them? How do you look for them? What kind of treat options? How do you choose between all the therapies we might have?

Claudine Isaacs, MD: I think that is an incredibly important question, and what we’ve seen over the last year and a half is a ton of different options. We used to have very clear paths in terms of what we did. We did CLEOPATRA, T-DM1 [trastuzumab emtansine], and then you gave trastuzumab with some chemotherapy, and then maybe threw in lapatinib somewhere along the way. I think the data from HER2CLIMB too really changed how we viewed both looking for brain metastases and what we wanted to do if we found them. Before, I wasn’t sure that I wanted to go look for problems because I didn’t have anything necessarily specific to do. That got changed when we saw the results of…the HER2CLIMB study, which showed us that first of all, it actively looked for patients with brain metastases, and I think found that about 50% of patients, if you looked for it, had brain metastases, some of them were occult. Those patients were allowed to enroll on the trial. They didn’t necessarily have to have local therapy beforehand if it was not felt that they needed something imminently, if they had stable disease, or they could have been known to have brain metastases and were stable. It showed that the drug was active, and the benefit in terms of progression-free survival and overall survival was seen in the population as a whole, it was seen in the planned subset analysis in the group of patients who had brain metastases, and it was about a 4-and-a-half month or so prolongation in overall survival. It was also seen though, which is important, in the population that didn’t have brain metastases.

Then there have been other looks at those data, looking at whether the activity was specifically in the CNS [central nervous system], and showing that it controlled disease in the CNS, for patients who had CNS disease. I think that really has changed things for me. If I know that somebody has brain [metastases], that’s going to push me much more toward using or thinking about tucatinib. I think there are subtleties to this though, and it’s very nuanced. If you have a patient on the CLEOPATRA regimen, and you find that they have a solitary brain metastasis, and they’re doing great on the CLEOPATRA regimen, the question that comes up is, should we treat that with a little stereotactic radiosurgery [SRS] and then keep on with the trastuzumab and pertuzumab plus or minus endocrine therapy, if they have hormone receptor-positive disease? Or do we need to think about switching their systemic therapy? But if it’s a time point when you’re switching systemic therapy because they have progression, if they have brain metastases, that’s what’s really going to push me right now to do the tucatinib, the triplet of tucatinib, cape [capecitabine], and trastuzumab. I think there are various permutations to this, and it depends on how many brain metastases? What’s going on? Could you treat them locally? It is very individual. I’d love to know what others think about this space. But it has forced us, in a very good way, to reconsider both how often we look for brain metastases, and then what we do when we find them. But I’d say my default is to think about tucatinib, and then there might be instances where I think there might be something different I could do for them.

Vijayakrishna Gadi, MD, PhD: Thank you so much. Dr Iyengar, I have a question for you. Are brain metastases important in HER2+ breast cancer? I’m setting this one up on a plate for you.

Neil Iyengar, MD: Well, I appreciate the softball. The answer is clearly, yes. We certainly know that outcomes are much worse, unfortunately, for our patients who develop brain metastases. We also see, Dr Isaacs mentioned that in HER2CLIMB, the incidence of brain metastases detected by the baseline MRI was nearly 50%. We also know that nearly 50% develop brain metastases by the time they get to the second line of therapy in the metastatic setting, so it can be a fairly early event. I agree with Dr Isaacs. Historically, we did not have good agents to treat this situation, and therefore we did not go looking. But now that we do, I think it’s very reasonable to think about that, and I think the practice is evolving there a little as we start to get the longer-term survival data. Certainly, the overall survival data in the subset of patients with brain metastases in HER2CLIMB are very reassuring and support using that tucatinib-based regimen for our patients with brain metastases. I think the area of asymptomatic brain metastases, or these small lesions, may be amenable to local therapy. Again, Dr Isaacs alluded to this perhaps as a question mark and whether we can continue the systemic therapy and use local therapy in that setting. I have started to lean a little further away from that, whether that’s right or wrong. I think it’s partly because of the reassuring long-term survival data that are now coming out. But also, we did see an interesting exploratory analysis from HER2CLIMB in which patients who did not have brain metastases at baseline and were randomized to the tucatinib-containing arm had a longer time to the development of brain metastases, or death. Those are 2 very relevant outcomes when we’re treating our patients in this setting. And so yes, I think I generally switch over to the tucatinib-based regimen in the setting of brain metastases, even potentially in our asymptomatic patients.

Vijayakrishna Gadi, MD, PhD: Dr Kaklamani, I have a question here kind of related. We have this amazing tool that we’ve used for years, SRS, and we would do drugs like trastuzumab emtansine, T-DM1. But now we have tucatinib. Would you think about repositioning tucatinib, for example, before T-DM1 plus SRS? Or how would you approach this? I’d love to hear about that.

Virginia Kaklamani, MD: I usually don’t. Our neuroradiation oncologists and neurosurgeons are now doing SRS on more than 20 lesions. It seems like the brain has become an SRS heaven for them. And patients are doing great, and they’re tolerating their treatment well. So I typically will give as much SRS as they tell me we can give. Then when we can’t anymore, I will move on to tucatinib. I think these are the questions that we probably will never have an answer to. I don’t think we’re ever going to be doing a clinical trial looking at SRS versus tucatinib. But these are great questions that we all face every single day in clinic.

Vijayakrishna Gadi, MD, PhD: That’s a tough one. My personal record was 36 lesions in a single setting, at which point you have to wonder, isn’t that the same as whole brain radiation? Well, thank you so much.

Transcript edited for clarity.

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