Breast Cancer Brain Metastasis: Which Tool to Pick at What Time? Guidance From Radiation and Medical Oncologists

Carey K. Anders, MD; Steve E. Braunstein, MD, PhD; Nancy U. Lin, MD; Michelle E. Melisko, MD


August 25, 2022

This transcript has been edited for clarity.

Carey K. Anders, MD: My name is Carey Anders, and I'm the medical director of the Duke Center for Brain and Spine Metastasis. I'm pleased to be here with my colleagues today to have a lively discussion about the management of brain metastasis arising from breast cancer. I'll let each of my colleagues introduce themselves, starting with Dr Melisko.

Michelle E. Melisko, MD: Hi. I'm Michelle Melisko. I'm a breast medical oncologist at UCSF in San Francisco. My primary interest in research is in CNS metastases, and specifically leptomeningeal disease.

Anders: Excellent. Dr Lin?

Nancy U. Lin, MD: Hi. I'm Nancy Lin. I'm a medical oncologist at Dana-Farber in Boston. I direct our metastatic breast cancer program and our program for patients with breast cancer brain metastasis.

Anders: Excellent. Dr Braunstein?

Steve E. Braunstein, MD, PhD: Hi. I'm Steve Braunstein. I'm a radiation oncologist here at UCSF. I have a focus in treatment of primary and metastatic CNS malignancies.

Anders: Excellent. We have much to cover today. Just to give a broad overview of what we plan to discuss, we want to talk about the general management of brain metastasis both from the local therapy perspective and from the systemic therapy perspective, and how these modalities can be integrated for best outcome for our patients. We will also address brain metastases that are stable upon decision-making and those that are active or progressing at the time of medical decision-making.

I'm also hopeful to have a discussion around the challenging clinical scenario that Dr Melisko has just described in leptomeningeal disease. Certainly, this can be conversational, and we can bring in cases of our own.

I'd first like to start in HER2-positive breast cancer. I think we are becoming more and more familiar with the many tools in our tool kit, and that's been a wonderful addition but it's also sometimes challenging to know which tool to pick at what time.

Dr Braunstein, maybe you can describe how you approach that patient who comes in on, say, maintenance trastuzumab/pertuzumab. They've already been diagnosed with metastatic disease, have been doing well extracranially, but present with new brain metastasis — and in this setting, we'll say maybe fewer than 10. How might you think about that when you're approaching that patient in clinic?

Braunstein: First and foremost, it's very much an interdisciplinary discussion. Even though my focus, for example, is on treatment of brain and using radiation techniques, I reach out to my colleagues, such as Dr Melisko, to really think about not only the local issue but also the broader issue. Our focus, of course, is from a patient-centered approach, so we're thinking about quantity of life, local control, and quality of life. That's a big part of these discussions in this day and age because, as you know, there are a number of tools available.

Historically, we've moved toward more focal therapies. For patients who have limited burden of brain metastases — as you noted, fewer than 10 — and have a good functional status, we really would put older techniques like whole-brain radiation off the table because we know that the subacute and late sequelae of that can be, frankly, devastating just in terms of the impact on cognitive function and quality of life.

We also have emerging data that are largely retrospective, but some prospective studies as well, that suggest that it's technically feasible to offer focal radiation to patients with brain metastases that are greater than five in number or so, especially if they're not high volume. It can be very effective at controlling the disease, not that there aren't risks of radiation-related injury even with our focal ablative stereotactic techniques.

We think about, from a patient perspective, whether there are alternative therapies that we could potentially employ. Systemic therapies with CNS penetrance may be able to control this disease, especially for patients who would have perhaps very small-volume punctate lesions, asymptomatic. Our primary resource in our tool kit would be the use of focal stereotactic radiosurgery (SRS) for patients, as you're describing.

Anders: When might you reach out to your neurosurgical colleagues when meeting a patient? What would be your decision tree as to when you might contact neurosurgery? It sounds very similar here, where medical oncology and radiation oncology communicate on a very regular basis. I'm also curious about when you might pull the third modality on a neurosurgical resection.

Braunstein: We as radiation oncologists perhaps have the closest relationship with our colleagues in neurosurgery. In most centers, they're very much involved in the practice of radiosurgery. First and foremost, when we're evaluating a patient, we're thinking about the location of the lesion and the need for tissue in some cases.

In some instances, this is a de novo presentation of metastatic disease, and there's value in that tissue. There may be value, even if this is not a de novo presentation, in acquiring tissue in that perhaps there might be molecular information that's valuable, as these tumors can show some genetic drift over time.

First and foremost, patients who perhaps have larger lesions with symptoms where a neurosurgical intervention and resection could immediately relieve mass effect and address any symptoms, those are the patients for whom we're reflexively most likely to engage our neurosurgery colleagues. Of course, they must have good performance status and be good operative candidates, but in this day and age, as a radiation oncologist, or perhaps as a medical oncologist, I'm amazed at how well patients do following a neurosurgical procedure, especially in high-volume centers.

You can take patients who are a little bit older, maybe have been through a fair amount of prior treatment, and they can do quite well with neurosurgical approaches. Again, it's not in my area of expertise per se, but the neurosurgical approaches are also evolving with motor mapping, eloquent area mapping, and LITT (laser interstitial thermal therapy) approaches. I think we're seeing perhaps improved patient outcomes with neurosurgical approaches, but again, for those patients who have a larger lesion that's symptomatic, nothing beats the ability to immediately relieve and decompress with neurosurgical approaches.

Anders: That's fantastic and I would say very much in line with our practice here. I'll turn to Dr Lin and ask a two-part question. Anything to add from the local therapy approach? Envisioning that this patient travels across the United States from California to see you in Boston, what would be your discussion around systemic therapy for a patient who's just received local therapy but on the trastuzumab/pertuzumab backbone therapy prior to arriving?

Lin: In addition to the considerations that Dr Braunstein mentioned, I'm looking, obviously, at their extracranial disease. I'm trying to think about whether there is some reason that I want to switch this person's systemic therapy. For example, if at the same time there were a couple of brain metastases discovered, a patient had progression of their liver metastases, then I'm going to be switching their systemic therapy anyway.

In that situation, if the brain metastases are not in locations where I'm worried that a small amount of progression is going to lead to some very bad outcome, I might just defer radiation with the blessing of the radiation oncologist and patient, and just switch their systemic therapy because that might work.

On the other hand, if somebody has controlled extracranial disease and they have three brain metastases, then I'm going to send them for radiation. From a quality-of-life perspective, 1 day of SRS or radiosurgery and then continuation of trastuzumab/pertuzumab, I think, is optimal for patients' quality of life rather than switching them to some more toxic chemotherapy-containing regimen.

Then there's the gray zone. Let's suppose somebody has eight or nine brain metastases and they're technically potentially able to be treated with focal radiation. I agree, like in these HER2-positive patients, that we try as hard as we can to kick the can down the road as long as possible in terms of whole-brain radiation because we don't want people to have long-term complications, and these are the patients who survive the longest.

When you get up to a larger number of brain metastases, I think the question that we debate — and the patient is very involved in this decision-making — is whether we offer SRS to multiple lesions and then leave people on trastuzumab/pertuzumab, or do we just switch systemic therapy in the hopes that it would treat both what we can see and micrometastatic disease that we can't see, and maybe delay the time to new CNS lesions.

There has never been a randomized trial to look at this, so it is very much a little bit of clinical judgment and some not exactly guesswork, but you're trying to play out potentially the likelihood of different possibilities. Patients have different preferences as well as to which path they would prefer to go down.

I think that would be the nuance that I would add there in that patient with multiple lesions that are technically SRS-able but maybe feel a little bit out of that comfort zone. In that patient, if I'm going to SRS and then switch to systemic therapy anyway, I might just skip the radiation and see if the systemic therapy alone is enough. Again, for those patients with a smaller number of lesions, I would routinely just have them see radiation oncology for SRS.

Melisko: I was going to mention, Nancy, that's exactly one of the challenges that I face at least once a month or so: A patient who has had SRS to a few lesions, is stable systemically, and they're on the MRI–every-3-month train. We're getting those MRIs, and we see the next MRI has one or two more brain metastases. In the past, before we had such good choices in terms of systemic therapy, we'd just send them back to radiation oncology, and generally that's my preference. I'll send them back because that 1 day of treatment is easier than putting them on a brand-new systemic therapy.

After you get two or three MRIs in a row where you're seeing one pop up here and one pop up there, then you kind of feel like you're playing whack-a-mole. At that point, I do start to think about the systemic therapies. I'm sure this is where you were going next, Carey, in terms of your questioning, but in terms of the choice of systemic therapy, we have the NCCN guidelines and the FDA approvals for various agents. Things are going to be all mixed up with new data from trastuzumab deruxtecan and tucatinib.

I'm curious to hear from either Nancy or you, Carey, about whether you have a patient who has been on maintenance HP [trastuzumab, pertuzumab] and you decide you need to make a change in treatment, and they're stable systemically. I think we were inclined to obviously be jumping over trastuzumab emtansine and putting them on tucatinib and capecitabine. Now, there are no randomized clinical trial data but very good extrapolated data for trastuzumab deruxtecan. With trastuzumab deruxtecan showing such amazing outcomes in terms of systemic control and long-term outcomes, what are you choosing?

A year ago, we all would have said let's go to tucatinib-capecitabine next. Now I tend to lean more toward trastuzumab deruxtecan. I'm curious to know what your thought process is.

Anders: I completely agree. I think this is one of the key questions. This is where we are really trying to determine whether the disease is stable or progressive in the brain, and sometimes that's hard to determine, particularly when we deemed a stable vs an active.

You could argue that the patient who, every 3 months, is having a new lesion might very well be active even though it's stable right after radiosurgery. To your point, Dr Lin, that will let you know you don't feel good about that. There's just a gestalt that it's time to change systemic therapy. We just recently put out an update on the ASCO guidelines, both for HER2-positive metastatic breast cancer and the brain metastasis setting, and this was one of the key questions.

The DESTINY-Breast03 study clearly showed us that trastuzumab deruxtecan was superior to T-DM1 [trastuzumab emtansine]. In that study, there was a pretty sizable number of patients with brain metastases that were deemed stable at entry. In that setting, I think we have some choices. Often, this depends on the patient in front of you.

If you feel that oral therapy compliance is just not going to work with that patient for whatever reason, then tucatinib is probably not the right direction. If the patient has some sort of underlying pulmonary disease and you're worried about their tolerance to trastuzumab deruxtecan, of course, you're taking all of these issues into consideration.

In the stable setting, I'm very comfortable with trastuzumab deruxtecan or the HER2CLIMB tucatinib, capecitabine, trastuzumab regimen. In the active brain metastasis setting, we have randomized phase 3 data based on HER2CLIMB for the tucatinib regimen. We have emerging data with trastuzumab deruxtecan, not hundreds and hundreds and hundreds of patients, but upwards of 50 to 75, where we've seen very nice intracranial responses to trastuzumab deruxtecan in the active space.

I do really feel like in the active space, I'll tend to go toward tucatinib if everything else is equal, and then also have trastuzumab deruxtecan for next-line therapy. That's how I've been thinking about it. Dr Lin, I'd be curious to hear your thoughts as well.

Lin: I've thought of it the same way. I am convinced at this point that trastuzumab deruxtecan has CNS activity. I think the studies have been small, but there have been multiple studies from multiple groups, all showing CNS responses. To me, that's not really so much in question.

What drives my thinking is that in the HER2CLIMB study, which is a randomized trial, you see that it delayed time to CNS progression and improved overall survival. The survival benefit was not trivial. It was a 9-month absolute improvement in overall survival for all brain metastasis patients and then more than 9-month delta in the active brain metastasis patients. That's not the median survival but the actual absolute delta, which is really dramatic. If you saw that in a typical metastatic trial, it would be really dramatic, and it's really dramatic in a brain metastasis population.

In DESTINY-Breast03, we don't have any data, and CNS progression-free survival has not been reported. The overall survival data are not mature and there are certainly not enough patients in the brain metastasis subset, plus the lack of maturity to really have a signal to know one way or the other. To me, at least at this point in time, you've got response data, CNS progression-free survival data, and overall survival data with tucatinib, and that's why I would tend to choose it in that second-line setting right now.

Now, if a patient had stable brain metastases and their problem was extracranial disease, I would, unless there was a contraindication, go for T-DXd [trastuzumab deruxtecan]. I think the data are so strong in DESTINY-Breast03. For the other types of brain metastasis patients, I tend to lean toward tucatinib. I think that may change over time as we see more data emerge with T-DXd in the brain metastasis population, but for right now, I think the data are stronger for tucatinib.

Anders: I completely agree. To think about the case a little further — and unfortunately, we've all seen this in our practice — after sometimes years of stability in the brain, our patients develop leptomeningeal disease (LMD), and that can be very challenging. I first wanted to start with Dr Braunstein to see what his approach from a radiation oncology perspective would be. When do you consider whole-brain radiation? Do you consider whole-brain radiation in patients who present with LMD? Please talk through some of the systemic therapy options that we have.

Braunstein: Absolutely. I acknowledge that it is a very challenging clinical situation. It's also a situation that can span a spectrum of presentation. There are some folks who have a very significant symptomatic burden of LMD and others who may have some radiographic presentation but without the sort of overt symptomatic component. Because of that, we address it accordingly.

We're thinking, maybe in this instance more so than ever, about interdisciplinary and patient-centered care. I think a patient should have a very strong voice when we talk about these very comprehensive or aggressive therapies. Historically, whole-brain radiation was employed to treat rather symptomatically, without really much benefit in terms of overall survival, in part because it's not a local problem at that point.

Interesting and timely, there is some emerging evidence that if we direct a therapy along the entire craniospinal axis, which is a very comprehensive treatment for some patients as compared to more focal, what I'd call whole brain or involved field, there is a benefit. A phase 2 randomized trial demonstrated that there is a benefit, perhaps, to proton-directed craniospinal irradiation for these patients. That's provocative, but really the focus of that trial was on CNS progression and overall survival.

There's also the question about quality of life. Now, these patients lived up to 10 months or so. I would argue that that is a substantial potential survival from the time of treatment, but of course, it's not curative and the durability is still questionable. I think one of the really interesting questions is not only in the treatment for patients who have overt LMD, but can we stratify? Can we identify those patients, as we're discussing, who maybe don't have stable brain metastases, but with some cadence we're seeing more and more burden of disease?

Is there a time when perhaps we could intervene with some comprehensive treatment or combination of radiation and systemic therapy to perhaps avert the presentation of true LMD? I think that is an area of opportunity now in the combination of these proven CNS-directed radiation techniques and CNS-penetrant therapies.

It doesn't answer the question altogether, but really, we're looking to avoid having that question come up and be able to treat earlier and make a bigger impact in terms of the trajectory of the disease.

Anders: That's fantastic. I had recently seen, as you said, those provocative data of the proton therapy along the entire neuro axis. I think it'll be really interesting to see how the data play out and how it also can be disseminated across other centers.

Dr Melisko, with your interest in LMD, what would be your approach for a patient with HER2-positive disease? We'll just pretend that the patient is therapy-naive, or you can think through what you might be considering if they've received certain things. We all recognize that many patients come to us with a very different treatment history, and you have to adapt your thinking based on what the tumor cells have already been exposed to systemically.

Melisko: We participated in the TBCRC 049 study, as did Dr Lin, with tucatinib, the HER2CLIMB regimen, and did see good outcomes for LMD, or what you would consider reasonably good outcomes for patients receiving this systemic therapy regimen. I think it all gets back to how these patients present. There's a big difference in someone who is getting their brain MRIs for follow-up of parenchymal brain metastases and we see a little bit of leptomeningeal enhancement.

In my practice, in the past, we were all hesitant to do the lumbar puncture and prove LMD because when you did prove it cytologically, then the patient was excluded from everything — every trial would exclude someone with LMD. Now I have a tendency to do more lumbar punctures partly because of my research interest in collecting those cells, looking for cell-free DNA, and looking at immune profiling. We're doing it, I know that they're doing it in Boston, and that you're doing it as well.

We are trying to be able to do that risk stratification, which I think really is going to be, in some ways, the future for patients who have these parenchymal brain metastases that we're picking off with SRS, to see if we can learn something either through biopsy by LITT, as Dr Braunstein brought up, getting a biopsy during a LITT procedure, or looking at CSF as a surrogate for what's going on in the brain.

If a patient presents with relatively asymptomatic LMD that we pick up incidentally, I will almost always go to the HER2CLIMB regimen first, so I will try tucatinib, capecitabine, and trastuzumab. If they're more symptomatic, they have dizziness, and there is clearly an area of the brain — we pick up a large amount of disease — I would consider a combination of some focal radiation, which may be whole-brain or cerebellar radiation, and then starting some type of systemic therapy like the HER2CLIMB regimen.

I was very enthusiastic about intrathecal trastuzumab. I was involved in those studies. I had some patients with great responses, but it is a labor of love to do intrathecal therapy twice a week for a month, and if it doesn't clear, you need to go longer with twice-a-week dosing. That is the challenge. I do use it. If I try tucatinib first and it isn't successful and there are no more radiation options, or if someone's already had whole-brain radiation, then I will try intrathecal trastuzumab.

There are case reports for neratinib. I did have one patient who actually developed some abnormal liver function tests on tucatinib when I was trying to treat them for LMD, so I switched to neratinib, and — cross fingers — they're stable so far.

I do think that we've talked about HER2-positive breast cancer, but more and more in the LMD space, I'm seeing a fair number of patients; of course, we see it with triple-negative patients, but they have this, often combined with massive systemic progression. A challenging group for me has been the ER-positive patients who are five or 10 lines of therapy in, especially the invasive lobulars. That has been a group of patients that I have had multiple cases of LMD in the last year.

Those are really this unmet need, where going back to radiation, we don't have as many good systemic therapies. If we identify more mutations for those patients with lobular cancers that have a high rate of HER2 mutations, we might be able to use neratinib in that space or other emerging TKIs. I use all the tools with LMD for HER2-positive disease, but it's the HER2-negative disease that I'm most challenged by.

I wanted to go back and ask Steve a question. For a patient where you're thinking about craniospinal irradiation, what about someone who had radiation to an isolated vertebral body 3-5 years ago? Almost all, or many, of our patients do. How would you consider doing craniospinal irradiation in someone who's had part of their spine previously radiated? Can that be done?

Braunstein: Yeah, that's a paramount consideration because we need to be mindful of what we're technically able to achieve in these patients. Certainly, we don't want to do any harm because any radiation-related injury to the spinal canal could be devastating.

There are some techniques that can be employed to try to be as thoughtful and conformal as possible, but you cannot stop having overlap in some cases. We need to be mindful of what the dose thresholds are, the time between treatments, and recognize that many of these patients you're describing may be on a very heavily pretreated background, which can affect sensitivity potentially to radiation, especially if they've had intrathecal therapies like methotrexate, for example.

It can be limiting. I think that's fair to say in terms of what we can technically achieve when we're re-irradiating these patients. One of the considerations is that, often in the metastatic setting, we're treating these patients up front for palliative osseous-based lesions. We can be mindful of using techniques to minimize dose to the actual cord because that's not where the disease is in the upfront patient who has a T8 vertebral lesion. We do have the techniques to be able to minimize dose to the actual cord so that we spare some threshold to potentially employ later in this type of situation.

Anders: That's fantastic. I think we're recognizing, just as Dr Lin said earlier, that our patients are living longer, which is fantastic. That makes our consideration of our therapies even that much more important in terms of mitigating the toxicities down the road, which is a challenge, but a wonderful challenge to have, right?

Dr Melisko, you gave a great segue to HER2-negative breast cancer metastatic to brain. I'd love to just hear from Dr Lin what your general approach is to a patient with both ER-positive/HER2-negative breast cancer and triple-negative breast cancer, where we certainly see a high proportion of our patients in the advanced setting recurring in the CNS.

Lin: I think that, in general, systemic therapies for CNS active disease are much less well developed in this setting. In the situation of HER2-positive disease, there are many situations where I might be conferring with radiation oncology and the patient. Should we defer radiation and try systemic therapy first?

For HER2-negative breast cancer patients, it's much more of a lean toward local therapy as the default, where sometimes we might use systemic therapy, and certainly if there's a trial, we might use systemic therapy. I think one big difference is that we just aren't as confident about the efficacy of systemic therapies.

The other is that for triple-negative breast cancer, patients who have multiple brain metastases, on average do very poorly. Those are patients where we do tend to be quicker about moving to whole-brain radiation. For a patient who has eight lesions with HER2-positive breast cancer, we might offer SRS. For a patient who has eight lesions with triple-negative breast cancer, at least at our institution, we routinely offer whole-brain radiation because our internal data have indicated that for patients who are offered SRS, their time to next CNS progression is very short. I think we do tailor things according to subtype in that way.

From a systemic therapy standpoint, we just don't have as many options, so we have to be more creative. Sometimes when we're stuck and somebody doesn't really have a good radiation option, obviously, we'll think about a systemic option. Often, we're looking at small phase 2 studies if we're lucky. Otherwise, it's a case report or a small case series.

You have to go with what you have data-wise and try to propose things. I try to propose things that have some known breast cancer activity and at least some indication that they may have CNS activity. Again, I'm much more inclined to lean patients toward local therapy approaches if there's a reasonable one to be offered.

Anders: That's fantastic, and I think it really highlights the difference in our approaches by the patient's tumor subtype. In my own practice, I tend to lean on, in the ER-positive space, abemaciclib, which, of the CDK4/6 inhibitors, I think is the most brain permeable. I was very intrigued by the MAINTAIN data at ASCO, which really looked at this question that we've had for quite some time, which was CDK4/6 inhibition after CDK4/6 inhibition with some transition in the endocrine therapy backbone from an aromatase inhibitor to a SERD [selective estrogen receptor degrader].

I am curious and ask the team whether, after a patient who potentially has been on palbociclib for 3 years, you would consider abemaciclib in that setting. I know we're in a bit of a data-free zone, but as you said, Dr Lin, we try to do the best that we can with the tools that we have.

Lin: I think it was Dr Melisko who talked about lobular cancer. In general, our endocrine therapies work better than chemotherapy. If I have a patient with lobular cancer who has a primarily CNS presentation, then yes, I will switch from one CDK to another or switch out the endocrine therapy because I am really trying to maximize that endocrine therapy benefit, whereas for a person who has more of a luminal B type of cancer and doesn't do so well on first-line endocrine therapy/CDK4, I'm more likely to cycle that person onto chemotherapy earlier.

There are some chemotherapies with some CNS activity, including capecitabine, the anthracyclines, and the platinums. There are options to consider.

Anders: I think those are very similar strategies that I use as well. Dr Melisko, I would love to hear your thoughts in the triple-negative space. I think this also dovetails with DESTINY-Breast04. It's hard not to talk about in a breast cancer forum after ASCO this year. There was a standing ovation for these amazing data. There were few data for brain metastasis in that presentation. I looked at it earlier and it was 6% of the patient population who had stable brain metastases. Take us through your approach to systemic therapy in the triple-negative space for patients who have CNS recurrence.

Melisko: Obviously, it's interesting to hear what Dr Lin was saying about their approach toward moving faster to whole-brain radiation. I think we may have a slightly different approach at UCSF, especially if someone has really aggressive triple-negative breast cancer where we're running after the liver, lung, and brain metastases and thinking about long-term quality of life.

It's true that if someone is only going to live for a year from their systemic disease, they're probably not going to suffer the long-term cognitive effects of doing whole-brain radiation. Our population just is quite resistant to whole-brain radiation no matter what, so that's a challenge for us. Dr Braunstein could probably chime in more there.

As far as the systemic disease, obviously there are some data for sacituzumab govitecan in the CNS. Dr Brenner has a SWOG trial that's moving forward. We're not part of SWOG, so I can't speak to anything about that design. Looking at sacituzumab govitecan and progressing CNS metastasis, I think that we have a desperate need to be more daring in terms of having study designs with patients with relatively clinically stable but progressing brain metastasis.

I've spoken extensively with Genentech. They've looked at their data, and obviously atezolizumab is not on the table for metastatic triple-negative breast cancer anymore, but they were pretty convinced that it wasn't an active agent. I know Dr Brastianos has done a small study with pembrolizumab and other checkpoint inhibitors for patients with LMD, which is obviously very different than a patient with a progressing parenchymal brain metastasis. I think that trying to dig more into the role of immunotherapies and antibody-drug conjugates in triple-negative breast cancer is just something that needs to be done.

I think no company wants to do that because they don't want to muddy the waters with patients who have a poor prognosis, which is unfortunate. I think it's on us as investigators to do our bit here and there to try to promote some investigator-initiated trials that are going on across the country.

With a triple-negative population, I might try sacituzumab govitecan outside the context of a trial because I might be giving that to them anyway. I am a big fan of cisplatin/etoposide. It's an oldie but goodie. There are data from Italian groups and Turkish groups, and then a Taiwanese group has published on use of that both in brain metastasis and LMD. One of the studies had bevacizumab as part of the regimen, and I have used bevacizumab in the past. I know that Dr Lin, years and years ago, had some interest in combining bevacizumab, but anti-angiogenesis agents haven't had much success in breast cancer long term.

I think trying different systemic therapies is important because there is no magic bullet for triple-negative breast cancer. Looking for those triple-negative patients who have HER2-low status — so that one or two by IHC [immunohistochemistry testing] — obviously, we're going to be reaching for trastuzumab deruxtecan and I think it's going to be like they're putting it in the drinking water. It's going to be so ubiquitous. You walk into the oncology clinic and you're going to get a cup of T-DXd after that presentation. For sure, I'll be biopsying more patients.

I've only become familiar with LITT in the last 6-12 months, but we have been sort of remiss in biopsying our CNS metastasis. I think this is the future of being able to get tissue and actually do more investigation of the biology to look for PI3K mutations, which I know you have looked at in terms of the responses to therapies, HER2 mutations, low-level HER2 expression, and things like MYC amplification, which I think is going to be the potential target for triple-negative breast cancers in CNS disease. I think that's really going to be the future for that population.

One place I still am curious to hear about what your thoughts are is that for these patients with ER-positive LMD, we're kind of up against the wall because we presume that by that point, they've already gotten abemaciclib. I still give intrathecal therapy. I think it works on occasion. I know that it's not very popular and I know most oncologists don't like to do it. I wish we had more drugs and options, but I'm curious about whether either of you have given intrathecal chemotherapy and how often you give it. I do give it.

Anders: I think that's a great question. I love your overview, and I also love your call to be more daring in our trial designs. The only other thing I would add from a targeted therapy perspective would be PARP inhibitors. I've had some very nice, durable responses intracranially for many — largely younger — patients, but I do have some patients over the age of 60 years. We found a germline BRCA mutation, and even in some cases a somatic BRCA mutation, on a clinical trial in one of the TBCRC studies.

I think, certainly, the literature there shows emerging evidence that brain metastasis may harbor deficient DNA repair responses. To your point, Dr Melisko, the more we know about the biology through less-invasive biopsies — for instance, like you're discussing through the LITT technique, which is through a small biopsy — the better. We'll have more information on the brain metastasis biology and not need to extrapolate from what we see in the extracranial metastases.

To answer your question around intrathecal therapy, I have used it, with the more recent tools that we've had, particularly in the HER2-positive space, less frequently than I had in the past. I'd love to hear Dr Lin's comments, and then we can probably close.

Lin: I do use intrathecal. For HER2-positive disease, if I'm going to do intrathecal, I tend to try intrathecal trastuzumab before I do intrathecal chemotherapy. In the HER2-negative patients, I do offer intrathecal chemotherapy, but I often offer systemic chemotherapy or endocrine therapy if they might have endocrine-responsive disease first, mostly from a convenience standpoint. I think the data from the intrathecal chemotherapy trials are not incredibly optimistic. I don't think it's wrong to offer people systemic options first. I offer capecitabine, for example, if they haven't had it before.

By the time people get to whether we are going to give intrathecal chemotherapy or not, in many cases, unfortunately, the other option on the table is hospice. I think that does influence our use of intrathecal chemotherapy, but I do offer it.

In terms of the question about being daring, our paradigm until now has been the assumption that drugs are not going to work in the brain until proven otherwise. Honestly, it really should be, in my opinion, the other way around. Drugs will work in the brain unless proven otherwise.

If we look at the ADCs [antibody-drug conjugates], for example, we pushed and pushed many different companies over many different years, and now look: T-DM1 is active in the brain, T-DXd is active in the brain, and sacituzumab is probably active in the brain. We'll see what the SWOG study ultimately shows, but certainly, the drug levels are there.

For ADC trials moving forward, my preference would be that they include patients with brain metastasis up front, assuming that they're going to have activity, and if they don't see activity in the early interim, just exclude them then. Why do it the other way around?

Similarly, for PARP inhibitors, we have several patients we have treated with LMD with greater than 1-year durable, dramatic responses and clinical improvement of very serious symptoms.

There will never be a randomized or even a small prospective phase 2 trial of BRCA1/2 carriers with LMD. That trial will never happen in a million years. If you only let people with CNS disease onto the registration trial, there might have been 10 patients total in the whole trial, but that would be the largest dataset in the world and it wouldn't have affected the primary endpoint at all.

From an advocacy standpoint, really advocating to be more inclusive of patients with brain metastases in trials is so important because in some cases, it's possible to do an IST (investigator-sponsored trial) and really show something in a small, single-arm type of experience that leads to changes in the guidelines. Other times, it's really not. You end up with this zone where you've got two published case reports and then you practice your medicine based on that. It doesn't feel good to do that, it doesn't feel good as doctors to do that, it doesn't feel good as patients to be told this might work, we're going to try it for this reason.

I just think that there have been very few instances where a drug that is truly active in breast cancer has had no CNS activity. It's usually the other way around, that there is. It might be less than the systemic activity, but there typically is some. I think changing the defaults would go a really long way.

Anders: Beautifully said. I think we need to move from the blood-brain barrier to the blood-tumor barrier. That's a very different interface. To your point, I love switching the order. Don't exclude up front. Include them and give us a reason to not want to move forward than not look at all. Otherwise, we wouldn't have had the information that we have now that we've discussed on this call.

Lin: What happens if there's a compound that the phase 3 has been fully accrued and then an IST in brain metastasis opens? That's many years of excluding patients and numerous lives lost.

Anders: Absolutely.

Melisko: Then you see that once the drug becomes approved, the community is not going to send the patient to put them on the trial, so it becomes difficult to accrue.

Anders: Absolutely.

Melisko: You miss out on that opportunity. It's a cost and a missed opportunity.

Anders: That's a really good point. Well, thank you all so much for your collective expertise. This has been a fantastic conversation. There is much to think about, and I look forward to seeing you all soon.

Melisko: Thank you.

Braunstein: Thank you.

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