Dr. Sara Tolaney:
Welcome to The ASCO Post-Roundtable Series on Evolving Paradigms in the Treatment of Hormone Receptor–Positive, HER2-Positive Metastatic Breast Cancer. My name is Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute, and today I'm joined by my two very esteemed colleagues, Dr. Mark Pegram from Stanford University, and Dr. Ian Krop from Yale. Today, we're going to be discussing the treatment and management of metastatic hormone receptor–positive/HER2-positive breast cancer with three patient case studies. Our final installment will focus on second-line therapy for ER-positive/HER2-positive metastatic breast cancer.
So, we're going to dive into our third case here. So this is a 62-year-old woman who had received first-line therapy with paclitaxel plus trastuzumab and pertuzumab for her de novo metastatic hormone receptor–positive/HER2-positive disease. After being on treatment for about seven cycles, she stopped the paclitaxel and initiated therapy with an aromatase inhibitor in combination with trastuzumab and pertuzumab, and had palbociclib added, given the very recent data that we had seen from PATINA.
So we're going to fast-forward and say she had been on that therapy for a few years, and then developed progressive disease, and has, in fact, now a new brain metastasis for which she was asymptomatic. So again, she's on HP/AI palbociclib maintenance, but has new liver mets and a single isolated new brain met.
So one question that I think comes up, and I'll be honest, I still struggle with this a little bit, is should we be getting routine brain MRIs in our patients who have metastatic HER2-positive breast cancer? We certainly know that the incidence of developing brain mets over someone's lifetime is probably about 50% if they have metastatic HER2-positive disease, so it's obviously quite common. So are you all getting brain MRIs, even if someone's asymptomatic? If so, how often, and how are you approaching this? So maybe I'll start with you, Ian.
Dr. Ian Krop:
So as you said, this is a question that I think different practitioners have different philosophies on, and it's kind of gone back and forth, I think, within the community a little bit about should we or should we not be doing screening brain MRIs. I typically don't do it. Obviously if someone has a symptom, I have a very low threshold for doing imaging of the brain, but I don't do it routinely on patients with HER2-positive disease or any other subtype of breast cancer. There are harms in detecting tiny little things that we're not even sure are clinically relevant, and it's certainly stressful for patients to get imaging. So my personal feeling, my personal practice, I don't do it. I know in Boston, there's been attempts to do a trial looking at the potential benefit of doing screening. But I don't think their results are available yet, so right now, I don't typically do it.
Dr. Sara Tolaney:
Yeah. It's an interesting point, because you're right, we sometimes do find tiny things. I've done that to patients. It is alarming for them to feel like, "Oh, I've got some new small couple-millimeter thing that may be irrelevant," but now they know it's there and it is hard. As you point out, we are actually doing a screening brain MRI study here at Dana-Farber, where we're trying to see if it could delay neurological symptoms.
So you could think if you pick up something that's really tiny, that's probably better for a patient to not have symptoms from that spot, rather than finding it when they're symptomatic and have a large brain lesion that now has neuro symptoms. But obviously we haven't proven that that is the case, and we do need more data here to understand what the impact is not only on symptoms, but also on survival. So that, I think, needs more work. But Mark, are you doing screening MRIs in your HER2-positive metastatic patients?
Dr. Mark Pegram:
No. Our practice pretty much matches exactly what Ian has said. That said, if somebody in the waiting room in your practice has an occult brain metastasis that's HER2-positive, on that day, everybody else in that waiting room with HER2-positive metastatic disease is going to demand one, and they're going to get one. You'll probably find another one in the mix.
So, we have a very low threshold. If somebody sneezes with any kind of neurologic sign or symptom, we do it immediately. But we are not doing it on a systemic basis with a screening program for allcomers. The incidence probably isn't high enough. Even with a 50% lifetime incidence, the incidence per scan is probably not high enough to justify the expense and the as you say, false positive possibilities, et cetera. So we need data, and I think your effort to give us data is long overdue.
Dr. Ian Krop:
It's not even false positive. I mean, I think it's possible if it's very small and when someone is just starting treatment, it's possible that the systemic therapy is going to take care of it. Whereas if you radiate it, then you may have sequelae of the radiation down the road. So, I do think it's something. I'm really happy that your group is studying this, Sara, because it would be great to have data on this rather than have this uncertainty about the question.
Dr. Mark Pegram:
Systemic therapy has gotten so good, as we'll talk about in a moment, the prolongation of time to CNS intervention with neurosurgery or radiation, that's an important clinical endpoint too, in my view because those both-
Dr. Sara Tolaney:
Thank you for that transition because that's an important question. So I'll say in this particular case, obviously this patient had both progression in the liver and in the brain, but only one brain met, and this is let's say, a brain met that could be a candidate for stereotactic radiation. So, what do you do in these cases? You just pointed out that our drugs are getting better at treating the brain. Do you radiate someone who has an oligometastatic brain met, or do you use systemic therapy here? Since they've progressed outside the brain as well and you're going to need to change systemic treatment, how do you think about that?
Dr. Mark Pegram:
We used to think about local therapies routinely, but in the wake of studies like the HER2CLIMB study that showed an overall survival benefit with the introduction of tucatinib into the therapeutic armamentarium, and even in patients with active brain metastases, and now more recently, the non-randomized data presented at ESMO last year by Nancy Lin looking at T-DXd in patients with measurable CNS disease at baseline, that had an extraordinary CNS confirmed objective response rate of over 70%. In the active brain met subset in that group, it was over 80% confirmed objective response in the brain.
This is a 138-patient, nonrandomized phase II trial, but with such extraordinary activity as T-DXd in the DESTINY-Breast12 trial that I mentioned, I think that's probably the new standard of care. You could probably delay consideration for stereotactic radiation or neurosurgery, or both in a case like this, especially if it's an occult, a clinically silent brain lesion, because you'll probably get a great response just with T-DXd. I think that probably is my go-to treatment in the wake of ESMO last year, whereas before, because of the OS benefit in a randomized phase III trial for tucatinib, that used to be the holy grail because of level I evidence of an OS benefit. But now, the T-DXd data are so extraordinary, with triple-digit numbers, that's just changed my view on what we should do systemically in a case like this.
Dr. Sara Tolaney:
You bring up I think a really important point. I mean, to see an 80% intracranial response rate in patients with active brain mets with T-DXd is clearly very impressive, and even their 12-month-
Dr. Mark Pegram:
It's the same as the extracranial response rate, isn't it? It's-
Dr. Sara Tolaney:
Yeah. It's true. So it sounds like you would be okay maybe starting this patient on T-DXd, given DESTINY-Breast03 shows obviously very prolonged, you have 28-, 29-month PFS in a second-line setting, and you have DB12 showing CNS benefit. Ian, what would you do? Would you do systemic therapy or would you think about SRS and then systemic therapy, or how do you think about it?
Dr. Ian Krop:
Yeah. Well, I mean, I'm sure on the same page in terms of needing systemic therapy, and certainly given the data that Mark was just talking about with T-DXd, that would be the go-to now. I think the question of whether to start with SRS is harder. Certainly that would've been my recommendation prior to the DB12 data, which was again, the single-arm study showing the very high intracranial response. Because we know that some patients who get stereotactic radiation to a lesion like this never have further progression in the brain, whereas I think the previous pre-T-DXd data has been, yes, we have good response rates with a tucatinib-based regimen, and even T-DM1 had responses in the brain.
But in general, most of those patients who don't get radiated would have progression in the brain as well as, or even oftentimes exclusively progression in the brain, whereas when you radiate, there is a sizable fraction of people who I think won't have further disease in the brain. That's something that's appealing I think for patients, so I'm kind of on the fence. I think it depends on the size of the lesion, where the lesion is, how worrisome it would be if it progressed neurologically. But I do think that we are at a transition point in our care that we can really rely much more on systemic therapy than we used to, and obviously that's a good thing for patients.
Dr. Mark Pegram:
Like you, Dr. Tolaney, we have a neuro-oncology team with a regular standing tumor board. So a case like this would be discussed with that group, which includes neurosurgeons or radiation therapists, imaging people, medical oncologists, et cetera. So, there would be much discussion over a case like this, each and every time.
Dr. Sara Tolaney:
It's nice to be able to have our multidisciplinary colleagues to be able to help us in these tricky cases, and I think maybe it would've been a little bit less complicated if in fact we said that this patient had multiple brain mets and needed whole brain, where I think maybe we would've felt it'd be more clear cut potentially to try to avoid whole brain and try systemic therapy given the potential toxicities of whole brain. Whereas with SRS, I tend to agree with Ian, that maybe I tend to pull the SRS trigger a little bit more often because if it's small and easily radiated, I think, "Well, maybe I will, and then move on to systemic treatment."
But what if we twisted this case a little, and let's just say she was on her maintenance therapy after induction treatment with taxane and only had a site in the brain with one small brain lesion, but didn't have systemic progression. So in essence, everything's controlled everywhere else. It's just that a new brain met popped up on that maintenance regimen. What do you do then? We just talked about how all these new drugs, tucatinib-based therapy, T-DXd, penetrates the brain and has activity and response. Would you switch systemic treatment or would you just radiate that new spot and continue the maintenance treatment? So Mark, I'll ask you, how do you approach that situation?
Dr. Mark Pegram:
Again, we would discuss this at our multidisciplinary oncology conference, but I think there would be high enthusiasm for local treatments in this case, especially with stereotactic radiation. I mean, the results can be superb with no discernible loss in cognitive function, et cetera, if you can get a really nice margin with the dosimetry calculations, et cetera. It can be very safe, very effective. The reason I'm enthusiastic about local control in this case is because of the lack of extracranial disease here.
If they're tolerating the dual antibody therapy well, I mean, that regimen can be extremely well-tolerated for very long periods of time. So I would be enthusiastic to maintain that for extracranial control, and then focus attention probably with radiation therapy for the solitary primary lesion. We might have to beat away the surgeons on a case like this too. They might be enthusiastic too, depending on anatomical location, if it's small and peripheral, sometimes those guys are very enthusiastic to resect solitary metastatic solid tumor lesions, including breast cancer.
Dr. Sara Tolaney:
Very true. So if you were to radiate, I think one of the questions that often comes up when discussing with our multidisciplinary colleagues is what to do about the systemic therapy and timing with radiation. So with if, let's pretend the patient had been on palbociclib with HP endocrine therapy maintenance, I think all of us would probably hold the CDK during any concurrent radiation. But I think a tricky question is with T-DXd, if someone had been on T-DXd and needed CNS radiation, we have seen case reports of radiation necrosis in the setting of people getting concurrent ADC and radiation. I'm curious, do your groups have any rules about timing, about holding T-DXd and timing of radiation? Maybe I'll ask Ian. Do you guys have any rules that you follow about that?
Dr. Ian Krop:
Yeah. I don't think that there are any written-down guidelines on this in our group. Because as you said, the data on necrosis has been certainly concerning and we've now seen several reports about this. But I think we've still in a multidisciplinary way try to take it on a case-by-case basis. I think holding the T-DXd, which doesn't have such a long half-life before, and then restarting it in what's felt to be some reasonable amount of time afterwards has been what we've been doing. But I mean, again, here's something that is going to become more and more common as we start using T-DXd so much more in patients who've now developed brain mets.
Dr. Sara Tolaney:
It'd be nice to have a little bit more clear guidance here because I know this does often come up, and as you point out, we don't have a great rule of thumb. We just try to space it out a little bit, so at least they're not getting that dose too close to the radiation. But thank you guys, because I think it's really nice to see that things have evolved a lot in the second line setting with T-DXd, really now transforming outcomes in the second line setting with PFS, in essence, four times as long as T-DM1 in this second line space, and also now seeing recent data with very robust CNS activity, it really has changed the paradigm, really establishing it currently as a second line standard. But we'll actually hopefully see data soon about T-DXd in the first line metastatic HER2-positive setting.
We'll have to see how all this evolves. I feel like every day, something new is changing in breast cancer, which is wonderful for patients. So thank you, guys. This does bring us to the end of this case, and please see the other segments for further discussion about the latest research in metastatic hormone receptor–positive/HER2-positive breast cancer, or visit ascopost.com. Thank you.
