Dr. Carey Anders:
Welcome to the ASCO Post Roundtable Series on Novel Therapies for HER2-Positive Breast Cancer Brain Metastasis. My name is Dr. Carey Anders and I'm a Professor of Medicine and the Director of the Duke Center for Brain and Spine Metastasis at the Duke Cancer Institute. I'm pleased that two of my colleagues today will be joining me. I'll let them introduce themselves. Dr. Sarah Sammons.
Dr. Sarah Sammons:
Hello, my name is Dr. Sarah Sammons, I'm a breast medical oncologist at Dana-Farber in Boston, Massachusetts.
Dr. Carey Anders:
And Dr. Rani Bansal.
Dr. Rani Bansal:
Hi, my name is Dr. Rani Bansal, and I'm also a breast medical oncologist at the Duke Cancer Institute in North Carolina.
Dr. Carey Anders:
Excellent. Today we will be discussing the treatment and management of breast cancer brain metastasis with three patient case studies. Our second installment will focus on a patient with intracranial progression while on an antibody-drug conjugate, which we will abbreviate as ADC therapy moving forward.
Mrs. TB is a 42-year-old female with a history of de novo ER/PR-negative, HER2-positive breast cancer metastatic to the liver in January of 2020. She was initially treated with the CLEOPATRA regimen with a taxane, trastuzumab, pertuzumab with a complete response in the liver. She was then maintained on trastuzumab/pertuzumab until March of 2022 when she developed word-finding difficulty and a headache. At that point a brain MRI was ordered, which illustrated six individual intracranial lesions. None were over 2 cm in both supratentorial and infratentorial spaces. Concurrently, she had extracranial staging, including a CT chest abdomen and pelvis, which showed the reemergence of two new liver metastasis.
So, she undergoes radiosurgery to each of the intracranial lesions and her symptoms are relatively quickly controlled and then she transitioned to the ADC trastuzumab deruxtecan. This systemic therapy was chosen for both intracranial and extracranial progression of disease. I want to pause and first ask my colleagues their thoughts on the trastuzumab deruxtecan choice here, particularly with regard to an ADC and blood-brain barrier permeability. Dr. Bansal, curious to get your thoughts on this choice of second-line therapy.
Dr. Rani Bansal:
Yes. Currently, we know that there is benefit to give T-DXd for second-line therapy on progression after regimen of a taxane and trastuzumab and pertuzumab. So, I think it was a great choice, it would've been what I would've chosen if this was my patient. We know that there is intracranial activity of T-DXd, we've seen that, and it can be very impressive, we can see response rates intracranially of anywhere from at least 70% for many patients. And so I think this was a great choice for this patient, especially given she has both visceral disease in her liver, as well as intracranial disease.
Dr. Carey Anders:
Absolutely, agreed. And I think this has been quite an interesting story to follow, in that I think originally we didn't envision that what we would consider a bulky antibody-drug conjugate would have activity in the CNS. Dr. Sammons, I'm curious to get your thoughts there and your experience with T-DXd and intracranial control.
Dr. Sarah Sammons:
I think in 2025, we are fortunate compared to before to have really two highly active regimens for our patients with stable or active HER2-positive brain metastasis, one being trastuzumab deruxtecan or T-DXd, the other being tucatinib, capecitabine, and trastuzumab. In terms of this patient has progressing intracranial and extracranial disease, and we do know that in the second-line setting, T-DXd does have an overall survival benefit including the brain metastasis population, so I absolutely would've chosen it in this case as well.
Dr. Carey Anders:
Excellent. So we move forward to approximately 1 year later and on restaging brain MRI, there is an increased enhancement in edema and several of the largest intracranial lesions with mild increase in size. This is a very frequent diagnostic dilemma in many of our clinics and on our tumor board following radiation therapy. I'm curious, Dr. Bansal, your thoughts here and what you might be thinking with regards to progression of disease vs potential radiation therapy necrosis and how the timing of this diagnosis with the changes being a year after the radiosurgery might impact your thought process there.
Dr. Rani Bansal:
Definitely. I think the timing does make me suspicious for radiation necrosis. We typically tend to see that a year to 3 years after radiation therapy. And so that is one thing that would make me a little nervous about that vs just progression of the lesions. This is very difficult though, and I do rely heavily on my neuro-radiology colleagues to really help us try to sort out, do they think based off imaging findings, is this radiation necrosis or we really are worried about progressive disease? Really the only way we can know for sure is to get a biopsy and to get that tissue and to see, is this truly progressive disease or is it all necrosis?
And so I think like you mentioned, Dr. Anders, it really does involve a multidisciplinary team to think about where the patient is in their timeline from radiation, what their imaging is showing, how are they feeling, all of those different aspects to try to figure out if this is necrosis or truly progression. I think many times what we do clinically, if the patient can get a biopsy safely, that's usually what we tend to favor just so we can be sure in our diagnosis. But if they can't, then a lot of times we will follow these areas closely on repeat imaging, so sometimes we'll repeat imaging in 6 weeks and start steroids in the meantime. I think there's different ways to approach it, but it is a complex situation.
Dr. Carey Anders:
Absolutely. Dr Sammons, curious if your approach would be similar at your institution?
Dr. Sarah Sammons:
Yes. I would say that we're seeing more and more radiation necrosis and it's just becoming more and more of a problem. In 2023, our colleagues at Memorial Sloan Kettering published a nice paper looking at a series of a hundred patients who received stereotactic radiosurgery concurrently with ADCs vs those who didn't receive stereotactic radiosurgery with ADCs. And what they found was that there was an increased risk of radiation necrosis when antibody-drug conjugates were delivered concurrently, which is either within a week before SRS or within 3 weeks after.
And it was particularly a problem if the radiated lesion was large. It was a problem more if the lesion was re-radiated, and so it's becoming more and more of an issue. I think the way we can diagnose it in 2025 is evolving. I hope that one day we can be a little bit more definitive with all the geographic tools that we have for fusion-based MRI, pet CTs of the brain, AI algorithms. We really need to be able to tell with some degree of certainty, non-invasively, between radiation necrosis or not. For this patient, if my radiation oncologist or neurosurgeon simply weren't sure what it was, then biopsy vs resection would be reasonable.
Dr. Carey Anders:
Absolutely. And these are all the discussion points that we have at our tumor boards nationally and internationally every week in this setting. And I agree, I think having some novel neuroimaging techniques just as you described to help us understand with more certainty in a more non-invasive way would be really welcomed. But I do think at this point in 2025 if safe, a biopsy really remains the standard of care. And that's what in our patient's case, she did move forward with a biopsy to one of the largest lesions and, interestingly and what we do see in many cases is, radiation therapy necrosis alone with no evidence of metastatic cancer.
In this case, she was treated with a steroid taper and her symptoms did improve and maintained on T-DXd with both intracranial and extracranial control given that there was no evidence of metastatic cancer in the biopsy. Thinking about this increasing consequence of excellent therapies, and I think the beautiful thing is our patients are living longer, these therapies are more effective, and so we're starting to see more of the later consequences of the therapies that have maintained tumor control. In this particular case, steroids were utilized, I'm curious if there are other strategies that you use in your own clinics, whether or not they're medical therapies or also more sophisticated surgical strategies for patients with radiation therapy necrosis.
Dr. Bansal, curious what you think about in your practice.
Dr. Rani Bansal:
That's a great thought, Dr. Anders. I think we do have data for the use of bevacizumab in terms of systemic therapy options. Typically, I believe the studies have used 4 doses and have shown improvement in radiation necrosis. I think there are certain patients I get a little nervous in terms of giving bevacizumab to. My patients that are older, have other comorbidities such as any issues with bleeding in the past or already uncontrolled hypertension. There are many things we have to think about when giving a systemic therapy for radiation necrosis, but I definitely think that it is an option and I think for a young patient who is otherwise healthy, is doing otherwise well in terms of their other treatment, I would consider it.
Dr. Carey Anders:
Yes, completely agree. And I think selecting the patient where it's going to be safest is really prudent., I think the dosing, and Dr. Sammons, I'm curious in your practice, the dosing we've seen here at the Duke Cancer Institute has largely been a low dose of bevacizumab, much lower than the standard 15 mg per kg every 21 days. Historically, and through the literature, we've seen on average around 5 mg per kg, and as Dr. Bansal stated about 4 treatments overall. In our patient's case, she was able to decrease symptom burden with steroids, but many times we can't taper patients off steroids and their symptoms recur. I’m curious to hear your thoughts as to bevacizumab administration, dosing, and duration.
Dr. Sarah Sammons:
It's a good question. For radiation necrosis, I would say the first line is generally steroids. If we either can't taper the patient off steroids or it's refractory despite steroids or the steroids are not helping, then you could move toward something like bevacizumab. The one problem with bevacizumab is that we don't have a lot of safety data for a lot of the different targeted agents that we give with bevacizumab, and so that can be a little bit challenging and sometimes we'll have to hold a certain therapy vs not. But similar dosing, usually 5 or 7.5 mg per kg. I usually scan their brain after 2 doses, which is around 6 weeks to see if there's any improvement at all. And also you're following their neurologic symptoms because of course you're going to do this more for symptomatic radiation necrosis and less so for asymptomatic radiation necrosis, but certainly no more than 4 at least at one time.
These problems are highly multidisciplinary, so we are very lucky to have our neurosurgeons and our neuro-oncologists and our radiation oncologists to help us in these discussions. But sometimes for various symptomatic radiation necrosis that's either steroid-refractory, bevacizumab-refractory, or the patient's not a candidate for steroids or bevacizumab, if it's a surgically resectable lesion, sometimes neurosurgery will talk to the patient about that as well. And so some options, but we definitely need more research in this area. It's a hard area to do research in.
Dr. Carey Anders:
Absolutely, couldn't agree more. And I think we do struggle when we have therapies that the patient needs for control, particularly with extracranial disease, but we don't have safety data with bevacizumab. We do have safety data for many therapies with bevacizumab, but not all. And I think that's where some ongoing registry studies internationally are looking at this particular issue to really help guide patients and clinicians when we need to consider bevacizumab for radiation therapy necrosis.
The other consideration of bevacizumab is it does preclude being able to move to the operating room because of the bleeding and the wound healing issues. I completely agree, steroids first and then this decision tree, are we going to do a resection or also a strategy called LITT therapy, laser interstitial thermal therapy, which involves the biopsy needle, including a probe that's heated, into the center of the lesion to really help heal the radiation therapy necrosis. I know we have been seeing that more and more at our institution and believe that other institutions are also engaging in LITT therapy as a less invasive way to help control radiation therapy necrosis. Curious if you've seen that at your center, Dr. Sammons?
Dr. Sarah Sammons:
Our center does not use LITT as much. I think the data on that approach is evolving and a little bit institutionally specific. I would say that we have the capacity to do it, I just haven't seen it done very often.
Dr. Carey Anders:
Excellent. And I think you're right. I think this really speaks to the multidisciplinary nature of the treatment of this disease process, institutional standards, so it’s a very interesting space with a lot to learn.
Dr. Bansal, I wondered if you could just comment on your practice in terms of the data that Dr. Sammons described with regards to the timing of ADC and radiosurgery and how you might consider integrating in radiosurgery with ADC therapy in your own practice.
Dr. Rani Bansal:
I was actually just about to ask you both that same question, Dr. Anders and Dr. Sammons. I think it's really interesting data. I struggle honestly clinically, especially if I have a patient that has visceral disease extracranially because I don't want to wait 3 weeks, at least, after they complete their radiation therapy because I'm nervous about the rest of their disease. I personally talk with my patients and then, of course, our review at our tumor board as well, if it is a patient that could potentially forego radiation up front and maybe we could start systemic therapy and see what response we get. That is something I do think about, especially as we are seeing more and more intracranial responses with our ADCs and our different newer agents.
I think it's the way the field is changing and I'm really curious to see what new data we see in newer ADCs coming out that have an intracranial response, but that is something for select patients. I do think about potentially starting systemic therapy first and then either utilizing radiation later on when I can take a break in the middle of treatment or if we don't necessarily even need it, if we get a very good response.
Dr. Carey Anders:
Great points. And I think it also highlights the individualized nature for each of the patients that we're seeing in clinic. If you have overwhelming visceral disease, you do worry about a potential 4-to-6-week overall delay. I think the 7 days prior to radiosurgery is a little easier to manage than the 3 weeks after. But we do know that takes a lot of coordination with our radiation oncology team because it can take several weeks to plan radiosurgery. I think just highlighting that communication between the multidisciplinary teams.
Excellent. All right, so the key clinical takeaways from this segment are that radiation therapy necrosis is a common consequence following focused stereotactic radiosurgery of brain metastasis arising from breast cancer, but really all cancers. In general, true radiation necrosis tends to occur later at least 9+ maybe 12+ months after radiosurgery, whereas changes early on are usually reflective of radiation resistant disease. The timing can really help us understand the clinical trajectory to help us determine whether or not we believe the changes we are seeing on MRI are more necrotic or due to disease progression.
I think we are seeing novel imaging techniques emerging, such as dynamic contrasted MRI, there are some amino acid PET imaging analysis that are emerging as possible ways to diagnose, and we are awaiting data in that space, but really biopsy or safe biopsy remains the gold standard. And there's emerging data from our partners at Memorial Sloan Kettering indicating that timing of our antibody-drug conjugate and radiosurgery administration can also potentially decrease risk of radiation therapy necrosis.
This brings us to the end of case 2. Please see the other segments for further discussion about the latest research in breast cancer or visit ascopost.com.
