Dr. Carey Anders:
Welcome to the ASCO Post Roundtable Series on Novel Therapies for HER2-Positive Breast Cancer Brain Metastasis. I'm Dr. Carey Anders, Professor of Medicine and the Director of the Duke Center for Brain and Spine Metastasis at the Duke Cancer Institute. Joining me today are two of my colleagues who I will ask to introduce themselves. Dr. Bansal.
Dr. Rani Bansal:
Hi, my name is Dr. Rani Bansal. I am a breast medical oncologist here at the Duke Cancer Institute in North Carolina.
Dr. Carey Anders:
And Dr. Sammons.
Dr. Sarah Sammons:
Hello, my name is Dr. Sarah Sammons. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston.
Dr. Carey Anders:
Thanks to you both for joining me here today. Moving into our third and final case, Mrs. RG is a 39-year-old female who was initially diagnosed with ER/PR-negative, HER2-positive de novo metastatic breast cancer to the liver and brain in January of 2023. She underwent neurosurgical resection of a dominant right cerebellar lesion at diagnosis, which was followed by standard-of-care post-operative stereotactic radiosurgery to the resection cavity. She was then placed on taxane, trastuzumab, and pertuzumab as per the CLEOPATRA study for 6 cycles with excellent response. On restaging approximately 9 months later, she had multiple intracranial lesions that were amenable to radiosurgery, and each of these lesions were treated. Based on the ASCO guidelines as her liver metastasis were well controlled, she maintained her backbone antibody therapy with trastuzumab and pertuzumab.
Approximately 4 months later, she presented to clinic with headache, photophobia, nausea, and vomiting over the course of the past several days, and she was admitted to the inpatient unit, at which time a brain MRI revealed leptomeningeal disease throughout the cerebellar folia. She also had a lumbar puncture confirming positive cytology consistent with the diagnosis of leptomeningeal carcinomatosis. A spine MRI was also performed showing several areas of leptomeningeal disease largely in her cauda equina that were largely asymptomatic. This is a really unfortunate consequence of HER2-positive breast cancer brain metastasis. And I'm curious as to my colleagues what treatment considerations they would be considering in the setting of symptomatic HER2-positive leptomeningeal disease in 2025.
Dr. Bansal, why don't we have you start with your thoughts on radiation options for this patient?
Dr. Rani Bansal:
Thanks. Yes, I think when we think about radiation, we can think about whole-brain radiation or craniospinal radiation. There is, I know, our radiation colleagues know more data looking at photon-based vs proton-based radiation therapies. And there is some data that proton-based CSI may be more beneficial than photon-based. So, that is a discussion I definitely have with my radiation colleagues in terms of what they recommend and think about for radiation options for our patients.
Of course, when we think about whole-brain radiation, there are side effects that patients can experience. Significantly, or one significant side effect is potentially cognitive decline. So, that is something we have to think about and discuss with our patients. Many times if patients are very symptomatic, I do consider moving forward with radiation first, and then I will consider what systemic therapy options we have. I'm very hopeful that we will continue to have novel agents that have better and better penetration in the CNS that maybe we could at some point forgo whole-brain radiation or other localized therapy options, but at this point, if I have a patient that's very symptomatic that I'm concerned about, I do have them evaluated by my radiation colleagues.
Dr. Carey Anders:
Absolutely. I think in my experience as well, radiation therapy along with upfront steroid therapy has been one of the quickest ways to help patients with relief of symptoms. I'm also hopeful that in the future we may have systemic therapies that will forgo the need for radiation, but it is certainly a very powerful tool in this setting. One of the conversations we have on our tumor boards here, Dr. Sammons, is the consideration of hippocampal avoidance. We have typically not seen our radiation oncologists recommend hippocampal avoidance in the setting of LMD given that it's such a diffuse process. Wondered if you could comment on hippocampal avoidance, as well as use of memantine in this setting.
Dr. Sarah Sammons:
Sure. Studies have shown that both hippocampal avoidance and memantine can be strategies to try to preserve cognition, which can certainly be a problem when patients are undergoing whole-brain radiation. Assuming that this patient is highly symptomatic, she's likely to be started on steroids, get a rather urgent radiation oncology consult, and be considered for whole-brain radiation, depends on the center. If they have a proton center, maybe some people would consider proton CSI, but proton CSI is usually for more minimally symptomatic patients, I would say. I agree, I have not seen hippocampal sparing recommended in the setting of leptomeningeal disease. I do still think it's reasonable to consider memantine during the whole-brain radiation therapy and then in the 6-month period after to try to preserve cognition.
Dr. Carey Anders:
At the time of her leptomeningeal disease recurrence, she was really maintained on backbone trastuzumab, pertuzumab. And I'm curious what you might be thinking about from a systemic therapy option in the HER2-directed space in 2025.
Dr. Sarah Sammons:
Yes. After her radiation, I would absolutely start this patient on a systemic therapy that has strong evidence for intracranial efficacy. I think that T-DXd or trastuzumab deruxtecan actually has fairly good data in leptomeningeal disease. We did a series at Duke, which showed it was short-term follow-up, but it showed almost a 50% intracranial response rate in our leptomeningeal disease patients and an overall survival nearing a year. There was a Japanese retrospective study that looked at 17 patients with active HER2-positive leptomeningeal disease treated with T-DXd with a 70% response rate and an overall survival beyond a year. And then there's a small DEBBRAH perspective clinical trial that also showed with T-DXd and HER2-positive LMD overall survival beyond a year. I do like T-DXd for this patient after her radiation. The HER2CLIMB regimen is also an option. Is it TBCRC049 that was the leptomeningeal disease study, I think it is. And that study showed a median overall survival of 10 months with HER2CLIMB. But I would probably favor T-DXd first.
Dr. Carey Anders:
Dr. Bansal, curious to hear your thoughts and what you might be considering for systemic therapy in this patient post whole-brain radiation therapy.
Dr. Rani Bansal:
I completely agree with Dr. Sammons, especially how we have all of that data. It’s in HER2-positive leptomeningeal disease that T-DXd does have a great intracranial response, so I'd feel very comfortable moving forward with that. I think we talk or a lot of times consider for patients T-DXd vs the HER2CLIMB regimen. What pros and cons? And I think I would probably favor using T-DXd in this case just given all the data that Dr. Sammons has cited already. But I do think there are some patients that prefer the HER2CLIMB Regimen. It does give an option for oral therapy. It does continue the infusion with trastuzumab. So, I do think there is the option for either one.
Dr. Carey Anders:
Absolutely, I agree. And I think the beauty here is we have both options. I think we're still grappling with what the resistance mechanisms are to both of those regimens, but we do at least with real-world experience, not necessarily in the leptomeningeal population, but in the general HER2-positive metastatic breast cancer population, have certainly seen continued efficacy when we sequence these regimens. I think some of the really positive things I'm hearing is that we do have options and historically our patients with leptomeningeal disease have lived on the order of weeks before we have these more advanced radiation techniques as well as systemic therapies. And here we're talking about survival times beyond a year, albeit knowing that we would always want to do better.
One of the questions that I get very frequently is whether or not I would consider intrathecal therapy. I'm curious, Dr. Sammons, how this is handled at the Dana-Farber Cancer Institute and then would love to get Dr. Bansal's thoughts as well.
Dr. Sarah Sammons:
Yes, there are some small perspective trials that looked at intrathecal trastuzumab, particularly in patients with HER2-positive leptomeningeal disease showing fairly respectable overall survival rates. I would say that I'm not generally going to that strategy unless the patient has already had exposure to maybe a T-DXd and tucatinib. If they have had exposure to T-DXd and tucatinib before but are still fit enough to pursue treatment, then I might consider something like an intrathecal trastuzumab, depending on, you always have to worry about their systemic therapy as well. If they have systemic therapy, maybe it would give some sort of chemotherapy with an intrathecal trastuzumab. But we have largely strayed away in general from intrathecal therapies, particularly for HER2-negative patients. They really just have not been shown to have overall survival benefits in large meta-analyses or studies or perspective studies. And getting them on my own reservoir is quite invasive.
Dr. Carey Anders:
Thank you for that perspective. Curious to your thoughts, Dr. Bansal.
Dr. Rani Bansal:
I agree with what Dr. Sammons had said as well. I think the Ommaya device can be very difficult for some patients, especially during administration of the drug. Intrathecally it can cause a lot of nausea and vomiting and headaches and other side effects. From that perspective, it is something I will consider for my patients who have progressed on an ADC, a TKI, and they are otherwise healthy and fit. But it's not the first thing that I would reach for.
Dr. Carey Anders:
I completely agree with both of those strategies.
Unfortunately, we know in 2025 that leptomeningeal disease is typically not curative. I'm curious to hear your approaches about how you discuss prognosis with the patient and her family, and when you might integrate in palliative care. Typically, our patients with leptomeningeal disease do have a high symptom burden. Curious, Dr. Bansal, what you've seen at the Duke Cancer Institute with regard to partnership with palliative care as an important component of this patient's journey.
Dr. Rani Bansal:
Yes, I definitely think really for patients, all patients with metastatic disease, we should be considering having our palliative care team involved as well. But especially for patients with intracranial disease and leptomeningeal disease, as you mentioned, Dr. Anders, they can have many symptoms and palliative care can be very helpful in managing that. I think this is very tough prognosis. Like we mentioned, for most patients this is measured in months. There are patients, especially in the HER2-positive space, that do have a prolonged response. But I do worry about that and that is a discussion once we diagnose leptomeningeal disease that I have with my patients.
Dr. Carey Anders:
Thanks, Dr. Bansal. Dr. Sammons, curious about your approaches at the Dana-Farber Cancer Institute and some of the conversations that you may have with your patients and their families as they're facing a diagnosis of leptomeningeal disease.
Dr. Sarah Sammons:
I think it's very important to address the significance and the severity of a leptomeningeal disease diagnosis, and that the prognosis can be pretty life-limiting because people need to know that so that they can make choices based on that. And I also think it's really important to talk to people about their goals and understand what their wishes are when they're facing a very life-limiting diagnosis. And I think that that should be brought up in every patient that has metastatic breast cancer really at some point. And certainly early on for any patient that has leptomeningeal disease. I think it would be reasonable to have every patient that has leptomeningeal disease have a palliative care physician as a partner to talk about their pain, their nausea, their goals, advanced directives, all of those things that we try to do as oncologists, but in the short periods of time that we are able to spend with them not always able to address. I think that that partnership in this population is really important.
Dr. Carey Anders:
Could not agree more. Beautifully said.
In this patient's case, she did proceed with photon-based craniospinal spinal irradiation, given the cauda equina involvement and concern for loss of lower extremity function, bowel, and bladder, which of course are very critical for maintaining quality of life. Following radiotherapy, she did transition to trastuzumab deruxtecan and did engage with our palliative care team to help with physical and emotional symptom guidance for her and her family. And luckily, with all of this palliative care, including the radiation, the systemic therapy, and the emotional and spiritual support, her symptoms were in much better control.
Key clinical takeaways from our third case include leptomeningeal disease is one of the most challenging consequences of advanced cancer, inclusive of breast cancer, but also other solid tumor types. Our treatment options are evolving. The proton-based craniospinal irradiation is now an option in select cases and does show a decrease in side effects from therapy, particularly as it pertains to cytopenia, functional status, so that patients can maintain their systemic therapy following craniospinal irradiation.
Systemic therapies in this space are evolving, and intrathecal therapy is less commonly used in this era of newer treatments. They do include our ADCs, such as trastuzumab deruxtecan, as well as the HER2CLIMB regimen in HER2-positive breast cancer, of tucatinib, capecitabine, and trastuzumab based on our available data. And as this illness can lead to a high symptom burden and limited life expectancy, encouraging palliative care consultation early is recommended to help support our patients in the best way that we can.
This brings us to the end of case 3. Please see the other segments for further discussion about the latest research in breast cancer or visit ascopost.com.
