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 here today are two of my colleagues. I will allow each of them to introduce themselves. Dr. Bansal?
Dr. Rani Bansal:
Hi. My name is Dr. Rani Bansal, and I am a breast medical oncologist at the Duke Cancer Institute.
Dr. Carey Anders:
And Dr. Sammons.
Dr. Sarah Sammons:
Hi. My name is Dr. Sarah Sammons. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts.
Dr. Carey Anders:
Great. Wonderful to have you both here today. Today we will be discussing the treatment and management of breast cancer brain metastasis with three patient case studies. Our first installment will focus on a patient with isolated brain relapse. So, case number 1, Ms. HG is a 35-year-old premenopausal female who was diagnosed with a clinical T2, N1, grade 3 triple-positive—ER/PR/HER2-positive—and invasive ductal carcinoma of the breast in June of 2022.
At that time, she did undergo a CT scan and a bone scan for staging, and both were negative for distant metastatic disease. She then proceeded with our standard neoadjuvant chemotherapy regimen of a taxane, carboplatin, trastuzumab-pertuzumab for 6 cycles with an excellent clinical response. Following her neoadjuvant therapy, she underwent a lumpectomy, a sentinel lymph node biopsy, and had a pathologic complete response.
Following surgery, she underwent definitive radiation therapy to the breast and regional lymph nodes and was placed on standard ovarian suppression, aromatase inhibition, trastuzumab, pertuzumab, with the plan to complete 1 year of therapy. One of the first questions is in this case, Dr. Bansal and Dr. Sammons. What do you order, if any, additional scans or blood tests at the completion of standard neoadjuvant/adjuvant, HER2-directed therapy for a high-risk patient? And at this point, would you consider a brain MRI? And maybe even thinking back, would you have considered a brain MRI at the initiation of therapy? Why don't I start with Dr. Sammons to get her take on these questions?
Dr. Sarah Sammons:
Thanks, Dr. Anders. This is a patient who had an early-stage HER2-positive, estrogen-positive breast cancer. She was treated neoadjuvantly and then had a pathologic complete response, completed a year of therapy. This is a patient that we would tell that her prognosis is actually quite good. We would tell her that there is a small risk of metastatic relapse in patients that have a pathologic complete response, but it's probably, certainly less than 10%, maybe in the 5% range.
And right now there's no recommendation to do any further screening as long as she remains asymptomatic. As long as the patient is not having any symptoms at this juncture, I would not recommend doing any routine CT scan, bone scan, brain MRI at this time. And the guidelines would not recommend that either. Certainly she should continue to get her routine breast imaging.
Dr. Carey Anders:
Absolutely. No, that's a really great summary as to where we are with the available data. And I'm curious Dr. Bansal, if you have any additional thoughts or considerations when you see a patient in this setting and follow-up.
Dr. Rani Bansal:
Yes, definitely. I completely agree with Dr. Sammons. She did have lymph node–positive disease at diagnosis and she did have a baseline, a CT chest, abdomen, pelvis, and a bone scan, which were both negative. So, that is reassuring. And I don't feel the need unless she had specific symptoms to repeat imaging at this time, especially as she's completed all her therapy, and it seems like she's otherwise doing well. And so I also don't order any other specific blood tests. Some of my patients will ask me, "What about tumor markers?" There's no data to support doing that, especially in the localized setting. And so I would otherwise feel comfortable monitoring her with her routine surveillance, like Dr. Sammons had mentioned.
Dr. Carey Anders:
Absolutely. And I think this can be sometimes disconcerting to patients. I think we all have these conversations in our clinic and I think the most important thing here is really having our patients understand what warning signals to look for and then really tailoring any future laboratory or imaging test based on the symptoms they may present with. And I think the pathologic complete response tends to be quite reassuring that, as Dr. Sammons did say, we still can see relapses in this patient population.
All right, great discussion. In the final month of the patient's adjuvant ovarian suppression, AI, trastuzumab, pertuzumab, she does develop dizziness and nausea.
She presents to the emergency department after a fall at home and upon triage was recommended for a gadolinium-enhanced brain MRI. And unfortunately this did show a contrast enhancing mass in the left cerebellum with associated edema. You'll see the images here. So this is a patient who is presenting with symptoms into the emergency department. We do have imaging concerning for metastatic disease. And so I wanted just to hear from our experts here about what they might be thinking in terms of consideration for workup and possible treatment of this mass.
As you're in the emergency department with this patient and you're thinking about considerations for treatment of the mass, one of the considerations is neurosurgical consultation. So Dr. Sammons, I'm curious about your thoughts about neurosurgical consultation, biopsy, resection, what you might be thinking about this relatively large lesion in the posterior fossa.
Dr. Sarah Sammons:
Yes, good question. So, there's a single isolated lesion, the patient is symptomatic, it's in the posterior fossa, there's edema there, and it's a rather sizable lesion. I would absolutely consult my neurosurgeon. I would recommend that the emergency department start steroids while we wait for the consultation. We do know that certainly for single, isolated brain metastasis, there is an overall survival benefit actually to doing resection and then following that up by radiation.
And this is a relatively young patient. We know that with optimal systemic therapy, local control, she could still do well for some time. And so I would absolutely be consulting my neurosurgeon with the goal of potential resection. And then in that way you also get a tissue diagnosis. I think we're all very suspicious that this is for HER2-positive breast cancer that has metastasized to the brain, but then we can get receptors again and confirmation by a pathologic diagnosis.
Dr. Carey Anders:
I think those are fantastic points around the management of this case. With tissue, you will not only make the diagnosis, you can repeat the receptors. We certainly know there is discordance in this space typically with gain of HER2. But it would be important to know that we are certainly treating the subtype in the CNS and not just relying on the extracranial disease in a patient who has indication for neurosurgical resection.
Dr. Bansal, this patient does go forward and is found to have HER2-positive breast cancer brain metastasis as a recurrence. And I'm curious as to your thoughts about after resection, the role of radiation therapy, particularly stereotactic radio surgery?
Dr. Rani Bansal:
Yes, I definitely think that, as Dr. Sammons had mentioned, that the patient should go on to receive radiation next. We do have great data that does improve outcomes. Also, another point that Dr. Sammons had mentioned, the importance of also getting pathology confirms receptor status. But I think also in our future as we get more and more targeted therapies, it'll be very important to be able to send mutational testing as well on the pathology. And so I think that will also be useful information to have in terms of getting the surgical pathology back. So, I agree with the plan for resection and then would have the patient also see our radiation oncology team for SRS post-surgery.
Dr. Carey Anders:
Excellent. Completely agree. And I think that will certainly decrease the risk of local recurrence in the resection cavity, which is certainly a concern. And the rates are just unacceptably high when we don't follow with radiosurgery. Consulting our radiation oncology colleagues after resection is certainly advisable. And then you bring up a really good point, having that tissue also really helps guide what we might consider for systemic therapy.
So Dr. Sammons, why don't we turn back over to you about what you might be thinking with regard to systemic therapy in a patient who was on adjuvant trastuzumab/pertuzumab at the time of the isolated intracranial recurrence?
Dr. Sarah Sammons:
Yes. This is probably one, this exact clinical scenario is one of the questions that I always get when I'm traveling around. We are assuming here that we did scans of her whole body, that she has no extracranial disease at all, that this is just a single isolated brain metastasis that has now been resected and we're following up that cavity with radiation. And so, really, she's somewhat no evidence of disease, but we do still worry about that patient and her risk for distant local brain failure, potentially even extracranial disease in the future.
And we do know from meta-analyses and retrospective studies that even in patients with isolated brain relapse, that in the HER2-positive setting, they can have an overall survival benefit to initiating HER2-targeted therapy. So, essentially for this patient with isolated brain relapse, stereotactic resection, who's now no evidence of disease, per ASCO guidelines, I would continue her trastuzumab/pertuzumab and her endocrine therapy at this time.
Dr. Carey Anders:
Excellent. Yes, very good points. And that's exactly where we are in 2025. I think we're all hopeful that we will have strategies in the future that will combine novel therapies, whether or not they are tyrosine kinase inhibitors or antibody-drug conjugates, to delay the time to intracranial progression. Dr. Bansal, I know you're very involved in the tucatinib, in adjuvant space and wondered if you could just comment briefly on the potential to prevent brain metastasis in this space.
I think it is very concerning. This patient had a pathologic complete response. And we do know from data from Dr. Laura Huppert that while the extracranial recurrence is decreased in the setting of pCR, we may not necessarily see an intracranial reduction in site of recurrence. As you said, Dr. Sammons earlier, somewhere in the luckily less than 10%, but we'd love to bring that down to even lower. I just wondered if you could comment Dr. Bansal, on the capacity to integrate in tyrosine kinase inhibitors earlier in a patient who might be at high risk for CNS recurrence.
Dr. Rani Bansal:
Thank you, Dr. Anders. I think that's a great point. I think what Dr. Sammons was also alluding to, we do know from information from the KATHERINE trial for patients that received T-DM1 compared to patients that received trastuzumab, there actually wasn't a difference in regard to recurrence intracranially.
I realize that we need to do a better job in preventing intracranial recurrence and that's where there is the current clinical trial ongoing that's called the CompassHER2 RD trial that is looking at adding a TKI, tucatinib, with T-DMI for patients with residual disease. To my knowledge, I don't know of a trial that's looking for patients with a pathologic complete response and adding other agents. I don't know if you know of one, Dr. Sammons, because I know you do a lot of work in this space as well. But I do think that that'll be a really interesting trial to see if we can change the rates of intracranial recurrence with the addition of a TKI.
Dr. Sarah Sammons:
Yes, there are no trials there for patients with pCR and trying to prevent this situation. It would be a very hard trial to design because the number of patients that you would need to screen in a pCR population to then prevent a CNS recurrence, which is probably only about 2% to 3% of the pCR population, would just be really challenging. But in the future, as we develop these very, very sensitive ctDNA tests and more tools to maybe help identify who may relapse and who may not, I think prevention trials will be more feasible.
Dr. Carey Anders:
I think that is exactly where we hope to be heading. Right? That we're able to identify patients with biomarkers early on in their disease trajectory so we can help prevent brain metastasis. So very well said.
This patient did go forward and proceeded to neurosurgical resection of the intracranial mass in the left cerebellum, posterior fossa. And the pathology did reveal ER-low (now 5%) downregulation of the estrogen receptor, PR-negative, and HER2-positive IHC 3+ adenocarcinoma consistent with breast primary. She did then proceed with postoperative radiosurgery to the resection cavity, as we discussed, to improve local control.
Very frequently we do see that there is no evidence of extracranial disease on staging. And as Dr. Sammons described, the patient did maintain ovarian suppression, aromatase inhibition, trastuzumab-pertuzumab, as per our current ASCO guidelines for HER2-positive breast cancer brain metastasis.
So, moving forward with the key clinical takeaways from our first case. Patients with HER2-positive localized breast cancer are at higher risk, approximately 10% to 12% of intracranial recurrence even in the setting of a pathologic complete response.
This is commonly in the absence of extracranial disease. And we don't currently have guidelines to do screening brain MRIs on the entire patient population, but would indicate low threshold to order a brain MRI if there was any evidence of neurologic concern or symptom. In a patient in this setting, neurosurgical resection when feasible should be considered. There is survival data that is more favorable for resection followed by radiosurgery for patients with a solitary brain recurrence. And in this case, and in many cases, this also has the quickest time to symptom recovery with relief of mass effect and decreased intracranial edema.
It also allows for histologic confirmation of breast recurrence, not another primary brain neoplasm and, as well, biomarker confirmation where we can see down-regulation of the estrogen receptor or gain of HER2 if this patient's primary tumor had been HER2-negative in about 20% of cases. And the current ASCO guidelines do recommend continuation of current HER2-directed therapy following local therapy for an isolated brain recurrence. But there are clinical trials in this space that we hope will show even longer time to distant brain recurrence for clinical care in the future.
This brings us to the end of the case. Please see the other segments for further discussion about the latest research in breast cancer or you can also visit ascopost.com.