Treatment Strategies in Patients with HER2+ BC and Active vs Progressive Brain Metastases


Rita Nanda, MD, reflects on the use of systemic treatment with tucatinib in patients with visceral and CNS disease, and Ryan Jones, MD, discusses the evolving role of concurrent systemic therapy with radiosurgery.

Erika Hamilton, MD: Rita, what patients are you thinking about for tucatinib? What patients are most suitable? Is there anybody you’re not thinking about giving tucatinib to?

Rita Nanda, MD: No. I think my biases, unlike Ryan’s, are to try to avoid radiation or delay it for as long as possible, because that radionecrosis issue I spoke about before is real. I’ve seen it in [many] patients. If we can use a systemic therapy that’s going to treat the visceral disease [and] the CNS [central nervous system] disease, I certainly would want to take advantage of that, especially in individuals who have very small CNS disease. If it’s larger and symptomatic, we’re talking about a different story. Tucatinib is a great option for individuals with brain metastasis. Although, as we’ve already spoken about, there are other agents that have CNS activity in addition to radiation, so it’s great to have all these options for our patients.

Erika Hamilton, MD: I completely agree with you. I think before, even 5 years ago, I would’ve been thinking about this case very differently, but as the drugs change and our profile changes, it enables us to change a little along with it. [Some] of the other things I think may have changed a little over the years are the drugs that we feel comfortable keeping somebody on while we’re radiating vs those we don’t. Anything to speak to?

Ryan Jones, MD: There’s a limited list that gives me some pause of running concurrently [with radiation]. Primarily, they’re not drugs we use in breast cancer—EGFR, [tyrosine kinase inhibitors, or] BRAF inhibitors in melanoma. I feel like a new drug comes out every 3 to 6 months for [you all], though.

Erika Hamilton, MD: We’re trying.

Ryan Jones, MD: Data on these drugs with concurrent radiosurgery [are] still pending, and there are some unknowns on the response you see on imaging later. You take it to surgery and it’s radionecrosis. We’ll probably see something similar [with] those other drugs I mentioned…. For example, if they’re getting chemotherapy, I’ll fit it between cycles for radiosurgery, just trying to minimize toxicity. We have good meta-analyses [suggesting] we can give concurrent chemotherapy. These HER2 agents in general seem fine, although we’re still waiting for data on the newer ones I mentioned. There’s some pause over whole-brain [radiation] with concurrent chemotherapy. Some suggest it may just add toxicity [and] not do much for you lesion control–wise, but we’re still trying to avoid whole-brain [radiation] if possible, of course. I want to echo that [this] was a well-selected patient [with] multisite progression outside the brain with just a few limited lesions. When I see that pattern outside the brain, I’m thinking [about] what else is going on there in the background in the brain. If I just go for these 3, what else are we going to see in a few months? That’s great for her.

Erika Hamilton, MD: Rita, how do you differentiate? We talk a lot about patients [who] do or don’t have brain metastases, but what about differentiation between active progressing brain metastases or stable brain metastases?

Rita Nanda, MD: Fortunately, we’re able to control a lot of the brain disease in patients with HER2-positive breast cancer these days, with combinations of radiation or systemic therapy. When brain metastases are stable, then I feel like I don’t necessarily have to pick a drug or combination that has CNS activity, per se, or consider a referral for radiation therapy. We’re fortunate that many of our most effective strategies have CNS activity, but I do differentiate in that I wouldn’t necessarily refer someone for radiation if their brain disease is stable. I feel [that] if patients are asymptomatic and we’re not seeing any growth on brain MRIs [magnetic resonance imaging scans], then we’re OK.

Erika Hamilton, MD: Absolutely. What about continuing systemic therapy vs switching for brain metastases? [Where] do you fall there?

Rita Nanda, MD: That’s a good question. If we have stable visceral disease and it’s only the brain progressing, that’s a very reasonable time to consider radiation therapy, particularly if it’s just 1 or 2 small lesions and we can do SRS [stereotactic radiosurgery]. If it’s much more extensive—I know you radiate 20 [to] 30 lesions—those are the situations where I might consider switching systemic therapy and not doing SRS to so many different lesions, in hopes we might get a little more regression there. I feel like it is a bit of whack-a-mole. Once we radiate this and then there’s a little more on the next MRI, can we do something that’s more holistic and treat it all—what we can see and what we can’t?

Ryan Jones, MD: In that number, 20 to 30, it speaks to what’s truly going on in the bloodstream outside the brain. Is it really as stable as what you’re seeing on imaging? If they’re showing up with that many new lesions, I’m a believer in that concept of the intratumor and intertumor genetic variability. We don’t have some clones persist after a regimen, and as much as we can help, it’s been a tough year for oligoprogression and oligometastatic disease trials for breast cancer. That’s a tangent, but we had the CURB trial [NCT03808662] from [Memorial] Sloan Kettering [Cancer Center on] oligoprogression, where the breast cancer subset didn’t seem to benefit. At [the 2022 American Society of Clinical Oncology Annual Meeting] this week, we got the NRG-BR002 [trial] [NCT02364557] for oligometastatic disease. [For the] primary end point of median progression-free survival, it didn’t seem to benefit to do [stereotactic body radiation therapy] to the oligometastatic breast cancer. We’re waiting and we’re helping to carefully select these patients for radiosurgery. That’s how I’m looking at it, as well. Could this be limited intracranial progression of clones that were resistant to the drug? Might we help you keep on that regimen for as long as possible?

Erika Hamilton, MD: Good point. Tiffany, for your patient, we hope this doesn’t happen for a really long time, but if she were to progress on tucatinib and she has brain metastases, [which is] the new kid on the block, what are you doing after tucatinib?

Tiffany Traina, MD: In her case, we have trastuzumab deruxtecan, so it’s nice to know I have that in my back pocket. We’ve seen data, as Rita mentioned, from a small subset from DESTINY-Breast01 [NCT03248492]. We have some data from TUXEDO-1 [NCT04752059] of [approximately] 15 patients. We also have some data from DESTINY-Breast03 [NCT03529110], where there was a small number of patients with brain metastases on that trial [who] also enjoyed a progression-free survival. I think my next choice for her would be trastuzumab deruxtecan. Hopefully those CNS lesions will stay quiet and stable so she’s a candidate for multiple next-line trials, too.

Transcript has been edited for clarity.

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