Radiation and Systemic Therapy for HER2+ Breast Cancer and Brain Metastases

Variables that impact decisions to treat HER2-positive breast cancer and brain metastases with radiation therapy and systemic therapy, and recommendations on using memantine following radiation therapy.

Sara A. Hurvitz, MD: Kamran, can you take us through how you address brain metastases? When is radiosurgery appropriate vs whole-brain radiation therapy? When is systemic therapy appropriate to try to control first? We’ve had some recent approvals in this area for systemic therapy. Typically, we don’t feel that systemic therapy penetrates that blood-brain barrier well enough to get into the brain, but now we have tucatinib available, which is changing our paradigm thinking. Can you take us through how you approach this?

Kamran Ahmed, MD: That’s a good question. There’s been a large amount of improvement in the space of managing HER2 [human epidermal growth factor receptor 2]–positive brain metastases. Local therapies have played the cornerstone in management of brain metastases for a long time. Typically, we like to consider stereotactic radiation treatment or focal radiation therapy when there’s more isolated or limited brain metastases. We have a good prospective data for treating up to 10 brain metastases, and then there’s another ongoing trial looking at patients who have up to 15 brain metastases. For patients who have more brain metastases, that can be detected on MRI. We’re also concerned about microscopic deposits that we’re potentially missing. In those instances, like Erika’s, we recommend whole-brain radiation therapy.

There are different ways of approaching whole-brain radiation therapy as well, to mitigate some of the long-term adverse effects of short-term memory loss, which have been well detailed prospectively. Those techniques include hippocampal sparing and the use of memantine. Another tool in our arsenal is systemic therapy. Particularly for HER2+ brain metastases, we’ve seen very good responses from tucatinib from the HER2CLIMB study, which showed that there was an improvement in CNS [central nervous system] progression-free survival within the treatment arm of tucatinib.

In our practice, we look at No. 1, whether patients are symptomatic at initial presentation. If patients are symptomatic, surgery and radiation therapy should be considered up front. If patients are asymptomatic and haven’t been exposed to systemic therapy, there are tools we can consider, such as tucatinib. I work closely with our medical oncologists and recommend we start systemic therapy first and do a quick interval MRI to see if there’s a response. If we don’t see a response, then we can add quickly to add radiation therapy.

Sara A. Hurvitz, MD: Great point. Tucatinib was definitely practice changing. The HER2CLIMB trial, looking at tucatinib-capecitabine-trastuzumab vs capecitabine-trastuzumab, did demonstrate an improvement in progression-free survival and overall survival in the overall population of patients but also specifically in patients with active, progressing, or previously untreated brain metastases. That study was uniquely designed to allow patients with progressive brain metastases. Owing to its CNS penetration, we did see a remarkable improvement in outcomes for patients with tucatinib added to therapy. That did allow patients who had previously untreated disease. Not large, bulky symptomatic metastases, where an urgent intervention was required, but smaller ones. That’s placed that regimen in the second-line setting for those with brain metastases, according to NCCN [National Comprehensive Cancer Network] Guidelines and the FDA approval if the patient is appropriate. As clinicians, we’ll change systemic therapy—Erika was on HP [trastuzumab, pertuzumab] at the time when her progression occurs—if progression is occurring outside the brain as well as inside. It was appropriate for her to switch therapy.

I want to get back to 1 thing you mentioned about memantine. Kamran, talk about when you’re using it and whether you’re noticing improvements in adverse effects from radiation with this agent.

Kamran Ahmed, MD: Quite frequently, I’ll recommend using memantine in patients who are receiving whole-brain radiation therapy. There’s been a prospective study that’s shown that there can be an improvement in cognitive function in patients who receive memantine during radiation therapy and then continuing that for at least 6 months afterward. I find that it’s well tolerated in patients. We increase the doses over about a month , increasing to about 10 mg twice daily. For both patients I’m recommending whole-brain radiation therapy. I’ll recommend trying memantine.

Transcript edited for clarity.

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