Real-World Analysis Sheds Light on Brain Metastases Incidence in HER2+ Breast Cancer


Sarah Sammons, MD, discusses what is known about the incidence of brain metastases in patients with breast cancer.

Sarah Sammons, MD

Sarah Sammons, MD

The incidence of brain metastases in patients with breast cancer was found to increase with each line of therapy received, but it is an early event in patients with hormone receptor (HR)­–negative/HER2-positive disease, according to data from a real-world cohort of patients presented at the 2023 San Antonio Breast Cancer Symposium.

The analysis utilized data from the longitudinal US Flatiron Health deidentified database on patients who had begun frontline treatment for metastatic breast cancer up to March 1, 2021, allowing for 2 or more years of follow-up. Of the 18075 patients, 6.1% brain metastases at the index date.

The cumulative incidence of brain metastases at 60 months was 23% in HR-positive/HER2-positive disease, 34% in HR-negative/HER2-positive disease, 10% in HR-positive/HER2-negative disease, and 22% in triple-negative breast cancer. The study was not without its limitations; investigators noted that brain metastases may be underdiagnosed, which could be attributed to underestimated incidence. Moreover, line of therapy and disease subtype definitions can be challenging in real-word datasets.

“Brain metastases are a very common problem in HER2-positive breast cancer. What we know from many retrospective clinical trials is that approximately 30% of all patients with HER2-positive breast cancer will develop brain metastases at some point in their disease course,” Sarah Sammons, MD, the associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute in Boston, Massachusetts, explained in an interview with OncLive®. “The incidence varies a little based on whether [they] have HR-positive or -negative. Patients who have HR-positive/HER2-positive metastatic breast cancer have approximately a 23% risk of developing brain metastases, although [risk level is] a bit higher for those whose disease is truly only HER2-driven and have HR-negative disease.”

In an interview, Sammons discussed what is known about the incidence of brain metastases in patients with breast cancer and expanded on findings from the real-world analysis dedicated to understanding the prevalence of these metastases as it relates to disease subtype and line of therapy.

OncLive: What were the key findings from the real-world study shared at the 2023 San Antonio Breast Cancer Symposium?

Sammons: In the analysis that we presented at the [meeting,] we looked at over 18,000 patients in the Flatiron database to see how the incidence of HER2-positive brain metastases vary per line of therapy. What we found was that, generally, across all breast cancer brain metastases, the incidence of metastatic disease to the brain increases per line of therapy. Surprisingly, we did find that those patients who have HR-positive/HER2-negative disease tended to develop brain metastases very early on, by the third line of therapy. Those patients, at least in this analysis, were more likely to develop early brain metastases.

What are some of the goals of treatment for patients with stable vs active brain metastases?

When we hear about clinical trials done in patients with brain metastases, often the clinical categories of [these] metastases are broken up into “stable” or “active.” Essentially, stable brain metastases have usually been treated with some sort of local regional therapy, like radiation; if it’s a solitary lesion, they may have undergone resection and then radiation to the treatment bed. Then, they have gone on and their brain metastases on subsequent scans are stable after local treatment. [In comparison,] we think of active brain metastases as those that have not been treated with local therapies or they’ve been treated with a local modality, such as radiation, but they continue to progress.

Our goals for treating all brain metastases are somewhat similar. We, of course, want to palliate or improve any neurologic symptoms that the patient is having; we want to prevent neurologic death; we want to prevent subsequent brain metastases from happening or progression of the current brain metastases; and we want to improve patients’ overall survival and quality of life.

How do you approach treatment for these different subsets?

When we’re thinking about stable brain metastases, local modalities such as radiation are highly effective. The goals for stable brain metastases [treatment] are to prolong the central nervous system [CNS] progression-free survival, which is the amount of time until we see another CNS event. Either we see that brain metastases that were already radiated grow, or more commonly, we see new lesions in the brain. We want to prolong that for as long as possible, mostly via systemic therapies.

For active brain metastases, we’re not treating them for some reason. If a patient maybe has multiple brain lesions, for example, more than 6 or more than 10, and we’re trying to hold off on whole brain radiation therapy by giving a systemic therapy that we know has strong intracranial activity, the main goal there is intracranial control. For that [patient with] active brain metastases, I want to find a systemic therapy that has a very high well-known intracranial response rate to shrink those lesions and control their brain disease rapidly because we’re either holding off on local therapy or they’ve had local therapy and it didn’t work well enough and they’re progressing so we need a quick response in the brain.

How do you determine when it is appropriate to defer local therapy for certain patients with brain metastases?

Deferring local therapy is still [an area that is] evolving, mostly in HER2-positive brain metastases. There are some nice guidelines that ASCO put out in 2022 for HER2-positive brain metastases, on what patients who you might think of deferring local therapy [in]. Notably, this must be a multidisciplinary decision that’s made with a radiation oncologist, potentially a neurosurgeon if they’re involved, and of course, the patient. However, we might think about deferring local therapy if the patient has a very favorable prognosis. We’re only going to consider it if a patient has an asymptomatic brain metastasis that’s on the smaller side and less than at least 2 centimeters, and there’s no symptomatic mass effect. Most importantly, we’re only going to think about delaying local therapy if we have systemic therapy that has a very high intracranial response rate, such as tucatinib [Tukysa], capecitabine [Xeloda], and trastuzumab [Herceptin], or fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd]. [These approaches] are known to have intracranial response rates of around 50%, and we’re going to monitor those patients extremely closely.

It is still evolving on whether or not we can do that. There are certainly some circumstances where we really want to try to delay whole brain radiation or high-volume repeat stereotactic radiation therapy. If we have one of these excellent systemic therapies with intracranial response, this is certainly something that we think about more and more.


Sammon SL, Leone JP, Sanglier T, et al. Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients. Presented at: San Antonio Breast Cancer Conference; December 5-9, 2023; San Antonio, TX. Abstract PS11-01.

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