Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease. But with a growing array of MBC treatments that cross the blood-brain barrier and target a range of tumor characteristics, outcomes for these patients should continue to improve.

Medscape spoke to Kevin M. Kalinsky, MD, acting associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.

Medscape: Before we dig into strategies to manage MBC brain metastasis, let's talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?

Dr Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.

At what point is it recommended to screen patients with MBC for brain metastasis?

Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.

That's where the guidelines are now. But as our systemic agents improve, there's always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.

How do you assess which patients with MBC should receive local therapy?

Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.

Giving a patient directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.

What about systemic therapies that cross the blood-brain barrier? What's available now and how do you choose among the options?

The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinibneratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.

Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs the primary breast tumor?

When a patient's disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it's good to check the tumor's estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.

But when a patient has multiple lesions, we don't go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.

We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.

This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.

HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?

This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.

Where are some of the main gaps in our understanding of brain metastases in patients with MBC?

One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.

For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.

The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.

Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.

Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.