Breast Cancer Brain Metastases: New Initial Therapy Options

Kate M. O'Rourke

Disclosures

September 17, 2019

Patients with advanced breast cancer are living longer, and with the availability of better diagnostic imaging, the incidence of brain metastases in these patients has increased in recent years.[1,2] The landscape for treating breast cancer brain metastases (BCBM) has also changed to include less whole-brain radiation therapy (WBRT) and the use of emerging systemic therapies. Here's an overview of the latest initial treatment options for BCBM.

"The biggest change in the treatment of brain metastases in the last 10 years is that we really try to avoid whole-brain radiation as much as we can, and the reason for this is patients with metastatic breast cancer [MBC] are living longer now," said Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh School of Medicine. "Now, patients are living so long [with] their systemic disease that they end up getting complications from whole-brain radiation [when that is the treatment used]."

Treatment Options: The Current Standard

Brain metastases occur in 20%-30% of patients with MBC and are associated with a poor prognosis.[1,2] The median overall survival for patients with BCBM ranges from approximately 2 to 25months; only 20% of patients are alive 1 year after a brain metastases diagnosis.[1,2] Brain metastases lead to significant morbidity, neurocognitive decline, and interruptions in the management of systemic disease.[2]

Treatment options for BCBM are limited and depend on the number of central nervous system (CNS) lesions, lesion locations, and primary tumor type, as well as patient performance status.[3] Surgery, WBRT, and stereotactic radiosurgery (SRS) have been the traditional treatment options for brain metastases, but clinicians minimize the use of WBRT when they can these days.[2,4] WBRT leads to significant neurocognitive decline compared with SRS, and clinical trials comparing surgery with WBRT have shown survival benefits and better neurologic functions with surgery compared with WBRT alone.[2] Hippocampal-sparing radiation therapy has been associated with less cognitive decline.[5,6,7]

"There has been a strong shift away from WBRT among patients with a limited number of brain metastases based upon randomized data showing equivalent overall survival and better neurocognitive outcomes with SRS versus WBRT," said Nancy Lin, MD, director of the Metastatic Breast Cancer Program at the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston. "New data from a randomized trial of WBRT with or without hippocampal avoidance (HA-WBRT) showing benefits [from] a strategy of HA-WBRT with concurrent and maintenance [for 6 months] memantine therapy are compelling for patients in whom WBRT is indicated."[8]

Brufsky explained that for initial treatment of BCBM, clinicians generally use surgery or radiation therapy and that focused-dose radiation therapy is increasingly used. "The big question is whether the patient has one or two metastases or multiple metastases. If it's multiple, is it less than 8-10?" said Brufsky. "If a patient has one or two that are relatively close together but in an area of the brain [where] the surgeon feels it won't cause too much damage to remove [them], they will remove [them]. If the metastases are in an area of the brain where the surgeon feels it would cause too much damage to remove them, they will give SRS with CyberKnife, which is single focused-dose radiation."

According to Brufsky, many clinicians use CyberKnife in a series, two or three times for up to 10 metastases, depending on their location in the brain. Studies have shown that SRS alone is a cost-effective strategy for patients with up to 10 metastases.[9] "When there are a lot of brain metastases, [which is] more than 10-15 in multiple areas of the brain, then we have to give whole-brain radiation," adds Brufsky.

Systemic Therapies in Development

When asked about the best options for initial treatment of BCBM, Lin said it's not a one-size-fits-all situation. "Options include surgery, SRS, WBRT, or systemic therapy," continued Lin. "Very much depends on the [patient's] performance status; number, size and location of lesions; symptoms; extracranial disease status; and prior lines of systemic therapy."

Brufsky said one clinical controversy in the initial treatment of BCBM is whether a clinician should change the systemic treatment for a person who develops brain metastases but has no other disease progression below the neck. According to current standards, clinicians should not switch systemic therapy for patients with MBC whose systemic disease is not progressive at the time of the brain metastases diagnosis.[4,10]

The development of drugs to treat BCBM has been hampered by the fact that most clinical trials of drugs for solid tumors exclude patients with brain metastases.[2] However, several small trials have recently shown targeted agents and immunotherapy may be useful for this population of patients.[2,4] "Most of the systemic chemotherapies for breast cancer don't cross the blood-brain barrier, but some of us believe that immunotherapy may be an option going forward, and there are clinical trials testing that hypothesis," said Brufsky.

Brufsky explained that for brain metastases that are estrogen receptor–positive, clinicians often provide hormonal therapy, such as aromatase inhibitors or fulvestrant with a CDK4/6 inhibitor, particularly abemaciclib because it is nimble at crossing the blood-brain barrier. In a phase 2 trial of patients with brain metastases secondary to hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative MBC, the intracranial clinical benefit rate with abemaciclib was 25%, and the median progression-free survival was 4.4 months.[11]

Lin said the most established systemic therapies for BCBM are in HER2-positive disease. For patients whose systemic HER2-positive disease is progressive at the time of brain metastases diagnosis, clinicians should offer HER2-targeted therapy according to the algorithms for treatment of HER2-positive MBC.[2] "Lapatinib-capecitabine has been shown to produce CNS objective responses in both the upfront [ie, radiation-naive, used in place of radiation] setting and in patients whose CNS disease has progressed after prior local therapy," noted Lin. "T-DM1 has been shown in several case series to produce CNS objective responses as well."

In the Translational Breast Cancer Research Consortium (TBCRC) 022 clinical trial presented at the 2019 annual meeting of the American Society of Clinical Oncology, the irreversible HER2-targeted neratinib given with capecitabine was superior to lapatinib and capecitabine in patients with BCBM, delivering a CNS overall response rate of nearly 50%.[12] "Based on results of this study, the regimen has an National Comprehensive Cancer Network compendium listing[13] for the treatment of patients with HER2-positive breast cancer brain metastases," said Lin. "The TBCRC 022 study is now enrolling a cohort of patients [with brain metastases] who will be treated with T-DM1 plus neratinib."[14]

One downside to using neratinib are the side effects.[15] "The problem with neratinib is that it causes diarrhea," said Brufsky.

For patients with de novo triple-negative MBC with brain metastases, Brufsky said that providing atezolizumab and nab-paclitaxel together is a good option because the combination is approved for systemic therapy of triple-negative breast cancer.[16]

According to Lin, a number of chemotherapy drugs, including capecitabine, anthracyclines, and platinum agents have been shown to lead to regression of brain metastases and could be considered for systemic therapy of BCBM. "Although there are ongoing trials of immunotherapy for BCBM, there are not sufficient efficacy or safety data yet to recommend their routine use for the specific treatment of active brain metastases outside of a clinical trial," said Lin.

Emerging systemic therapies for BCBM provide new options and new challenges. "A general question in the field is when and how to prioritize trying systemic therapy ahead of initial radiation," said Lin. "For the moment, radiation therapy is considered the standard of care for most patients as initial therapy."

Dr Brufsky disclosed relevant relationships with Puma Biotechnology, Roche, and Pfizer. Dr Lin disclosed relevant relationships with Daiichi-Sankyo, Genentech, Pfizer, Puma Biotechnology, and Seattle Genetics.

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