Clinical Challenges of Managing Breast Cancer Brain Metastases

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“Breast cancer brain metastases are a clinical challenge that are only increasing in incidence and are a consequence of advanced breast cancers, largely HER2-positive and triple-negative,” according to Carey K. Anders, MD, Professor of Medicine and Medical Director of the Duke Brain and Spine Metastases Program at Duke Cancer Institute, Durham, North Carolina. Meeting the challenge has been hampered in the past by the lack of clinical trials including patients with brain metastases, but recent initiatives by ASCO and the National Cancer Institute have led to “an increase in the number of clinical trials that allow patients with brain metastases,” she noted. Dr. Anders presented the results of some recent trials at the 2020 Lynn Sage Breast Cancer Symposium,1 hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

Carey K. Anders, MD

Carey K. Anders, MD

Options for systemic therapy for patients who have breast cancer with brain metastases are grouped in the National Comprehensive Cancer Center Clinical Practice Guidelines in Oncology (NCCN Guidelines®) into two categories depending on HER2 status. Commercially available options for patients with HER2-positive breast cancer and brain metastases include HER2-directed tyrosine kinase inhibitors, in combination with capecitabine, as well as antibody-drug conjugates, including ado-trastuzumab emtansine (T-DM1) and more recently fam-trastuzumab deruxtecan-nxki (T-DXd), said Dr. Anders. Treatments for patients with HER2-nonspecific or HER2-negative breast cancer include cytotoxics, mostly platinum agents.

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors used to treat patients with HER2-positive breast cancer and brain metastases include lapatinib, neratinib, and more recently tucatinib, “which was added to this list in the spring of 2020,” Dr. Anders said. The NALA study randomly assigned 621 patients with HER2-positive metastatic breast cancer, including those with asymptomatic and stable brain metastases, to neratinib/capecitabine vs lapatinib/capecitabine. “Neratinib and capecitabine improved progression-free survival at 8.8 months vs 6.6 months for the lapatinib and capecitabine treatment arm,” Dr. Anders reported.

Tucatinib, a brain-permeable tyrosine kinase inhibitor targeting HER2 selectively, “has been shown in preclinical models of HER2-positive brain metastases to improve survival,” she added. “In the phase I experience of tucatinib in combination with capecitabine and trastuzumab, the extracranial response rate was around 60%, and interestingly, the central nervous system (CNS) overall response rate was more than 40%, illustrating the activity of this compound in brain metastases.”

“The newer-generation antibody-drug conjugate T-DXd,” Dr. Anders continued, was “evaluated among patients who had previously received T-DM1 for advanced HER2-positive breast cancer, and patients with stable treated brain metastases were allowed in this study.” Among the 68 patients in this phase II study, the confirmed overall response rate was 60.9%. “This corresponded with an unprecedented progression-free survival at 16 months and an overall survival that was not yet reached at the time of reporting,” Dr. Anders said. Median progression-free survival among 24 patients with treated asymptomatic brain metastases was 18 months.


HER2CLIMB is a phase III double-blind study with 612 patients randomly assigned in a 2:1 fashion to receive tucatinib/trastuzumab/capecitabine vs placebo/trastuzumab/capecitabine. All patients in this study had previously been treated with trastuzumab, pertuzumab, and T-DM1. The primary analysis showed the study “met all of its prespecified primary endpoints, including progression-free survival, with the risk of disease progression or death reduced by 46% with the addition of tucatinib, and overall survival, with the risk of death reduced by 34%,” Dr. Anders said. “Of note, the secondary endpoint of progression-free survival in patients with brain metastases was met,” with the risk of death or disease progression reduced by 52%.

This led to an additional analysis of the HER2CLIMB study for the 291 patients with brain metastases at enrollment: 174 with active brain metastases and 117 with treated and stable brain metastases. The median CNS progression-free survival was 9.9 months among patients in the tucatinib arm vs 4.2 months in the placebo arm. Among those with stable brain metastases at enrollment, the CNS progression-free survival was 13.9 months with tucatinib vs 5.6 months with placebo. For those with active brain metastasis, the corresponding median survival time was 9.5 months vs 4.1 months, showing “significant improvement for the addition of tucatinib to capecitabine and trastuzumab,” Dr. Anders said.

“Similarly, there was an overall survival benefit,” she added. Overall median survival was 18 months for those in the tucatinib arm vs 12 months in the placebo arm. “For those with stable brain metastases, this corresponded to survival of 15.7 months with tucatinib vs 13.6 months with placebo. For those with active brain metastases, the overall survival was 20.7 months vs 11.6 months favoring the tucatinib arm. In addition, the intracranial response rate for patients with active brain metastases and measurable intracranial lesions at baseline favored tucatinib at 47% vs 20% for those who received placebo,” Dr. Anders reported.

“An interesting analysis embedded in this study was the benefit of continuing tucatinib beyond first CNS progression,” Dr. Anders commented. Among patients who maintained tucatinib after first CNS progression, the time to next CNS progression was 7.6 months vs 3.1 months for patients who continued with trastuzumab/capecitabine/placebo.

The studies reviewed showed the multiple options for patients with stage IV HER2-positive metastatic breast cancer. For patients with stable brain metastases, following pertuzumab and T-DM1, “both trastuzumab/T-DXd or tucatinib/capecitabine/trastuzumab
are reasonable options, and this may be based on the patient’s preference of oral vs intravenous therapy at that point and their disease journey,” Dr. Anders said.

“For patients who have progressive or untreated metastases, the HER2CLIMB data clearly illustrate the benefit of tucatinib, capecitabine, and trastuzumab in this setting.”

Options for HER2-Negative Cancer

“Systemic therapy options for patients who have HER2-negative breast cancer and brain metastases are driven by subtype,” Dr. Anders noted. “Specifically, for hormone receptor–positive/HER2-negative breast cancer brain metastases, endocrine therapy as well as brain-permeable chemotherapy, largely capecitabine and platinums, are options. In addition, we do rely on CDK4/6 inhibitors, with abemaciclib having the greatest degree of blood/brain barrier permeability.”

In a phase II study, women who have HER2-negative disease and estrogen receptor–positive breast cancer and brain metastases, the CNS response rate with abemaciclib “was only 6%, but this was comparable to the single-agent efficacy of lapatinib in historical studies,” Dr. Anders reported. “The intracranial clinical benefit was 25%, with an intracranial progression-free survival of 4.9 months, extracranial progression-free survival of 6.6 months, and median overall survival of 12.5 months.”

A small study evaluating abemaciclib in seven patients with estrogen receptor–positive leptomeningeal breast cancer, overall survival “was improved compared to historical controls at 8.4 months,” according to Dr. Anders. “This is an attractive option for patients who want to avoid intravenous therapy for leptomeningeal disease.”

Treatments of Triple-Negative Breast Cancer

“Women with triple-negative breast cancer are treated with chemotherapy and topoisomerase inhibitors,” Dr. Anders said. PARP inhibitors and immunotherapy are emerging as potential therapies for breast cancer brain metastases, she noted.

“The SWOG 1416 study evaluated the combination of cisplatin chemotherapy with the brain-permeable PARP inhibitor veliparib (ABT-888) vs cisplatin with placebo for patients with metastatic triple-negative breast cancer or for those who harbored a germline BRCA mutation,” Dr. Anders explained. “For patients with germline BRCA mutations, progression-free survival and overall survival were not significantly improved with the addition of veliparib to cisplatin. However, among patients whose tumors were categorized as BRCA-like by biomarker analysis, progression-free survival improved from 4.2 months to 5.9 months with the addition of veliparib, and overall survival improved from 12 to 14 months.

“The specifics of patients with brain metastases from this study have yet to be reported,” noted Dr. Anders. However, “in addition to the biomarker-driven analysis that was part of the 1416 study, I think these specifics will shed light on when we may be able to add a PARP inhibitor to standard chemotherapy for patients with brain metastases.”

Niraparib has shown efficacy in BRCA-mutant, triple-negative breast cancer intracranial models in vivo, stated Dr. Anders. “Data illustrate that niraparib not only crosses the blood/brain barrier in these intracranial models, but also inhibits the PARP target, which correlates to improvement in survival for animal models of triple-negative brain metastases that harbor a mutation,” she continued.

“The combination of niraparib with checkpoint inhibition has shown durable responses in metastatic triple-negative breast cancer among patients who had either BRCA-mutant or BRCA wild-type breast cancer,” Dr. Anders said. “This combination of niraparib with checkpoint inhibition is an attractive combination therapy for patients with triple-negative breast cancer and brain metastases, with study plans ongoing.”

Other Treatment Opportunities

Other opportunities to target brain metastases involve “learning about the biology of brain metastases from the metastatic tissue itself, which about 50% of the time will illustrate a targetable alteration that is not seen in the extracranial site,” Dr. Anders said. This has led to the design of the Alliance A071701 clinical trial, which is currently enrolling patients with brain metastases across multiple solid tumor primaries, largely lung and breast cancers.

“[In Alliance A071701,] based on alterations inherent to the brain metastases themselves, patients would receive either abemaciclib, a brain-permeable kinase inhibitor called GDC 0084, or entrectinib. The results of these trials are eagerly awaited,” Dr. Anders remarked.

Among immunotherapy strategies being evaluated is the use of the PD-1 antibody pembrolizumab for patients with progressive solid tumor brain metastases and those diagnosed with leptomeningeal disease. Early efficacy with this agent has been shown in the leptomeningeal cohort, with a median overall survival of 3.6 months. “This study did achieve its primary endpoint in that 12 patients were alive at 3 months, correlating to an overall survival at 3 months of more than 40%,” she shared. The best response in this 18-patient cohort was stable disease in 10 patients. 

DISCLOSURE: Dr. Anders has received research funding from Puma, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1 Therapeutics, Novartis, Zion, and Pfizer; has served as a compensated consultant to Genentech, Eisai, Ipsen, Seattle Genetics, Novartis, AstraZeneca, Elucida Oncology, and Immunomedics; and has received royalties from UpToDate and Jones & Bartlett.


1. Anders C: Update on brain metastases. 2020 Lynn Sage Breast Cancer Symposium. Presented September 12, 2020.