Emerging Systemic Therapies for Breast Cancer Brain Metastases

Kate M. O'Rourke


October 23, 2019

Systemic therapies for breast cancer have made leaps and bounds forward over the past 20 years, but this has left oncologists with an insidious and particularly difficult problem.

"In a lot of these diseases now, particularly HER2-positive, what typically kills the women are the brain metastases," said Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh School of Medicine. One of the biggest questions in breast cancer at the moment is finding agents that cross the blood-brain barrier. "We are really trying to find therapies that can cross the blood-brain barrier and can palliate or eliminate disease in the brain," said Brufsky.

Surgery and radiation have been the backbone of treatment for breast cancer brain metastases (BCBMs), but emerging systemic therapies are increasingly being used in this difficult-to-treat population of patients. Recently, Medscape reached out to experts in the field to discuss these systemic approaches.

"A general question in the field is when and how to prioritize trying systemic therapy ahead of radiation therapy," said Nancy Lin, MD, director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston. Currently, Lin said, radiation and surgery are prioritized ahead of systemic therapy for BCBMs much of the time.

Blood-Brain Barrier

The formation of brain metastases is poorly understood, but to grow in the brain, single tumor cells must pass through the tight blood-brain barrier.[1] "The biggest challenge to managing BCBMs is that most of the systemic therapies can't cross the blood-brain barrier," said Brufsky.

Although the physiologic blood-brain barrier limits their activity, some systemic treatments nonetheless have significant antitumor activity at the central nervous system (CNS) level.[2] A number of chemotherapy drugs, said Lin, including capecitabine, anthracyclines, and platinum agents, can be considered for systemic treatment of BCBMs.

The propensity to develop BCBMs varies by subtype, occurring in up to one half of patients with triple-negative breast cancer, up to one half of patients with HER2-positive breast cancer, and 10%-15% of those with hormone-positive disease.[3,4] Survival of patients with breast metastases also varies by tumor subtype (luminal, HER2, and triple-negative metastatic breast cancer), highlighting the need for tailored treatment approaches.[5] Median survival after BCBM diagnosis can be as short as 5 months in triple-negative breast cancer and 10-24 months in other subtypes.[3,6]

HER2-Positive Disease

"Historically, it has been assumed that monoclonal antibodies do not penetrate into brain metastases," said Lin. "[However], data from in vivo studies in patients administered Zr-labeled trastuzumab, which allows it to be used as a PET tracer, have called this assumption into question, because there is uptake in brain metastases."

To date, no systemic therapy has gained an indication for the specific treatment of BCBMs; however, some regimens have been associated with efficacy in the CNS in nonrandomized studies.[4] The most established therapies for BCBMs are for HER2-positive disease. Most reported studies have used lapatinib as treatment of HER2-positive BCBMs, a treatment with modest effect as a single agent; adding capecitabine improves response rates.[7] In patients with HER2-positive breast cancer, the combination of lapatinib and capecitabine has been associated with CNS response rates of 66% in the upfront setting, and 18%-38% in patients whose disease has progressed after prior radiation therapy.[4,8]

"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," said Lin. "Trastuzumab emtansine (T-DM1) has been shown in several case series to produce CNS objective responses, as well. Most recently, we have shown in the Translational Breast Cancer Consortium 022 clinical trial (TBCRC 022) that the combination of neratinib and capecitabine is associated with a CNS objective response rate of nearly 50%, and on the basis of the results of this study, the regimen has an National Comprehensive Cancer Network (NCCN) compendium listing (in the NCCN Neuro-Oncology guidelines) for the treatment of patients with active/progressive HER2-positive BCBMs."

T-DM1 produces CNS objective responses in up to 40% of patients with BCBMs, including complete responses.[9,10,11] The TBCRC 022 study, said Lin, is currently enrolling a cohort of patients with brain metastases who will be treated with T-DM1 plus neratinib.

Another HER2-targeted agent, tucatinib, is associated with less diarrhea than neratinib and is being tested in clinical trials for HER2-positive BCBMs.[12,13,14] Tucatinib, capecitabine, and trastuzumab were associated with a CNS response rate of 42% in a small trial of patients with brain metastases.[4]

Pertuzumab is another HER2 agent showing promise for BCBMs.[7,14,15] In a recent case study, a 40-year-old woman with a HER2-positive solitary brain metastasis underwent surgery resection followed by stereotactic radiotherapy and, after early progression, first-line therapy with pertuzumab, trastuzumab (Herceptin), and weekly paclitaxel; she had complete disappearance of brain recurrence that persisted for more than 24 months.[16] Treatment of a solitary lesion with pertuzumab, trastuzumab, and docetaxel induced a complete response in a patient that persisted for over 5 months in another case report.[17] The PATRICIA trial is testing an escalated dose of trastuzumab, to 6 mg/kg weekly, in combination with standard-dose pertuzumab in BCBMs.[18] "We anticipate presentation of results of the phase 2 PATRICIA trial within the next year," said Lin.

ER-Positive/Triple-Negative Disease

For patients with ER-positive breast cancer, endocrine therapies, such as tamoxifen and aromatase inhibitors, have been reported to induce CNS responses in case reports and small case series.[4] CDK4/6 inhibitors, including abemaciclib, also show promise.[19,20] In a phase 2 trial of patients with brain metastases secondary to hormone receptor-positive, HER2-negative metastatic breast cancer, the intracranial clinical benefit rate with abemaciclib was 25%, and the median progression-free survival was 4.4 months.[20]

"If a brain metastasis is ER-positive, we will often give aromatase inhibitors and fulvestrant with a CDK4/6 inhibitor, particularly abemaciclib, which is the one we feel crosses the blood-brain barrier the best," said Brufsky. "This is generally after surgery or CyberKnife treatment."

No commercially available targeted agents have demonstrated efficacy against brain metastases from triple-negative breast cancer.[4]


One barrier to systemic therapy for BCBMs, including immunotherapy, is that patients with brain metastases have predominantly been excluded from clinical trials.[21] In early clinical trials for patients with brain metastases from melanoma and non-small cell lung cancer, immune checkpoint inhibitors have shown intracranial activity.[22] A variety of immunotherapies are being tested in patients with BCBMs, including the programmed death cell protein 1 (PD-1) inhibitor nivolumab with stereotactic radiation, the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab with stereotactic radiation, and chimeric antigen receptor (CAR) T cell therapy.[23,24,25,26]

"Although there are ongoing trials of immunotherapy for BCBMs, there is not sufficient efficacy or safety data as of yet to recommend their routine use for the specific treatment of active brain metastases outside of a clinical trial," said Lin.

Other Agents

Other targeted agents in clinical trials for BCBMs include the mammalian target of rapamycin (mTOR) kinase inhibitor everolimus, in combination with trastuzumab and vinorelbine.[27] The use of liposomal doxorubicin and liposomal irinotecan are also being explored for BCBMs.[28,29,30] "There is a lot of interest in liposomal irinotecan," Brufsky commented.

Dr Brufsky disclosed relevant relationships with Puma, Roche, and Pfizer. Dr Lin disclosed relevant relationships with Daichii, Genentech, Pfizer, Puma, and Seattle Genetics.

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