Breast Cancer Brain Metastases: Biology and New Clinical Perspectives

Isabell Witzel; Leticia Oliveira-Ferrer; Klaus Pantel; Volkmar Müller; Harriet Wikman


Breast Cancer Res. 2016;18(8) 

In This Article

Local and Systemic Treatment of BM

Historically, breast cancer BM were treated with whole-brain radiation therapy (WBRT) or with surgery if possible. The role of WBRT after the surgical resection of a single metastasis has been well established for controlling local recurrence.[17] However, the use of WBRT has come under recent criticism because of the possibility of neurocognitive decline related to brain radiation.[18]

The rise of stereotactic radiosurgery has become an alternative for patients with limited disease due to its advantage of a single-session delivery and a minimal delay for systemic therapy. Both local therapy and systemic treatment enhance OS.[19] In 420 patients with BM receiving WBRT, the median survival in a scenario of BM in patients without and with systemic treatment after WBRT was 3 and 10 months, respectively (P < 0.0001). No survival benefit for systemic treatment was observed only in the triple-negative subset. In all other subgroups (HER2-positive, luminal A and B), a survival benefit from systemic treatment could be achieved.

Most cytotoxic agents do not cross the blood–brain barrier (BBB), and the presence of BM has been an exclusion criterion for nearly all clinical trials on treatment in metastatic breast cancer. Studies examining chemotherapy regimens usually included various solid tumors and reported response rates of between 4 and 38 %.[20] Therefore, it is largely unclear how existing therapies function in patients with BM; there is thus no global consensus regarding the ideal treatment strategy.

Although trastuzumab is effective for treating HER2-positive breast cancer, it is not clear whether it also acts in the brain. A study by Stemmler et al. examined trastuzumab levels in serum and cerebrospinal fluid. Prior to radiotherapy, the median serum versus cerebrospinal trastuzumab level ratio was 420:1. After the completion of radiotherapy, the ratio was 76:1. In patients with concomitant meningeal carcinomatosis, this ratio was 49:1.[21]

In more recent publications, a higher incidence of BM was reported in HER2-positive patients treated with trastuzumab.[22] Data analysis showed that the enhanced risk of BM after trastuzumab treatment was due to an improved systemic control of the disease. The continuation of trastuzumab treatment in patients with BM is beneficial; however, it is unclear whether this benefit is due to drug efficacy in the brain or better systemic control.[5]

The small molecule kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, was presumed to be able to cross the BBB. In findings from a mouse model, the average lapatinib concentration in BM was only 10–20 % of that in peripheral metastases. Only in a subset of brain lesions (17 %) did the lapatinib concentration approach that of systemic metastases.[23] In HER2-positive breast cancer patients who progressed after WBRT, lapatinib monotherapy showed minor activity as a single agent.[24] In 39 patients, only one partial response was observed. In another study, lapatinib monotherapy showed a response of 6 %.[25] Interestingly, the addition of capecitabine increased the response rates to 20 %. In the LANDSCAPE trial,[25] the combination of lapatinib and capecitabine administered prior to WBRT in newly diagnosed HER2-positive BM revealed a central nervous system (CNS) response rate of 67 %. A study in patients with resected BM found that capecitabine and lapatinib penetrate to a significant although variable degree into the brain and that drug delivery to BM is variable and in many cases appears partially limiting.[26] A recent report from a study found that the incidence of BM as the first site of relapse was 3 % for the combination of lapatinib–capecitabine and 5 % for trastuzumab–capecitabine.[27] These data do not support a better activity for lapatinib compared with trastuzumab in the prevention of BM.

Despite these reports suggesting the direct activity of agents in the brain, chemotherapy is generally prescribed secondary to surgery or radiotherapy.

Recent clinical findings showed some efficacy of antibody-based therapy in BM with trastuzumab-DM1 (T-DM1).[28,29] In the EMILIA trial,[30] T-DM1 was associated with significantly improved OS compared with lapatinib and capecitabine in patients with asymptomatic BM at baseline.

The efficacy of bevacizumab (a vascular endothelial growth factor (VEGF) antibody) in combination with radiotherapy and chemotherapy was investigated in 35 patients with a CNS-objective response in 13 patients (37.1 %).[31] Additionally, the combination of WBRT and bevacizumab without chemotherapy showed some efficacy in a phase I trial including 13 patients with breast cancer BM.[32]

Some agents show moderate activity in the brain; however, tumor cells that manage to spread into the brain have other resistance mechanisms. Therefore, it would be of high interest to understand the nature of breast cancer tumor cells that outgrow in the brain in an effort to prevent this process.