Therapeutic approaches for HER2-positive brain metastases: circumventing the blood-brain barrier

Abstract

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood-brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting.

Fig. 1

Time to central nervous system recurrence in patients with HER2-negative, or HER2-positive metastatic breast cancer who had and had not received treatment with trastuzumab. HER2 indicates human epidermal growth factor receptor 2. Reproduced with permission from Dawood et al.

Fig. 2

Structure of the blood–brain barrier (BBB). The cerebral capillaries are composed of endothelial cells that are sealed by tight junctions. The capillaries are in close contact with pericytes and are ensheathed by astrocyte foot processes and the basal lamina. The passage of molecules across the BBB is tightly regulated; some hydrophilic molecules enter the brain via specific transporters and carrier-mediated endocytosis, and a limited number cross the barrier via diffusion through tight junctions.

Fig. 3

PET image showing penetration of the brain in a patient with HER2-positive metastatic breast cancer. Arrow indicates a HER2-positive brain lesion. HER2 indicates human epidermal growth factor receptor 2; PET, positron emission tomography; ⁸⁹Zr-trastuzumab, zirconium 89–labeled trastuzumab. Reproduced with permission from Dijkers et al.

Fig. 4

Concentrations of functional, reactive trastuzumab in serum and cerebrospinal fluid (CSF) of patients with metastatic breast cancer in relation to clinical parameters. Reproduced with permission from Stemmler.

Fig. 5

Approaches to enhance drug delivery across the blood–brain barrier (a) bradykinin analogs, (b) receptor-mediated endocytosis, (c) absorptive transcytosis, (d) ultrasound. Adapted with permission from Eichler et al..