CNS metastases in breast cancer: old challenge, new frontiers

Abstract

Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities.

Figure 1.. Schematic of preclinical experimental brain metastasis experiments.

Using the 231-BR model system, tumor cells were injected into the left cardiac ventricle of immunocompromised mice on day 0. For metastasis prevention experiments, mice were randomized three days post-injection to either placebo or drug, given continuously until the experimental endpoint. For metastasis treatment experiments, placebo or drug was begun after micrometastases and macrometastases had formed, usually between days 14 and 21 post-injection, and continued until the experimental endpoint. At necropsy, step sections were cut through one brain hemisphere, and lesions quantified under a microscope in five H&E stained sections. Lesions were dichotomized into micrometastases and macrometastases based on a 300 micron cutoff in a single dimension, roughly equivalent to a lesion that is detectable in a human brain on MRI.

Figure 2.. Variable penetration of paclitaxel into experimental 231-BR brain metastases of breast cancer.

A-C, Mice were inoculated with EGFP tagged 231-BR-HER2 brain-tropic tumor cells, and permitted to develop metastases. Before necropsy, mice were injected with 3kDa Texas Red dextran (B) or ¹⁴C-Paclitaxel (C), and free drug was then perfused from the vasculature. A single section of brain was imaged for metastases (EGFP, A), Texas Red Dextran uptake (B) and imaged for ¹⁴C-paclitaxel uptake. Variability is noted within and between lesions. D, The fold-uptake of paclitaxel relative to normal brain was determined for 379 experimental metastases. Only 9.8% of lesions demonstrated >50-fold greater drug uptake as compared to normal brain, while 14% of lesions were statistically indistinct from normal brain. In experiments not shown, paclitaxel only caused cytotoxicity in the 9.8% of freely permeable lesions. E, Paclitaxel distribution over time in experimental metastases (purple) versus systemic lesions and normal brain. While drug uptake is higher in experimental metastases than normal brain, it remains logs below systemic lesions. Adapted from Lockman, et al. (26).

Figure 3.

⁸⁹Zr-trastuzumab-PET demonstrating uptake in a brain metastasis in a patient with HER2-positive breast cancer (adapted from Dijkers, et al (54)).

Figure 4.. ¹⁸FLT-positron emission tomography (PET) for detection of brain metastases and evaluation of early response.

Upper panels: Post-contrast, T1-weighted magnetic resonance imaging (MRI) of brain and corresponding ¹⁸FLT-positron emission tomography (PET) images at baseline. Lower panels: Post-contrast, T1-weighted MRI of brain and corresponding ¹⁸FLT-PET images after one cycle of GRN1005.

Figure 5.. Advanced magnetic resonance (MR)-based techniques for evaluation of early response to anti-angiogenic agents.

A) Baseline (day −1), after a single dose of bevacizumab (day +1), and after 2 cycles of carboplatin plus bevacizumab (day +54) showing a) post-contrast, T1 weighted brain MRI, B) permeability maps (Ktrans), C) apparent diffusion coefficient (ADC) maps showing water movement and D) fractional anisotropy (FA) maps from white matter diffusion tensor imaging (DTI) illustrating the degree of anisotropy in the water diffusion process [a.u. arbitrary units].