New Insights and Emerging Therapies for Breast Cancer Brain Metastases

Breast cancer brain metastases (BCBMs) are the second most frequent secondary central nervous system metastases following those associated with non–small-cell lung cancer. It is increasingly evident that BCBM arises as a function of the biology of the primary tumor and the metastatic niche, which combine to create a unique microenvironment in the brain impacting both metastatic colonization and therapeutic response. Clinical outcomes are improving for BCBM patients as a result of modern combinatorial therapies, challenging the traditionally nihilistic approach to this patient subgroup. This review will focus on the breast cancer subtypes with the highest incidence of BCBM-human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and triple-negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) breast cancer (TNBC)-and will characterize differences in the clinical behavior of brain metastases that arise from these different subtypes. We will also highlight some of the recent preclinical studies that may shed light on the biological mechanisms and mediators underlying brain metastases. Finally, we will review published and current prospective trials of systemic therapies specifically for BCBM, including novel pathway-specific therapies.

The Changing Landscape of Breast Cancer Brain Metastases

The diagnosis of central nervous system (CNS) recurrence is a much dreaded outcome among breast cancer patients, and its incidence varies with disease stage and cancer subtype. While less common than bony, lung, or liver metastases, breast cancer brain metastases (BCBMs) are associated with the shortest survival time once diagnosed.[1] BCBMs are also the second most frequent secondary CNS metastases following those associated with non–small-cell lung cancer. BCBMs are typically multifocal and intracerebral, and less commonly solitary and leptomeningeal.[2,3] It is increasingly evident that BCBM arises as a function of the biology of the primary tumor and the metastatic niche; the latter is comprised of the blood-brain barrier (BBB), pericytes, astrocytes, and glial cells, which combine to create a unique microenvironment in the brain that impacts both metastatic colonization and therapeutic response. Improvements in systemic therapy have altered the natural history of breast cancer, and BCBM occurs in a significant proportion of patients. However, patients with BCBM are excluded from many clinical trials, despite the urgent need to develop treatments for this critical challenge. In this article, we will compare the clinical behavior of BCBM associated with the various breast cancer subtypes, with a focus on the subtypes with the highest incidence of BCBM, human epidermal growth factor receptor 2 (HER2)-positive breast cancer and triple-negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) breast cancer (TNBC). We will also review therapies and research strategies currently in use and in development.

TABLE 1

Clinical Characteristics of CNS Metastases According to Breast Cancer Subtype

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