Emerging treatment strategies for breast cancer brain metastasis: from translational therapeutics to real-world experience

Abstract

Systemic therapies for primary breast cancer have made great progress over the past two decades. However, oncologists confront an insidious and particularly difficult problem: in those patients with metastatic breast cancer, up to 50% of human epidermal growth factor 2 (HER2)-positive and 25-40% of triple-negative subtypes, brain metastases (BM) kill most of them. Fortunately, standard- of-care treatments for BM have improved rapidly, with a decline in whole brain radiation therapy and use of fractionated stereotactic radiosurgery as well as targeted therapies and immunotherapies. Meanwhile, advances in fundamental understanding of the basic biological processes of breast cancer BM (BCBM) have led to many novel experimental therapeutic strategies. In this review, we describe the most recent clinical treatment options and emerging experimental therapeutic strategies that have the potential to combat BCBM.

Keywords: breast cancer brain metastasis; emerging treatment strategies; translational therapeutics.

Figure 1.

Summary of recent translational therapeutic strategies in repositioning known drugs to target BCBM tumorigenic signaling especially the microenvironmental factors. Silibinin, a commercially available nutraceutical reduced BCBM in animal models and a cohort of 18 patients through suppressing STAT3 activation in the STAT3+ pro-metastatic As subpopulation. Meclofenamate, a FDA-approved anti-inflammatory drug inhibited BCBM tumor growth by blocking PCDH7-Cx43 gap junction between Tu and astrocytes. Edlfosine, a phase II clinical trial drug in treating leukemia with bone marrow transplants inhibited BCBM by suppressing the PCDH7-PLCβ signaling that mediates the crosstalk between astrocytes and brain-tropism CSC. Letrozole, a clinical aromatase inhibitor for ER+ breast cancer treatment, decreased the large BCBM by suppressing ER+ pro-metastatic astrocytes. Fludarabine, a FDA-approved chemotherapeutic drug for treatment of chronic lymphocytic leukemia, inhibited the tumorigenic property of XIST-low and the tumor suppressive M2 microglia that not only delayed onset, but also suppressed growth of BCBM. CpG-C, a clinical trial TLR9 agonist, prevented BM by activating M1 microglial cells to kill and phagocytose the tumor cells during the early stages of invasion into the brain. A, astrocyte; BCBM, breast cancer brain metastasis; CSC, cancer stem cells; ER+, estrogen receptor-positive; FDA, United States Food and Drug Administration; TLR9, Toll-like receptor 9; Tu, tumor cells; XIST-low, XIST^low tumor cells