To develop strategies to prevent brain metastases, researchers need to better understand the molecular, cellular, genetic, and clinical mechanisms underlying metastatic progression. [ 16 , 17 ] Research has shown that inhibition of an integrin complex from cancer cells prevents them from attaching to blood vessel walls and moving across the blood vessel and into the brain parenchyma. [ 18 , 19 , 20 ] "The integrin mechanism has been considered a target for trying to prevent brain metastases from occurring and keeping those cells in the blood vessels where they can be most impacted by systemic chemotherapies," said Bovi.
Increased expression of HER2 amplification is one underlying change that leads to an increased rate of brain metastases. [ 21 ] "Patients who have a HER2-positive primary tumor can develop brain metastases very early in the course of their disease. The method by which HER2 amplification leads to brain metastases is not well known," said Boire. "The other types of changes that we see are changes at the transcriptome level and gene expression changes, and these changes are conserved throughout different subtypes of breast cancer."
COX-2, the EGFR ligand HBEGF, and the alpha-2,6-sialyltransferase ST6GALNAC5 have been identified as mediators of cancer cell passage through the BBB. [ 22 , 23 ] While EGFR ligands and COX-2 are associated with breast cancer infiltration of the lungs, ST6GALNAC5 specifically mediates brain metastasis. [ 22 ]
According to Boire, several molecular targets could be used to form a preventative strategy for BCBMs, including ST6GALNAC5. "The classic changes associated transcriptionally with brain metastases in breast cancer involve ST6GALNAC5. This glycoprotein sits on the surface of breast cancer cells and allows them to adhere to the capillaries in the brain. It is associated with a cancer cell's ability to enter the brain," said Boire. "Other genes associated with brain metastasis in breast cancer include L1CAM and connexin43. Overexpression of these three genes together lead to an increased rate of brain metastases.
Recently, Boire spearheaded a pilot study to provide meclofenamate to individuals with recurrent or progressive brain metastases from solid tumor primaries. [ 24 ] Meclofenamate, a nonsteroidal anti-inflammatory drug capable of penetrating the BBB, inhibits connexin43-based gap junctions. "The pilot study was quite promising, with some patients showing great responses," said Boire.
Tumor-infiltrating lymphocytes have been found to surround brain metastases, and therapeutic approaches to activate the immune system against cancer cells in the brain are being evaluated in patients with brain metastases. [ 25 ] "How the immune system recognizes the presence or fails to recognize the presence of cancer in the brain is an area of very active study," said Boire. A number of clinical trials are currently exploring the role of checkpoint blockade and CAR-T cells in brain metastases. [ 26 , 27 , 28 , 29 , 30 , 31 ]
So, how close are we to preventing BCBM? According to Boire, treating brain metastases will require multiple orthogonal strategies, similar to the way that cancer is treated elsewhere in the body. "A strategy for preventing brain metastases is very far away from clinical practice," said Boire.
Dr Boire disclosed relationships with Arix Biosciences and Everon Biosciences, as well as a patent pending involving connexin43. Dr Cardoso and Dr Bovi have disclosed no relevant financial relationships. References
Medscape Oncology © 2019 WebMD, LLC Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape. Cite this: Preventing Breast Cancer Brain Metastases: How Close Are We? - Medscape - Dec 30, 2019. Tables
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