By: Kate M. O’Rourke
While no avenues exist for preventing breast cancer brain metastases (BCBMs), new research into how these metastases form may open doors to a prophylactic approach. A major clinical challenge, brain metastases occur in roughly 20% of patients with breast cancer and cause a significant decline in quality of life and increased chance of mortality.[1,2,3] In an effort to develop strategies to prevent brain metastases, researchers are working to better understand the molecular, cellular, genetic, and clinical mechanisms underlying metastatic progression.
“Many people are investing time and resources into trying to understand why tumors go to the brain, and which type of tumors go to the brain, to see if there is anything we can do in terms of prevention,” said Fatima Cardoso, MD, director of the breast unit of the Champalimaud Clinical Centre in Lisbon, Portugal.
BCBMs occur in up to one half of triple-negative breast cancers, up to one half of HER2-positive breast cancers, and 10%-15% of hormone-positive cancers.[4,5] For some cancer patients at high risk for brain metastases, such as those with leukemia, small cell lung cancer, or non–small cell lung cancer, prophylactic whole-brain radiation therapy is used, but patients with breast cancer do not fall into this category.[1,3,6,7] “Breast cancer patients, even HER2-positive patients who are at a higher risk, still don’t have a high enough risk of brain metastases that we are willing to say that they should have prophylactic treatment, because the current prophylactic treatments are so toxic,” said Adrienne Boire, MD, a neuro-oncologist at Memorial Sloan Kettering Cancer Center in New York City.
Potentially clinically informative alterations occur in roughly half of brain metastases that are not detected in the matched primary tumor sample, and these alterations are sensitive to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors. Lapatinib combined with capecitabine can produce central nervous system response rates of 66% in the upfront setting in HER2-positive breast cancer; however, most drugs that control extracranial disease are not effective against brain metastases because they cannot cross the blood-brain barrier (BBB).[3,5,9,10] This highly selective barrier regulates the uncontrolled diffusion of most molecules into the brain. The pivotal component of the BBB is a monolayer of endothelial cells in brain capillaries that are connected by tight junctions.
Metastases: A Multistep Process
Many of the processes that drive metastases to the brain are conserved among different tumor types.[12,13] “There is such a huge number of changes that have to occur for a cancer cell from outside the brain to learn how to live in the brain itself, that many of those changes are similar between a breast cancer cell or a lung cancer or melanoma cell, for example,” said Boire. “There are also a number of processes that are exclusive to breast cancer cells.”
Cancer metastasizing to the brain is a multistep process that involves cancer cells dissociating from primary tumors, migrating to distal sites, and finally colonizing the brain, eventually leading to metastatic tumors.[13,14,15] “First, cells in the primary tumor have to invade the tissues surrounding the primary tumor itself. Then the tumor cells need to detach and enter into the blood, and they need to be able to survive in suspension. Tumor cells are not usually able to survive in suspension, as they have anchorage-dependent growth. These processes are going to be conserved among different metastatic sites,” said Boire. “The next step is being able to arrest in the capillaries and enter into a given capillary bed. Some proportion of that is site-dependent, but there are some molecular markers that are thought to be expressed everywhere, in all capillary beds.”
Before reaching the central nervous system, cells of the primary tumor acquire mutations that lead to genetic instability, sustained proliferative signaling, evasion of growth suppressors, increased invasive potential, replicative immortality, and resistance to hypoxia and cell death. Some cancer cells develop stem-like capabilities.
According to Joseph Bovi, MD, associate professor of radiation oncology at Medical College of Wisconsin, Milwaukee, the mechanism of metastatic progression specific to the brain is complicated. “These cancer cells move within the blood vessels and they start to grow along the walls of the blood vessels in the brain, not on or in the nerve cells or in the brain parenchyma per se,” said Bovi. “By staying close to those vessels, the cancer cells can get all of the nutrients and oxygen they need to grow without making their own blood vessels for survival.”
Strategies for Prevention
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. “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.
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. 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. “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.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.