Breast to Brain Metastasis-Wolf in Sheep’s Clothing

BY Dr. Josh Neman


October is breast cancer awareness month, which is an annual campaign to increase awareness of the disease. While most people are aware of primary breast cancer, many forget that it is the metastasis that is the patient’s ultimate malice. Breast cancer metastasizes to the brain in approximately 30-40% of patients with either triple negative or Her2+ subtype (1). 90% of patients with these breast cancer subtypes will die of metastasis to the brain. While advances in cancer treatments has resulted in  breast cancer patients living longer, extended survival from primary disease has unmasked brain metastases as one of the new major challenge limiting outcomes for those with advanced disease.

Several factors underlie this epidemiological shift. Major advances in neuroimaging have led to increased detection of brain metastases in patients. However, early detection does not equate to better prognosis. Brain metastases indicates poor prognosis, likely exclusion from clinical trials (thus greatly reducing treatment options), and causes neurological deficits that impair patients’ lives in fundamental ways. Existing therapies are restricted to palliative radiation and neurological surgery, with limited chemotherapeutic options. While targeted therapies have improved management of the disease outside of the brain, poor bioavailability to the brain increases its potential as a sanctuary site for metastatic disease.

Traditionally metastatic spread was conceived as a late event occurring long after primary tumors progressed locally. We now know that micrometastasis can occur very early in cancer, sometimes even before a detectable primary disease. Fortunately, despite spreading to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. Ultimately, metastasis is the result of successful interplay between tumor cells and newly encountered microenvironments. After crossing the brain’s protective gateway (blood-brain-barrier), disseminated breast cancer cells arrive in a dynamic cellular and molecular landscape that presents unique selection pressures. The brain is one the most complex biological system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain’s microenvironment comes from the field of neurobiology. Thus, as neuroscientists our approach is to study breast cancer and its ultimate metastasis to the brain from the perspective of the brain. Thus far, our research has established that the microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by breast cancer cells (2). We further show breast to brain metastasis display characteristics similar to that of brain cells (3, 4). Therefore, breast cancer cells that successfully metastasize to the brain may represent a discrete type of tumor cells that best mimic brain cells and adapt to the resources available in the brain’s microenvironment- the proverbial “wolf in sheep’s clothing.” Consequently, successful future therapy for brain metastases should potentially target both the breast cancer cells and the microenvironment that facilitates tumor cell growth and tumor resistance to drugs—leading to potential therapeutic avenue for breast cancer patient treatment.

1. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18-43.
2. Neman J, Choy C, Kowolik CM, Anderson A, Duenas VJ, Waliany S, et al. Co-evolution of breast-to-brain metastasis and neural progenitor cells. Clin Exp Metastasis. 2013;30:753-68.
3. Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM, et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci U S A. 2014;111:984-9.
4. Termini J, Neman J, Jandial R. Role of the Neural Niche in Brain Metastatic Cancer. Cancer Res. 2014.

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