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Page 2 of 18 Malone et al. J Cancer Metastasis Treat 2021;7:40 https://dx.doi.org/10.20517/2394-4722.2021.37

BREAST CANCER AND BREAST-TO-BRAIN METASTASIS: CLINICAL AND BIOLOGICAL
BASIS
[1,2]
It is estimated that over 42,000 women succumb to breast cancer in the United States every year . Past data
show that 90% of breast cancer mortalities are attributed to recurrent and metastatic disease . Though
[3,4]
some patients can develop metastases within 3 years of detection of a primary tumor, it is also common for
metastases to occur more than 10 years after the initial diagnosis . Among metastatic sites, the central
[3,5]
nervous system (CNS) carries a grim prognosis: for breast-to-brain metastases the one-year survival rate is
just 20% [Table 1].
[6]

Metastasis is the process by which tumor cells invade the stromal tissue surrounding the primary tumor,
[12]
enter vasculature, and disseminate throughout the body . The circulating tumor cells (CTCs) then arrest in
the capillaries of distant organs, and either persist as quiescent cells or proliferate and form
micrometastases [13,14] . The phases of this metastatic process are Dissemination, Dormancy, and Colonization
and Outgrowth at the distal site .
[15]
DISSEMINATION
Dissemination can start very early during primary tumor progression and can continue until the primary
tumor is removed. As cancer cells undergo epithelial-to-mesenchymal transition (EMT), a combination of
expression changes of cell adhesion, migratory and invasive genes of the cancer cells occur that lead to the
[15]
remodeling of the ECM, and intravasation through a leaky vasculature or lymphatics . The contribution of
the lymphatic system in metastasis is debated, since clinical trials have shown that breast or ovarian cancer
patients who had undergone regional lymph node dissection did not exhibit any survival benefit over
control patients ; however, it has been proposed that the lymphatic system may contribute to the CTCs
[16]
from the blood stream or the lymphatic system extravasate at the distal site, and then enter the phase of
Dormancy during which the cancer cells at the distal site do not yet form a clinically defined lesion because
the host environment presents barriers, physical, metabolic, and immune, which hinder tumor growth.
Finally at the host tissue the metastatic process enters the Colonization and then Outgrowth phase. The most
common sites of metastasis can change depending on breast cancer subtypes .
[9]
There are numerous risk factors that increase the likelihood of metastasis in breast cancer patients, such as
breast cancer molecular subtypes, patient age, number of metastatic sites, and tumor size [17-22] .

The overall likelihood of metastasis depends upon molecular subtypes. Currently four major molecular
subtypes of breast cancer have been characterized, depending on the expression of the estrogen receptor
(ER), progesterone receptor (PR) and of human epidermal growth factor receptor 2 ERBB2/HER2: Luminal
A (described as ER+, PR±, HER2- with low Ki67 expression), Luminal B (ER+, PR±, HER2± with high
expression of the proliferation marker Ki67), HER2+ (ER-, PR-, HER2+) and Triple Negative (TNBC: ER-,
PR-, HER2-). In breast cancers with hormone receptor expression, concerted Ki67 expression increases the
chance of metastasis from 27.8% to 42.9% whereas concerted ERBB2/HER2 expression increases the chance
of metastasis to 47.9%. Sole expression of ERBB2/HER2 results in a 51.4% chance of metastasis and an
[23]
absence of receptor expression yields a 43.1% chance . Independent of molecular subtype, breast cancer
most commonly metastasizes to bone. The frequency of metastasis to distant sites, however, is dependent on
subtype. Breast cancers with hormone receptor expression are the most frequent of all subtypes to form
distant metastases in bone; with the additional expression of ERBB2, the second most frequent metastatic
site switches from the lungs to liver. With sole ERBB2/HER2 expression, the likelihood of forming liver
metastases is similar to that of bone metastases. TNBC drives both bone and lung metastases at similar
[9]
rates . Though each subtype has the propensity to form brain metastases, ERBB2/HER2-positive and