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Page 4 of 18 Malone et al. J Cancer Metastasis Treat 2021;7:40 https://dx.doi.org/10.20517/2394-4722.2021.37

TNBC are the most common subtypes to drive metastases to the brain. Of the two, TNBC has been reported
to have a higher propensity to metastasize solely to the brain [7,24,25] . Luminal A breast cancers are more likely
to metastasize to bone and less likely metastasize to brain, liver, and lung, and are less likely to present as
[26]
multiple metastases . Both ERBB2/HER2-positive and TNBC subtypes are also associated with the lowest
median survival with brain metastases at 10 and 4 months. Patients with concurrent hormone receptor and
[7]
ERBB2 expression have a median survival of thirteen months .
Patient age is linked to location and number of metastatic sites. Younger patients are more likely to form
single metastases in the brain or liver than in other organs . None the less, those who present with multiple
[25]
metastatic sites also tend to be younger or middle-aged [8,25] . The increased incidence of metastases in
younger patients may be in part due to the higher rate of diagnosis of TNBC in younger patients and the
[8]
difficulties that surround its treatment . Elderly patients (> 69 years) are more likely to have metastases in
the lungs and less likely to solely have distant lymphatic metastases [8,25] . Among all patients with metastatic
disease, age was linked to overall survival, with the median overall survival rates for younger and elder
groups decreasing from 32 to 16 months .
[25]
The likelihood of developing metastases increases with the presence of cancer cells in the lymph nodes,
making it a commonly used prognostic marker [27,28] . The presence of lymph node metastases in patients with
ERBB2-overexpressing breast cancer is associated with worse prognosis than those without lymph
metastases . However, its use as a marker is not absolute, as approximately one third of patients without
[29]
lymph-node metastases will still develop distant metastases, while approximately one third of patients with
nodal metastases will not form distant metastases 10 years after therapy [30,31] . Though the number of nodal
metastases is often correlated with the primary tumor size, the two act as independent but additive
indicators of disease state. With an increase in lymph involvement, regardless of tumor size, patient survival
decreases .
[27]
Tumor size has long been considered a prognostic marker for metastasis, with primary tumors larger than
2 cm in diameter having a high risk of metastasis, and those over 5 cm having a very high risk [27,28,31,32] . There
is a linear correlation between tumor size and likelihood of metastasis for tumors between 1 and 5 cm in
diameter, which allows for the prediction of tumor behavior and provides the rationale for therapy
recommendations [33,34] . These recommendations are based on the linear model of breast cancer progression
[35]
(Figure 1, adapted from ), where the disease progresses linearly from initiation of cancerous growth to
invasion of surrounding tissue to lymphatic metastasis and, finally, distant metastasis . This model is used
[36]
to describe breast cancer progression regardless of molecular signature: according to the linear progression
model, both lymphatic and distant metastases are seeded by the primary tumor, thus the observed linear
relationship between size and metastatic potential would be extrapolated to both tumors smaller than 1 cm
or larger than 5 cm; a tumor smaller than 1 cm would have a lower potential for metastasis to either the
lymph nodes or other sites, and a larger tumor would have a higher potential for metastasis [30,37,38] . However,
this model becomes unreliable for small tumors (< 1 cm) and large tumors (> 5 cm). For small tumors and
large tumors, the relationship between size and metastatic potential becomes non-linear, and thus the ability
[39]
to accurately predict the likelihood of metastasis becomes more difficult . To explain the nonlinear
relationship, a parallel model of breast cancer was proposed [Figure 1] in which a small number of cancer
stem cells with metastatic potential are disseminated into breast tissue, lymph nodes, and distant organs.
Based on this model, these cancer stem cells and inherent tumor biology, rather than the size of the primary
tumor , are the major contributors to the metastasis.
[40]