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in intracranial brain tumor growth (P < 0.0001) and an increase in OS (P < 0.002, P < 0.04 respectfully) in
comparison to vehicle groups. Ultimately, the novel therapeutic QBS10072S is highly selective to TNBCs
[51]
and has been shown to significantly slow TNBC’s proliferation rate . Although this study shows a more
targeted treatment for TNBCs, it should be mentioned that the effectiveness of the drug relies on the LAT1
expression in TNBCs, and expression levels may differ from patient to patient.

Luminal A and Luminal B
Brain metastases are a common byproduct of aggressive breast cancers such as HER2+ and triple-negative.
However, a study conducted by Oehrlich et al. suggests that patients with luminal breast cancer have a
lower risk of developing brain metastases . Luminal A tumors are characterized to display high expressions
[52]
of estrogen-related genes and low expression of proliferation genes, while luminal B tumors display lower
expression of estrogen and progesterone receptor genes and high expression of proliferation, cell cycle
genes, and growth factor receptor genes . Both luminal A and luminal B cancer are positive for estrogen
[36]
receptor (ER+), but luminal B has lower expression in comparison to luminal A. Luminal B also has higher
proliferation rates, which contributes to its aggressive phenotype [6,51] .

Treatments targeting luminal B tumors focus on the proliferating phenotype of these cells due to the
responsiveness they have against hormones and chemotherapy [3,6,51] . Inhibition of the P13K/AkT/mTOR and
ERK pathways reduces the survival, angiogenesis, and metastasis of these tumor cells . Due to luminal A
[36]
and B’s high estrogen receptor expression, drugs like Tamoxifen are used to bind to the receptors and
prevent cancer cells from developing resistance to the innate anti-cancer mechanisms . Due to the potential
[3]
of developing tamoxifen resistance and current cytotoxic therapies, insulin-like growth factor-1 receptor
(IGF-1R) is becoming a potential target for luminal cancer treatment. This pathway has been found to have
a great effect on limiting tumor proliferation. Most resistance to Tamoxifen derives from the
communication between ER and IGF-1R receptors in the tumor cells . The PR loss is associated with the
[53]
IGF-1R in Luminal B Cancer cells. The IGF-1R inhibitor BMS-536924 significantly suppressed cancer
growth in vitro in various cell lines, including MAC-7 Tam-R cells, which have tamoxifen resistance. IGF-
1R inhibitors may become a novel therapeutic strategy, but even identifying the presence of the receptor has
the potential to become a significant prognostic factor in diagnosis .
[54]

In a 2018 study, Hwang et al. evaluated the efficacy of tamoxifen as a therapeutic for luminal A subtype
breast cancer [Table 1] . The authors report that luminal A subtype showed a higher survival rate
[55]
[55]
compared to TNBC (P = 0.009) . Androgen receptor (AR), while not commonly noted, is frequently
expressed in luminal A and B subtypes of breast cancer and thus may be a potential therapeutic target. In
their study, Bergen et al. evaluated AR expression within the tumor-cell nucleus by performing
immunohistochemical staining of AR on brain metastases samples from patients with breast cancer
(n = 57) . They report that AR expression ≥ 1% was evident in 35.1% of samples and the median AR
[56]
expression rate was 10%. AR expression in ≥ 1% of tumor cells was observed in 52.4% of brain metastases of
the luminal/HER2-negative subtype and 23.1% of the luminal/HER2-positive subtype. This suggests that
there is potential for the development of future therapeutics that target AR expression in luminal type
cancers.

Nanotechnology
A prevailing obstacle in the development of therapeutics targeting brain metastases is the inability of drugs
to cross the BBB. As such, any potential drug targeting brain metastases must be BBB permeable. One of the
newest strategies for the treatment of all types of metastases originating from breast cancer is using a nano-
sized drug delivery system. Some newly investigated nano-drugs include: the PEGylated nano-liposomal
doxorubicin; the non-pegylated liposomal doxorubicin; albumin-bound paclitaxel; and a polymeric