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Page 2 of 15 Klaas et al. J Cancer Metastasis Treat 2023;9:23 https://dx.doi.org/10.20517/2394-4722.2022.125

[2]
after lung cancer . Because of early diagnosis and advances in therapy, the survival rate of patients with
[3]
breast cancer has greatly increased, with 5-year relative survival up to 90% . However, the rapidly
increasing medical costs of tests, surgeries, and top-of-the-line treatments can be almost as devastating as
the disease and may be prohibitory in allowing access to the care that is needed for many patients.

Breast cancer is a complex disease that is difficult to treat, especially for patients who are diagnosed with
late-stage or metastasized breast cancer. Up to 30% of women diagnosed with early-stage breast cancer later
develop metastases, and about 10%-15% of patients with late-stage cancer have brain metastases . These
[1]
cases require not only consideration of the primary tumor genetics, but also the microenvironment and
histology of the metastasized tumors. Despite advances in research and understanding of the disease, breast
cancer treatment is still a multifaceted process that may include chemotherapy, immunotherapy, hormonal
therapy, radiation, surgery, or a combination of any or all of them. It is important to first understand the
type of cancer a patient has before choosing the best method of treatment.

Breast cancer is largely organized into five categories: Luminal A, Luminal B, luminal B-like, triple-negative
or basal-like, and human epidermal growth factor receptor 2 enhanced (HER2-positive). More aggressive
forms, like triple-negative and HER2-positive, are more likely to metastasize to other organs, including the
brain. HER2-positive cancers are likely to respond better to chemotherapeutic or targeted pharmaceutical
treatment due to the expressed HER2 protein that can be targeted. Triple-negative cancers do not express
any of the common receptors such as HER2, estrogen receptors, or progesterone receptors. This makes
triple-negative cancers considerably more difficult to treat due to no specific receptor targets that can be
targeted for therapeutic intervention .
[1]
Luminal A cancers are typically regarded as less aggressive with a good prognosis and account for 73% of
breast cancer cases . A characteristic of luminal A cancers is low levels of the Ki-67 protein, indicating a
[2,4]
slower proliferation rate of cancerous cells. Luminal B type cancers, which account for around 11% of cases,
can be notably more aggressive than luminal A cancers. This may be due to a higher proliferation rate of
cancerous cells and increased invasive potential for metastasis . Luminal B has been linked to a worse
[1,4]
prognosis and early recurrence compared to luminal A, potentially due to higher expression of the Ki-67
protein and increased proliferation of cancer cells . Luminal B-like subtype can have any level of Ki-67
[5]
protein expression, with progesterone expression that may be positive or negative, and is HER2-positive .
[1]
These markers indicate poor prognosis when left untreated or diagnosed at advanced disease stages.
However, this subtype has a lower risk of metastasizing outside of the breast tissue, which can provide the
patient with a slightly better prognosis as the disease may take longer to invade other parts of the body. Both
luminal A and B types are estrogen receptor positive, making a prime target for therapeutics . While
[1]
luminal cancers may have independent levels of risk, both triple-negative and HER2+ cancer types are
considered more aggressive than luminal types.

Brain metastases typically originate from malignant cells that reach the brain after traveling via the vascular
system from an aggressive primary tumor in the breast. Like the primary tumors, metastatic breast cancer
brain tumors are typically treated systemically with chemotherapy or hormonal therapy and may include
surgical removal of the tumor(s) [Table 1]. However, because the brain can present obstacles like the blood-
brain barrier, treatment for brain metastases may also include more localized approaches like radiotherapy.
Luminal cancers respond very well to hormonal therapies that target the receptors they express, and
radiation is also commonly used after surgery. However, this could make tumors that metastasize more
difficult to treat because metastases may not express the same receptors as the primary tumor, requiring a
different approach for treatment as the disease progresses .
[1]