HER2-Positive Breast Cancer-Current Treatment Management and New Therapeutic Methods for Brain Metastasis

Abstract

Background: Breast cancer can be classified based on the immunohistochemistry (IHC) phenotypes, defined by the presence or absence of the main IHC markers. IHC phenotyping is important as it determines the prognosis and guides treatment. For example, human epidermal growth factor receptor 2 (HER2) overexpression, which triggers cell growth and division, is observed in HER2-positive breast cancer. Methods: The standard treatment is based on trastuzumab plus pertuzumab in combination with taxane chemotherapy. The possibility of developing metastases depends on those phenotypes. Approximately 25-50% of patients with HER2-positive breast cancer experience brain metastases. This aspect is especially important, as 20% of those patients die as a result. Results: Through the years, many advanced therapies have been introduced to treat brain metastases, including whole brain radiotherapy, stereotactic radiosurgery, and a tyrosine kinase inhibitor (TKI), neratinib. Nonetheless, this still remains a therapeutic challenge. Conclusions: In this review, we focus on the treatment and efficiency of therapies targeting HER2-positive breast cancer, mainly concentrating on the current and newly developed treatment options for brain metastases, such as trastuzumab deruxtecan and tucatinib.

Keywords: CNS; HER2-positive breast cancer; brain metastasis; metastatic breast cancer; trastuzumab; trastuzumab emtansine.

Figure 1

Mechanism of HER2 signaling. This figure represents the signaling pathway leading to cancer cell survival and proliferation. Breast cancer is one of three cancers with the highest incidence of PIK3CA mutations. PTEN negatively regulates the PI3K cascade, inhibiting cell proliferation. HER2 receptors also interact with PUMA, resulting in its degradation and survival of the cancer cell. Abbreviations: RTK—receptor tyrosine kinase; PI3K—phosphoinositide 3-kinase; p85/p110—subunits of PI3K; PIP3—phosphatidylinositol (3,4,5)-trisphosphate; PIP2—phosphatidylinositol 4,5-bisphosphate; Akt—protein kinase B; mTORC2—mTOR complex 2; PDK1—3-phosphoinositide dependent protein kinase-1; PUMA—p53-upregulated modulator of apoptosis; TSC2—tuberous sclerosis complex 2; TSC1—tuberous sclerosis complex 1; ERBB2—human epidermal growth factor receptor 2; PIK3CA—phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN—phosphatase and tensin homolog deleted on chromosome ten.

Figure 2

The process of brain metastasis development. This figure represents the process of brain metastasis development in HER+ BC. The BBB in the process of vascular remodeling turns into a porous BTB, supporting micrometastases development. Micrometastases eventually occupy the brain. Abbreviations: BBB—blood–brain barrier; BTB—blood–tumor barrier; HR—hormone receptor; HER2+ BC—HER2-positive breast cancer, ZO-1—zonula occludens-1; MMP—matrix metalloproteinases; VEGF—Vascular Endothelial Growth Factor; COX-2—cyclooxygenase-2; HBMEC—human brain microvascular endothelial cells; ST6GALNAC5—a2,6-sialyltransferase.