The Correlation between HER-2
Status and Brain Metastases in
with Metastatic Breast Cancer
Ka-Kiu Claire Fung
Literature Review: Biochemistry/ Molecular Biology Project
Dr J A Smith
C a n d i d a t e
N u m b e r :
2 0 7 7
Ka-Kiu Claire Fung
It is widely known that patients with HER-2-positive advanced breast cancer are at particularly high risk of developing brain metastases, especially if patients have been managed with trastuzumab-based treatments. However, the biologic reason for this is not fully understood.
Currently, there are three hypotheses that explain this. Firstly, the basic biologic role of the HER-2 receptors is considered. Excess HER-2 receptors over-activate the PI3K/Akt and MAPK pathway, leading to an inhibition of apoptosis and depression of regulatory proteins of the cell cycle respectively. Coupled with other survivalpromoting factors such as the secretion of basement membrane degradative enzymes, the formation of invadopodia to assist in cell migration and the promotion of angiogenesis via VEGF, overexpression of HER-2 leads to a more aggressive, more invasive type of cancer.
Secondly, trastuzumab does not come into contact with brain metastases, as its molecular weight is too large to allow it to cross the blood brain barrier. Lastly, trastuzumab is very effective in prolonging the life of HER-2-positive breast cancer patients. Since brain metastases are considered a late manifestation of the disease, it may be safe to assume that the correlation between trastuzumab and brain metastases is due to the fact that patients merely live long enough for the central nervous system involvement to become apparent.
Currently, the development of treatment targeted to brain metastases from the breast is focusing on drugs that can cross the blood brain barrier, or different ways to administer trastuzumab that would guarantee its contact with the tumours. However, the lack of HER-2 receptors in brain metastases have been postulated, deeming the latter redundant. Lapatinib has shown promising results at preventing the appearance of brain metastases. It is currently undergoing clinical evaluation for its use for such patients.
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Ka-Kiu Claire Fung
Presently, breast cancer is hypothesized as one of the most common causes of metastases to in the central nervous system (CNS), second only to lung cancer1. Furthermore, a higher incidence is found in HER-2-positive metastatic breast cancer (HER-2+ MBC). CNS metastases occur in around 18% of MBC patients, however autopsy studies suggest that around 25% of all MBC patients develop brain metastases (BM)1. A number of previous investigations have also noted an even higher incidence rate (around 30%) in patients who have received trastuzumabbased treatment for HER-2 overexpressing MBC2. Trastuzumab is a humanized monoclonal antibody directed against the HER-2/neu oncoprotein. Encoded by the Her-2/neu proto-oncogene, it is overexpressed in 2530% of all human breast carcinomas3. The HER family receptors are responsible for monitoring appropriate cell growth, proliferation and survival, and an overexpression of the HER-2 protein would lead to uncontrolled cell growth. This is reported as a key pathway to aggressive tumorigenic action of HER-2 overexpressing cells4. Trastuzumab is used as a first and second line treatment in 50% of HER-2+ MBC patients5, bringing the percentage of patients alive and disease free four years after diagnosis up to 85% from 67%6. It is also used in conjunction with either anthracycline or taxane based chemotherapy as a first-line treatment, which has led to a 33% fall in the risk of mortality6.
Little is published about the pharmacology of trastuzumab, but it is understood that it is not capable of penetrating the blood brain barrier (BBB) due to its...
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