Aug. 4, 2008 Lapatinib reduces the number of large brain metastases in a mouse model of metastatic breast cancer, relative to untreated mice, researchers report in the July 29 online issue of the Journal of the National Cancer Institute.
Symptomatic brain metastases affect between 10 and 20 percent of women with metastatic breast cancer, and the problem is particularly common for women whose tumors overexpress the HER2 protein. However, trastuzumab, an antibody that blocks the HER2 protein activity and is the standard of care for HER2-positive disease, does not cross the blood–brain barrier. Therefore, other therapies are needed to reduce the brain metastases in patients with HER2-positive disease. Lapatinib, a small-molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR), is able to cross the blood–brain barrier.
In the current study, Patricia Steeg, Ph.D., of the National Cancer Institute and colleagues injected mice with a breast cancer cell line that preferentially gives rise to metastases in the brain, called MDA-MB-231-BR. The researchers engineered some of the cells to overexpress the HER2 protein. Five days after the mice were injected with the cancer cells, the researchers started treating them with lapatinib or a placebo. After 24 days of therapy, the investigators measured and counted brain metastases.
Among mice injected with the HER2-overexpressing cells, those treated with lapatinib developed fewer than half of the large metastases as those that did not receive the drug. A similar reduction occurred among mice injected with the unmodified cells, although a higher dose of lapatinib was required. Lapatinib did not completely prevent the formation of brain metastases, suggesting that some of the tumor cells are resistant to the drug.
"We propose a scenario in which standard treatments such as neurosurgery and stereotactic radiosurgery are used to treat clinical metastases and currently unavailable molecular therapeutics are then used to hold the remaining micrometastases in check. One possible molecular therapeutic is lapatinib, a dual inhibitor of EGFR and HER2 kinases," the authors write.
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