"Lapatinib was tested in a human clinical study of brain metastases and showed only modest results," said Steeg. "However, we asked a different question. Rather than asking lapatinib to melt a golf ball-sized metastasis in the brain, we asked if it would be more effective at preventing micrometastases, or small, undetectable metastases, from growing into large metastatic tumors."

To explore the effects of lapatinib on micrometastases, the research team injected human breast cancer cells that overexpressed EGFR only, or overexpressed both EGFR and HER2, into mice. Five days later, lapatinib or a placebo solution was administered twice daily for 24 days. When the researchers examined the mouse brains for metastatic breast cancer tumors, they found that lapatinib reduced the development of large brain metastases by 50 percent or more compared to the placebo solution and that it also hit one of its targets - it reduced the activation of HER2.


To gain a better understanding of how lapatinib was working, researchers investigated its effects on breast cancer cells in the lab. They found that breast cancer cells that expressed more of the targeted receptors had greater sensitivity to the drug. Those that expressed high levels of both EGFR and HER2 were approximately 30 percent more sensitive to the growth inhibition effects of lapatinib than cells that expressed high levels of only one of these receptors. However, cells that only expressed EGFR or HER2 were equally sensitive to the drug. The researchers also found that lapatinib inhibited activation of the EGFR and HER2 proteins, as well as of proteins that are involved in cell signaling pathways that regulate gene expression, cell division, and cell survival - and which, ultimately, may contribute to the development of cancer.

"These findings indicate that lapatinib may be beneficial in the treatment of patients with HER2-positive breast cancer who may have micrometastases and are thus at risk for the development of brain metastases," said Steeg. Having completed their studies in the lab and in mice, the researchers await the results of ongoing clinical trials of lapatinib where it is given in addition to the primary therapy, such as the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation study, or ALTTO trial, which opened in 2008. This study was funded by NCI and the Department of Defense Breast Cancer Research Program.

For more information on Dr. Steeg's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5851.

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