Endoxifen shows promise as breast cancer treatment

Vol. 3, Issue 1, 2014


New drug may offer some women an alternative to tamoxifen.

Photograph showing Matthew P. Goetz, M.D., a Mayo Clinic Cancer Center oncologist

Matthew P. Goetz, M.D.

Researchers at the Mayo Clinic Cancer Center are developing a new drug to help women with estrogen receptor positive breast cancer who are unable to derive benefit from the drug tamoxifen. These women need an alternative to tamoxifen because their bodies are unable to effectively metabolize the drug to its active agent, endoxifen.

Tamoxifen is a hormone therapy that has been used for more than 40 years to reduce the risk of breast cancer and to prevent recurrence. However, research has demonstrated that patients with very low levels of a critical enzyme called CYP2D6 and those with low endoxifen levels have a higher risk of recurrence or progression when treated with tamoxifen.

In a recent phase I clinical trial of endoxifen, an active metabolite of tamoxifen, researchers found that the experimental drug is safe and that it showed early evidence for anti-tumor activity.

"We achieved up to sixtyfold higher levels of endoxifen compared with endoxifen levels achieved with the standard dose of tamoxifen," said Matthew P. Goetz, M.D., a Mayo Clinic Cancer Center oncologist who led the research. "We have seen evidence for tumor regression in patients who had failed standard hormonal therapies, including aromatase inhibitors, fulvestrant and tamoxifen."

In 2008, Dr. Goetz and Mayo Clinic pharmacology professor Matthew M. Ames, Ph.D., began to collaborate with the National Cancer Institute (NCI) to develop formulations of endoxifen. One formulation, known as Z-endoxifen hydrochloride (endoxifen), was tested through preclinical pharmacology studies, toxicology workups and, most recently, clinical trials conducted at the Mayo Clinic Cancer Center and the NCI.

In the phase I study, researchers gave endoxifen once daily to 22 women with estrogen receptor positive breast cancer that was resistant to standard hormone therapies. The drug appeared to be safe even at the highest dose of 160 milligrams a day.

Dr. Goetz and his colleagues are now working to determine the optimal dose of endoxifen for breast cancer patients. After that work is complete, he would like to see the drug studied in premenopausal patients, for whom tamoxifen is the only Food and Drug Administration-approved hormone agent for the treatment of estrogen receptor positive breast cancer.

"Endoxifen may turn out to be a better drug than tamoxifen," Dr. Goetz said, "and not just in patients who have limited CYP2D6 metabolism. This is something that has to be prospectively tested."

Watch a video of Dr. Goetz discussing endoxifen study

Watch a video of Dr. Goetz discussing this study.