Research on Tamoxifen Leads to Recommendation for CYP2D6 Gene Test

Findings from a new study have prompted Mayo Clinic researchers to recommend CYP2D6 gene testing for postmenopausal women about to begin tamoxifen therapy. This data confirms that women with an inherited deficiency in the CYP2D6 gene, which is important for the metabolism of tamoxifen, have a nearly fourfold higher risk of early breast cancer recurrence compared to women who have not inherited the deficiency. The research findings, announced jointly by investigators from Mayo Clinic and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) confirmed results from a previous study conducted by Mayo Clinic.

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The latest findings will be presented today at the Cancer Therapy & Research Center-American Association for Cancer Research (CTRC-AACR) 31st annual San Antonio Breast Cancer Symposium.

Tamoxifen, approved by the Food and Drug Administration (FDA) to both prevent development of estrogen-receptor-positive (ER+) breast cancer and as a therapy to stop ER+ breast cancer from coming back, is a “pro-drug”; it must be metabolized in the liver to become active.

Mayo researchers had previously discovered that the drug is less effective in postmenopausal breast cancer patients who had a deficiency in the CYP2D6 gene, which is key for activating tamoxifen and many other drugs. However, until now, testing for the gene has not been done routinely at most medical centers.

“These new results validate our earlier findings,” says the study’s lead investigator, Matthew Goetz, M.D., an assistant professor of oncology and pharmacology at Mayo Clinic, “and strongly suggest that going forward, postmenopausal patients being considered for tamoxifen therapy should be tested for CYP2D6 before beginning therapy.”

The research teams examined DNA from a subset of postmenopausal women treated in the ABCSG-8 study, which previously randomized nearly 3,900 women whose ER+ breast cancer had been surgically treated. One group was randomized to five years of tamoxifen therapy, and the other randomized to tamoxifen for two years followed by three years of anastrozole, an aromatase inhibitor. The initial results of ABCSG-8, reported in 2005, concluded that women who switched to anastrozole had a 40 percent reduced risk of breast cancer recurrence compared to staying on tamoxifen.

The aim of the new study was to determine whether CYP2D6 genetic variation would identify a subgroup of patients at higher risk of recurrence within the context of the ABCSG-8 trial. “Among the patients randomized to tamoxifen, poor metabolizers had a 3.8-fold increase in risk of developing breast cancer recurrence than extensive metabolizers across the five-year span,” said Michael Gnant, M.D., professor of Surgery at the Medical University of Vienna, Austria, and president of ABCSG. “That is the key message coming out of this great collaboration between the Mayo Clinic team and the Austrian Breast and Colorectal Cancer Study Group.”