Approximately half a million women in the United States alone currently take the drug tamoxifen, either as an adjuvant therapy for preinvasive or invasive breast cancer, or as a chemopreventive agent for those at high risk of the disease.

Now, a new study led by Dr. Matthew Goetz, an investigator for the Breast Cancer Specialized Program of Research Excellence (SPORE) at the Mayo Clinic, has shown that up to 10 percent of women taking the drug may not receive the intended benefit due to genetic differences in the way tamoxifen is metabolized. Additionally, a larger percentage of women may be at increased risk of treatment failure because of drug interactions.

Both genetic polymorphisms and many commonly administered drugs - such as selective serotonin reuptake inhibitors - can affect the activity of an enzyme called cytochrome (CYP) 2D6. Dr. David Flockhart's group, which is funded by the National Institute of General Medical Science's Pharmacogenetics Research Network, has performed extensive basic science work and early clinical studies demonstrating that CYP2D6 activates tamoxifen, producing a molecule called endoxifen, which is thought to be the metabolite primarily responsible for tamoxifen's therapeutic effect.

"Basic science has told us for the past 30 years that this enzyme is genetically polymorphic, and we expected people with the polymorphisms to make about five times less of the active metabolite," explained Dr. Flockhart, chief of the Division of Clinical Pharmacology at Indiana University and a collaborator on the SPORE project.

The SPORE data used to test this hypothesis came from a prospective randomized trial conducted by the North Central Cancer Treatment Group, in which postmenopausal women were administered 5 years of tamoxifen therapy for estrogen-receptor-positive breast cancer. Both CYP2D6 genotype and medications that interfere with CYP2D6 were known for 180 women randomly assigned to the tamoxifen-only control arm of the trial.

Researchers classified 65 of these women as having decreased metabolism of tamoxifen based on expected genetic or drug-induced inhibition of CYP2D6. The SPORE investigators then compared time to breast cancer recurrence, disease-free survival, and overall survival between those with decreased CYP2D6 metabolism and the 115 patients expected to metabolize tamoxifen normally.

The clinical benefit of tamoxifen was greatly decreased for women with factors that negatively affected CYP2D6 metabolism. These women had significantly shorter time to disease recurrence and significantly worse disease-free survival compared with women able to metabolize the drug normally. Women with the largest decrease in CYP2D6 metabolism (CYP2D6 poor metabolizers or those taking a potent CYP2D6 inhibitor) had a threefold higher risk of breast cancer recurrence while taking tamoxifen. The final results from this study, which was also funded by a K-12 training grant to Dr. Goetz, were published online November 18 in Breast Cancer Research and Treatment.

On October 18, a presentation of this study and related historical data by Dr. Goetz to the Food and Drug Administration led to an advisory committee unanimously recommending a label change for tamoxifen. This change would include information about the increased risk both from genetic factors and drug interactions affecting CYP2D6. The majority of the committee also recommended that the label mention CYP2D6 genotype testing as an option for women before they are prescribed tamoxifen.

"The promise of pharmacogenetics is the ability to individualize therapy for our patients," said Dr. Goetz. "In the case of tamoxifen, CYP2D6 may be a marker which identifies patients who can be successfully treated with sequential tamoxifen followed by an aromatase inhibitor or who should be treated up front with an aromatase inhibitor."

By Sharon Reynolds