Mayo Clinic researchers gave a presentation 12/11/08 at the 31st annual San Antonio Breast Cancer Symposium that further confirms the importance of the liver enzyme CYP2D6 in individualizing tamoxifen dosing in breast cancer patients. Tamoxifen is often prescribed to block the effects of estrogen in breast tissue preventing breast cancer recurrence in ER+ (estrogen receptor positive) cancers which require estrogen to grow and spread. Previous studies have already revealed that tamoxifen is less effective in women with reduced CYP2D6 activity caused by genetic variations or co-administration with medications that inhibit CYP2D6 but the mechanism of action for tamoxifen was not well understood. Tamoxifen is a pro-drug that is metabolized and converted into the metabolites endoxifen and 4HT; both previously believed to play a key role in suppressing estrogen. However the Mayo Clinic study shows that endoxifen degrades estrogen receptors in breast cancer cells and is the key metabolite creating a benefit of tamoxifen. Since CYP2D6 is the enzyme that converts tamoxifen to endoxifen; this new study further indicates that widespread genotyping and medication management can improve outcomes for many of the 35% of ER positive breast cancer patients who currently fail tamoxifen treatment. On October 18 2006 an FDA Advisory Subcommittee was convened to review the tamoxifen research findings to date and to make a recommendation regarding a label change. The consensus of the Subcommittee was that the label should be updated to reflect the fact that postmenopausal candidates for tamoxifen who are CYP2D6 poor metabolizers (by genotype or drug interaction) are at increased risk for breast cancer recurrence. For this reason treatment alternatives would be considered in these patients. The FDA declined to act on the Advisory Committee's recommendation. This label change has still not been made and now the case is even stronger. So what can be done with this information to reduce the risk of breast cancer recurrence? First genotyping should be considered for every ER-positive breast cancer patient taking tamoxifen. Insurance typically covers testing and alternative therapies exist for treatment for the 10% of patients who are CYP2D6 poor metabolizers. Second healthcare providers and patients need to carefully monitor tamoxifen co-administration with other medications herbals and over-the-counters. For example “hot flashes ” a common side effect of tamoxifen are typically treated with selective serotonin reuptake inhibitors and fluoxetine paroxetine and high doses of sertraline are notoriously potent CYP2D6 inhibitors. Additionally 35% of patients are CYP2D6 intermediate metabolizers and are at risk with less potent inhibitors of CYP2D6 such as the commonly used herbal goldenseal as shown in the interaction report below. Genelex is a leading genetic testing company that offers clinical profiling of the CYP2D6 metabolic machinery. They include GeneMedRx drug and gene interaction software with each tamoxifen CYP2D6 test so healthcare providers and patients can quickly see if co-administration is going to reduce CYP2D6 activity. The Mayo Clinic study has further confirmed the critical role of CYP2D6 in tamoxifen treatment. It is time to start putting this research to use in the clinic.