Gene mutation found in some women may decrease effectiveness of tamoxifen breast cancer drug

Jun 7 2004

Researchers from the Johns Hopkins Kimmel Cancer Center, Indiana University and the University of Michigan have found that some women have a gene mutation that may decrease the effectiveness of tamoxifen, a commonly used breast cancer drug. The findings, to be reported at the 40th annual meeting of the American Society of Clinical Oncology on June 5, may tell physicians which women might have reduced benefit from tamoxifen therapy. Results also suggest that some frequently prescribed antidepressants may reduce tamoxifen's effects because the antidepressants affect a similar metabolic pathway.

Although a test for the mutation in the CYP2D6 gene is not widely available, the investigators recommend that women currently on long-term tamoxifen therapy and using such antidepressants as paroxetine and sertraline consult their health care provider for guidance. These drugs, known as selective serotonin reuptake inhibitors (SSRIs) include such well-known brands as Paxil and Zoloft. The investigators estimate the prevalence of the CYP2D6 mutation to be approximately 40 percent, and in this study of 80 women, 35 percent had the mutation.

"There's no evidence from this study that a woman who is taking tamoxifen should automatically stop using a particular antidepressant if it is helping her," says Vered Stearns, M.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center. But the researchers advise that women on tamoxifen who are considering antidepressant therapy, may opt to use an antidepressant, such as venlafaxine, which may not alter tamoxifen's metabolism and has less of an effect on tamoxifen.

"Our findings are leading us in the direction of recommending therapies based on an individual's genetic profile," says Stearns. "If a woman has a particular gene mutation, we may be able to predict how she'll react to a therapy."

Tamoxifen is widely prescribed to reduce the risk of breast cancer recurrence or spread and increasingly is given in efforts to prevent breast cancer in women at high risk for the disease.

The CYP2D6 gene controls production of an enzyme that breaks down and processes tamoxifen. Mutations in the gene reduce the enzyme's ability to properly break down tamoxifen.

The women in the study had taken tamoxifen daily for four months. Analysis of blood levels of a newly characterized byproduct, called endoxifen, were approximately 75 percent lower in women with a CYP2D6 mutation in both copies of the gene. The lower levels of endoxifen suggest that mutation alters the metabolism of tamoxifen and may affect potency of the drug.

"At this point, we do not know precisely what lower levels of endoxifen signify, or if other byproducts of tamoxifen metabolism are equally or more important to measure for monitoring tamoxifen's effectiveness," cautions Stearns.

The investigators also found lower endoxifen levels in women taking antidepressant drugs regardless of whether or not they had a CYP2D6 gene mutation. Certain antidepressant drugs, such as paroxetine and sertraline, are known to block the CYP2D6 enzyme. Antidepressants are being prescribed in up to 20 percent of breast cancer patients for depression, anxiety, other psychiatric disorders or hot flashes, a common side effect of tamoxifen.

In upcoming studies, the investigators will compare antidepressant therapies in women taking tamoxifen and how gene variations in the estrogen receptors of breast cancer patients may impact the effectiveness of tamoxifen.

This research was funded by the National Institutes of Health (NIH/NIGMS).

Additional participants in this research were Yan Jin, Bryan Ward, Todd Skaar, Anna Maria Storniolo, Anne Nguyen, Zeruesenay Desta and David A. Flockhard from Indiana University School of Medicine; and Linda Ullmer, Jill Hayden and Daniel F. Hayes from the University of Michigan.