MANY PEOPLE with early-stage hormone receptor-positive breast cancer receive maintenance tamoxifen after surgery to reduce their risk of cancer coming back. This hormone therapy, which is usually taken for five to 10 years, works by blocking estrogen receptors on cells so that estrogen cannot bind to cancer cells and spur their growth.

But tamoxifen itself binds only weakly to estrogen receptors. The drug becomes active after the liver converts tamoxifen into another molecule called endoxifen, which binds estrogen receptors more tightly than tamoxifen. The protein that converts tamoxifen into endoxifen is called cytochrome P450 2D6, or CYP2D6 (pronounced “sip-two-dee-six”).

A meta-analysis published Feb. 6, 2025, in Cancer Epidemiology, Biomarkers & Prevention, shows that women with breast cancer who were treated with tamoxifen and had less metabolically active CYP2D6 protein had an increased risk of poorer treatment outcomes than those with normal CYP2D6 activity. In the study, which looked at 33 clinical trials and grouped patients according to their CYP2D6 status, poor CYP2D6 metabolism was associated with a 28% increased risk of recurrence or death compared with normal CYP2D6 metabolism.

Looking at the results of the study, “you can see that patients who have lower or less CYP2D6 activity do seem to have worse outcomes from tamoxifen treatment,” says Daniel Hertz, a clinical pharmacologist at the University of Michigan College of Pharmacy, who was not involved in the research. “This association has been long speculated and has been extremely challenging to validate in clinical studies,” he adds.

The Research on CYP2D6 and Endoxifen

There are more than 100 different variants of the CYP2D6 gene, which provides the genetic blueprint for the protein that metabolizes tamoxifen and many other drugs. The versions of the CYP2D6 gene that patients inherit—their CYP2D6 genotype—influence how actively the CYP2D6 protein metabolizes drugs. Pharmacogenomic testing, which analyzes a person’s genes to predict response to medications, can identify these genetic variants. Based on these tests, patients can be classified as poor, intermediate, normal or ultrarapid metabolizers.

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Studies show that people taking tamoxifen who have lower CYP2D6 activity generally have lower levels of endoxifen in their bloodstream, but research findings have been mixed on whether poor CYP2D6 activity is associated with poorer breast cancer outcomes for people taking tamoxifen—with some studies showing an increased risk of cancer recurrence and others showing no effect.

These mixed findings may be due to the design of previous studies that incompletely characterized the CYP2D6 genotype, according to Matthias Schwab, a clinical pharmacologist and director of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, Germany, who co-authored an commentary about the meta-analysis but was not involved in the research. Some studies, for example, may misclassify CYP2D6 status because they only factor in a few CYP2D6 variants, he says. In addition, some studies have used DNA collected from patients’ tumors to determine CYP2D6 genotypes, Schwab says. DNA from a person’s tumor often contains genetic changes that are not present in the rest of the body. By contrast, Schwab notes that germline DNA—which a person inherits and is carried in all the body’s cells—could provide a more accurate measure of CYP2D6 activity, especially since tamoxifen is metabolized in the liver.

After the authors of the meta-analysis adjusted for these factors, the difference in the risk of death or recurrence between poor metabolizers and normal metabolizers widened from 28% to 34%.

To Genotype or Not

Schwab, who is a co-author of a Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline that helps clinicians interpret patients’ CYP2D6 genetic test results when prescribing tamoxifen treatment, says he believes people can benefit from CYP2D6 testing if their doctors are considering tamoxifen. The CPIC guideline notes that clinicians can opt for a higher dose of tamoxifen or for another therapy, such as an aromatase inhibitor, if patients have lower CYP2D6 metabolism

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However, people with breast cancer do not routinely receive CYP2D6 testing in the U.S., Schwab says. The Food and Drug Administration, which approves drugs in the U.S., and professional organizations, such as the National Comprehensive Cancer Network, do not recommend CYP2D6 testing for patients who are receiving tamoxifen. Insurance companies typically do not cover the costs, he explains.

Hertz does not recommend routine CYP2D6 genotyping for most patients, noting that poor metabolizers make up a minority of the people who receive a breast cancer diagnosis. Globally, about 6% or fewer people have poor metabolizer status. He notes he would use CPIC guidance if patients had already received pharmacogenetic testing and knew their CYP2D6 status.

Maryam Lustberg, a breast medical oncologist at Yale Cancer Center in New Haven, Connecticut, does not recommend CYP2D6 genotyping for her patients receiving tamoxifen, either. “Really, we’ve gotten away from the recommendation of doing any type of genotyping to see if there is variation in enzymatic activity of women taking tamoxifen” due to the inconsistent relationships between CYP2D6 genotype and outcomes observed in different studies, she says.

Lustberg says people with hormone-receptor positive breast cancer would be better served by following the established practices for reducing recurrence risk, including taking hormone therapy consistently and for the duration prescribed. However, Lustberg stresses that patients should make doctors aware of other medications they are taking, since certain antidepressants, such as fluoxetine (Prozac) and paroxetine (Paxil), inhibit CYP2D6 activity and could impair tamoxifen metabolism. 

Ashley P. Taylor is a writer and science journalist based in New York City.

Disclosure: Ashley P. Taylor has previously done some writing for the Yale School of Medicine, which was unrelated to reporting for this article.