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Test for Tamoxifen Effectiveness Falls Short

January 31, 2010

Written By Michael J. Formica, MS, MA, EdM
Reviewed By Richard A. Michaelson, MD

Results from two studies presented at the San Antonio Breast Cancer Symposium show no association between CYP2D6 levels and tamoxifen effectiveness in postmenopausal women.

One study looked directly at whether the enzyme CYP2D6 predicts the effectiveness of the hormonal therapy tamoxifen in preventing breast cancer recurrence. The second study focused on the relationship of hormonal therapies to recurrence, and considered the link between CYP2D6 and tamoxifen as part of that investigation.

The Reason for the Study

Tamoxifen, a common cancer treatment, blocks estrogen from stimulating breast cells. When tamoxifen is metabolized, or absorbed into your body, it is changed at a certain point into another substance called endoxifen, a powerful anti-estrogen agent that is active in killing cancer cells. This change is called bioactivation. CYP2D6 is one enzyme that converts tamoxifen to endoxifen in that process.

When tamoxifen is converted into endoxifen, there is a double benefit, because tamoxifen and endoxifen work together. A small number of people have a mutation, or misspelling of the gene that makes CYP2D6. These women metabolize tamoxifen in a different way that does not include producing endoxifen.

Previous studies suggested that postmenopausal women with very low levels of the CYP2D6 enzyme do not benefit as much from tamoxifen, because the way these women metabolize tamoxifen does not produce endoxifen. However, study findings were inconclusive. Researchers, seeking to address this question, thought that by measuring CYP2D6 levels before women began taking tamoxifen and tracking rates of recurrence, they could predict the effectiveness of the medicine.

First Study Overview

The first study, Arimidex, Tamoxifen Alone or in Combination (ATAC), compared the differences in rates of recurrence, rates of local recurrence and rates of contralateral cancer—cancer that recurs in the opposite, healthy breast—in postmenopausal women.

Participants were randomly separated into three groups, and those groups were each divided into three categories based on their absorption of endoxifen—poor metabolizers of CYP2D6, intermediate metabolizers and extended or “super” metabolizers. One group was given anastrozole (Arimidex) along with a placebo, or sugar pill. The second group was given tamoxifen, along with a placebo, and the third group was given anastrozole and tamoxifen together. Anastrozole, an aromatase inhibitor, was chosen as a comparison medicine because aromatase inhibitors, which block the production of estrogen in postmenopausal women, are not metabolized by the enzyme CYP2D6.

This study found no measurable difference in the predictability of recurrence among any of the groups, no matter what the CYP2D6 category. This suggests no relationship between CYP2D6 levels and absorption of endoxifen. Researchers concluded that there was insufficient evidence to recommend regularly measuring CYP2D6 levels to predict the effectiveness of tamoxifen.

Second Study Overview

The second study, BIG 1-98, compared the effectiveness of letrozole (Femara) to tamoxifen in controlling recurrence. Because the study was structured the same way as ATAC—using tamoxifen, an aromatase inhibitor (letrozole) and the two in combination—it was another opportunity to look at the relationship between CYP2D6 levels and the effectiveness of tamoxifen.

Participants were randomly separated into four groups—those receiving tamoxifen, those receiving letrozole, and those receiving the two medicines together, in different order—first one, then the other. When these four groups were each divided into the three categories of poor metabolizers of CYP2D6, intermediate and extended metabolizers, researchers found no difference in the effect of tamoxifen for controlling recurrence in those categories.

What Does This Mean for Me?

While the results of these studies do not resolve the controversy prompted by earlier research, they raise serious doubts about the usefulness of CYP2D6 tests to measure the potential effectiveness of tamoxifen, said lead investigator Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minnesota.

Although most researchers do not recommended regular CYP2D6 testing for postmenopausal women with breast cancer, your doctor may or may not order the test for you. If your doctor suggests the test, or you have already had it, you may want to ask how the findings may influence your doctor’s recommendation for treatment.