Ability to metabolize tamoxifen affects outcome in patients with breast cancer

Genetic differences in the liver enzyme CYP2D6 play a key role in how well tamoxifen works. This was confirmed by a recent study examining breast cancer recurrence and deaths and comparing these to test results of liver enzyme efficiency.

For nearly a decade, breast cancer researchers have been divided about if genetic differences in CYP2D6 impact the effectiveness of tamoxifen and the likelihood of the breast cancer recurring. This clinical trial studied the rates of cancer recurrence and death in two groups: postmenopausal women with primary estrogen receptor-positive breast cancer who received tamoxifen for 5 years and those who received tamoxifen for 2 years followed by anastrozole for 3 years. Metabolism of the aromatase inhibitor anastrozole does not require the CYP2D6 enzyme.

The study showed that women who were born with genetic alterations of CYP2D6 that abolish the enzyme's critical metabolizing activity and who took tamoxifen for 5 years had recurrence of breast cancer, or died at a rate 2.5 times higher than women with normal CYP2D6 enzyme activity. Women with intermediate levels of the CYP2D6 enzyme had rates of recurrence or death 1.7 times higher than women with normal CYP2D6 activity. Importantly, noted Matthew Goetz, MD, of the Mayo Clinic, genetic alterations in CYP2D6 did not affect the likelihood of recurrence or death in women who switched to anastrozole after 2 years of tamoxifen.

“Our findings confirm that, in early breast cancer treated with tamoxifen, genetic alterations in CYP2D6 lead to a higher likelihood of recurrence and death,” said Goetz.

“Switching from tamoxifen to an aromatase inhibitor may be one reason for the discrepant studies surrounding CYP2D6 and tamoxifen—as information about whether a patient took an aromatase inhibitor after tamoxifen was not available in most of the prior studies,” said James Ingle, MD, of Mayo Clinic, an expert on hormone therapies for breast cancer.

A blood test can determine whether a woman has alterations in CYP2D6 and predict how efficiently her body will convert tamoxifen to endoxifen. Approximately 5% to 7% of European and North American populations are considered poor metabolizers of tamoxifen.

If a woman is unable to effectively metabolize tamoxifen into its most active form, Goetz believes that the current recommendation of switching from tamoxifen to an aromatase inhibitor is likely to result in the greatest benefit in women with decreased CYP2D6 metabolism.  For CYP2D6 poor metabolizers, avoiding tamoxifen altogether and starting out with an aromatase inhibitor may be the best approach, he said.

This study was published in Clinical Cancer Research (2012; doi:10.1158/1078-0432.CCR-12-2153).

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