How Important Is CYP2D6 Status in Hormone-Sensitive Cancers?

The hormonal drug tamoxifen has been a staple in breast cancer therapy for decades.

Even so, one in three women with hormone-sensitive, early-stage tumors who take tamoxifen will likely see their disease return within 15 years after initial treatment.

In recent years, scientists discovered that an enzyme called CYP2D6 could possibly predict whether a patient would respond to the drug. Small studies aimed at confirming the predictive link, however, have been consistently inconsistent.

But on Thursday at the San Antonio Breast Cancer Symposium, researchers presented findings from two large studies that found no relationship between CYP2D6 and risk of recurrence in postmenopausal women with early-stage, estrogen receptor-positive breast cancer. Calling the results “definitive,” Brian Leyland-Jones, MD, PhD, lead researcher on one of the studies, said CYP2D6 plays no role in the effectiveness of tamoxifen.

Tamoxifen itself doesn’t fight cancer. It must first be converted, or “metabolized,” into an active metabolite called endoxifen. CYP2D6 facilitates that crucial switch. For women with an inherited deficiency in the CYP2D6 gene, as well as those taking a medication that interferes with CYP2D6 function, the hypothesis was that tamoxifen wouldn’t work in these so-called poor metabolizers.

Leyland-Jones’s study looked at CYP2D6 status in roughly 1,000 women who received tamoxifen alone in BIG 1-98, a trial comparing tamoxifen with the aromatase inhibitor Femara (letrozole). A second study analyzed CYP2D6 in nearly 600 tamoxifen recipients who took part in the ATAC trial testing tamoxifen versus another aromatase inhibitor called Arimidex (anastrozole). Poor metabolizers of CYP2D6 didn’t fare any worse than extensive metabolizers, the studies found.

The BIG 1-98 analysis also examined whether CYP2D6 status had any correlation with hot flashes (also called hot flushes), a common side effect of tamoxifen. Research has suggested that women who do not experience hot flashes may not be getting the full benefit of tamoxifen because their bodies do not metabolize the drug sufficiently. “It’s been one of these debating points for four or five years,” said Leyland-Jones, a professor at Emory School of Medicine in Atlanta.

When Leyland-Jones and his co-investigators looked for an association, they found that reduced activity of CYP2D6 did not result in decreased hot flashes. “The presence or absence of hot flushes should not be used as an indicator of tamoxifen efficacy, as it sometimes has been done in the past,” Leyland-Jones said. The findings, however, did not control for possible use of drugs to treat hot flashes, such as certain antidepressants.

With previous studies offering little direction on the utility of CYP2D6, James Rae, PhD, admits he was “one of these people sitting on the fence.” But as lead investigator of the ATAC study analysis, “I think clearly what the data are showing is that it’s not 2D6 alone,” said Rae, an assistant professor of internal medicine at the University of Michigan.