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.

That’s not to say CYP2D6 enzyme activity plays no role, said Matthew Goetz, MD, a breast oncologist and researcher at the Mayo Clinic in Minnesota. “It’s probably a number of different factors,” said Goetz, who was not involved in the studies. Leyland-Jones and his team are now looking at six or seven other markers in the BIG 1-98 participants to see whether they make any difference in tamoxifen’s effectiveness.

Both studies presented in San Antonio looked only at postmenopausal women with early-stage disease, so the possible influence of CYP2D6 activity in premenopausal patients or in those with metastatic disease remains unknown, although research is ongoing.

Based on these newest findings, experts agree CYP2D6 gene testing doesn’t belong in the cancer clinic. “The party line is no, we do not believe that the data are sufficient to recommend testing to determine whether or not a patient should take tamoxifen. … [But] I think everybody should be tested for 2D6 because it does help in determining which medications patients should take or avoid.”

Rae said one in four clinically used drugs are metabolized by CYP2D6, so knowing CYP2D6 status would mean knowing a drug such as codeine won’t stop the pain if you’re a poor metabolizer. Or for an extensive metabolizer, the side effects of the cough suppressant dextromethorphan may be worse than the cold itself.

Goetz said these new findings mean he won’t be recommending routine CYP2D6 testing to his patients. But if a patient was previously tested for another reason and knows they’re a poor metabolizer, “

Despite his recommendation at the San Antonio meeting two years ago that postmenopausal women considering tamoxifen should be tested for CYP2D6,I would probably use that information to help guide how I manage that patient.” Goetz notes, however, that since aromatase inhibitors have proven superior to tamoxifen in postmenopausal women, this scenario would only come into play for women not able to take one of those drugs.

Whether CYP2D6 status is known or not, experts agree patients should not take drugs known to inhibit the activity of the enzyme. Relief from depression or hot flashes should come from drugs that have little or no effect on CYP2D6, for instance, Zoloft (sertraline) and Effexor (venlafaxine),instead of potent CYP2D6 inhibitors such as Prozac (fluoxetine) and Paxil (paroxetine).

“The recommendation there is to avoid inhibitors, not so much because of the influence on tamoxifen response but just because you wind up potentially running into trouble with a number of other drugs,” said Rae. Even so, Rae and his co-investigators looked at other medications patients were taking in the ATAC trial while on tamoxifen therapy. Among the small number of women taking drugs that inhibit CYP2D6, they again observed no effect on response to treatment. Details of concomitant medication were unavailable in the BIG 1-98 study.

Considering that tamoxifen must be converted into the active agent endoxifen in order to treat breast cancer, scientists are now developing endoxifen as a drug. In collaboration with the National Cancer Institute, Goetz and his colleagues will move the agent into clinical testing next year in women with breast cancer. Jina Pharmaceuticals is also developing endoxifen.

Hidden in the CYP2D6 story may be a simple fix: take tamoxifen as prescribed. Women who extensively metabolize tamoxifen sometimes stop taking it because of severe side effects, such as hot flashes.

“If you’re a poor metabolizer and you take tamoxifen for five years, you’re going to get more benefit than an extensive metabolizer who stops taking the drug after six months due to side effects,” said Rae. “The most important thing, and actually more than knowing your 2D6 genotype, is to take your drug as recommended.”