How Important Is CYP2D6 Status in Hormone-Sensitive Cancers?

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.

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.

Related Articles
Views on Evolving Chemotherapy Options—and Beyond—in TNBC
Treating patients with triple-negative breast cancer (TNBC) remains a challenge because these tumors do not rely on hormone receptors or HER2 amplification for tumor growth.
Extracting Clues from a Rare Type of Breast Cancer
A detailed tumor profile of molecular and protein alterations in a rare breast cancer subtype called metaplastic breast cancer, was one of the top studies presented at the Miami Breast Cancer Conference this year.
Chemobrain—It’s Real, It’s Complex, and the Science Is Still Evolving
Talk with almost any cancer survivor, and he or she is likely to bring up the topic of “chemobrain,” that fuzzy, murky state that patients blame for impaired memory. A review of the research shows how we're focusing on the problem.
“Cross-Pollination” of Breast Cancer Knowledge was Encouraged at SABCS
While science sometimes moves forward in quantum leaps, it more often advances in small steps, and this year’s San Antonio Breast Cancer Symposium demonstrated both sides of that coin.
Dating, Love, Sex ... and Cancer
I went into dating after cancer with one goal, a decent date, and I got far more than I ever dreamed.
Related Videos
Health Advocate Amy Byer Shainman Discusses Risk Management of Hereditary Cancers
When it comes to managing your risk of cancer, especially when dealing with a familial cancer risk, "what is right for one person, may not be right for another," says Amy Byer Shainman.
Research Updates on HER2-Positive Breast Cancer from the 2015 Miami Breast Cancer Conference
Debu Tripathy, editor-in-chief of CURE magazine, discusses updates from the Miami Breast Cancer Conference, including the changing landscape of HER2-positive breast cancer.
Medical Updates from the 32nd Annual Miami Breast Cancer Conference
The evolution of the treatment for hormone receptor-positive breast cancer was a hot topic for this year's Miami Breast Cancer Conference. Debu Tripathy, CURE's editor-in-chief and breast oncologist, reports from the meeting.
Joan Lunden Discusses the Physical and Emotional Effects of Breast Cancer Treatment
Journalist Joan Lunden shares her experience with breast cancer, side effects and working through treatment.
Journalist Joan Lunden Discusses Her Breast Cancer Diagnosis and Treatment
Roy Firestone interviews longtime journalist, author and television host Joan Lunden on her recent breast cancer diagnosis and treatment.
Recent Publications
  • photo
  • photo