CYP2D6 Does Not Predict Tamoxifen Effectiveness, New Studies Show

Zosia Chustecka

December 10, 2010

December 10, 2010 (San Antonio, Texas) — New analyses of data from 2 large trials have found no association between the CYP2D6 genotype and the effectiveness of tamoxifen in preventing breast cancer recurrence, in contrast to several previous positive studies.

The new findings come from retrospective analyses of 2 huge trials — the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial comparing tamoxifen and anastrozole, and the Breast International Group (BIG) 1-98 trial comparing tamoxifen and letrozole.

They were presented here at the 33rd Annual San Antonio Breast Cancer Symposium (SABCS).

The fact that both studies were negative led experts to recommend that CYP2D6 testing not be used routinely to decide whether or not to prescribe tamoxifen.

Even the strongest proponent of this approach, Matthew Goetz, MD, from the Mayo Clinic in Rochester, Minnesota, who led the original studies showing an association, concedes.

Although criticizing some aspects of the new analyses in a discussion after the presentation, he concluded that physicians should not routinely test for CYP2D6 status before deciding whether to prescribe tamoxifen or an aromatase inhibitor, an approach that he had been advocating until now.

"We should stop offering these tests outside of clinical trials," Edith Perez, MD, from the Mayo Clinic in Jacksonville, Florida, told Medscape Medical News.

The rationale behind CYP2D6 testing is that women who have an inherited deficiency of this gene are poor metabolizers of tamoxifen, and have lower levels of the active metabolite endoxifen. In previous positive studies, including those by Dr. Goetz and colleagues, these poor metabolizers have shown less benefit from tamoxifen and higher rates of breast cancer recurrence.

This has always been a controversial area. To date, there have been 14 separate studies that have shown this association; however, 15 other studies have not found this effect, Dr. Goetz told the meeting.

This is another beautiful theory in danger of being slain by ugly fact.

"This is another beautiful theory in danger of being slain by ugly fact," said Peter Ravdin MD, codirector of the SABCS and director of the Comprehensive Breast Health Clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio.

Both of the analyses presented at the meeting were negative; this "will bury the idea that CYP2D6 is a biomarker here," he told Medscape Medical News.

Negative Finding From ATAC Analysis

Both of the analyses were retrospective and involved going back to women who had taken part in large trials and testing them for the CYP2D6 genotype.

The analysis of data from the ATAC trial was presented by James Rae, MD, from the University of Michigan in Ann Arbor, and colleagues. They genotyped 588 of the 3116 women (18%) who took part in the trial, and categorized the women as poor, intermediate, or extensive metabolizers of tamoxifen.

There was no difference in breast cancer recurrence in any of these categories in either the tamoxifen or the anastrozole group (which served as a control group in this instance). If the theory about CYP2D6 was correct, the poor metabolizers would have been expected to do worse.

Dr. Rae and colleagues also found that there was no effect on clinical outcome from the concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors (SSRIs). About 9% of women were taking drugs that are known to be potent inhibitors, he said.

This finding is in contrast with previous research that has shown that women taking drugs that are potent inhibitors of CYP2D6, especially SSRIs, have an increased risk for breast cancer recurrence. The theory here is that these drugs inhibit the metabolism of tamoxifen, so they have lower levels of the active metabolite endoxifen, which is responsible for the beneficial effect. As a result of that research, it has been recommended that clinicians avoid prescribing certain drugs in women taking tamoxifen.

Dr. Rae concluded his presentation by saying that the "evidence is not sufficient" to recommend either CYP2D6 genotyping or to recommend avoiding the concomitant use of SSRIs in women taking tamoxifen.

Negative Finding From BIG 1-98

Dr. Brian Leyland-Jones

The other analysis was based on data from the BIG 1-98 trial, presented by Brian Leyland-Jones, MD, PhD, from Emory University in Atlanta, Georgia. In this case, 48% of participants underwent genotyping (1243 of 2459 women). The researchers found that 9% were poor metabolizers, 27% were intermediate metabolizers, and 59% were extensive metabolizers; it was unclear in the remaining 5%.

This analysis found no difference in the different metabolizers on the effect that tamoxifen had on the breast-cancer-free interval. There was also no difference in any of the different metabolizers in the letrozole group (which served as a control group in this analysis).

In addition, these researchers found no association between the incidence of hot flashes and metabolizer status. This was based on another theory, which suggested that women who are extensive metabolizers of tamoxifen — who would thus have high levels of the active metabolite endoxifen and derive the most benefit from tamoxifen — would also experience a higher level of adverse effects from the drug, including hot flashes. However, Dr. Leyland-Jones reported that in their analysis, the extensive metabolizers had the lowest incidence of hot flashes.

"This is important," Dr. Leyland-Jones told Medscape Medical News, because some physicians are using an absence of hot flashes as a sign that tamoxifen is not working and stopping the drug. "Our data show that hot flashes should not be used as a surrogate pharmacodynamic marker for tamoxifen efficacy," he said.

Dr. Leyland-Jones concluded that CYP2D6 genotype testing is "not justified" in determining whether or not to prescribe tamoxifen. In addition, he emphasized that the presence or absence of hot flashes should not be used to determine the efficacy of tamoxifen.

Controversy Unresolved

In his discussion of both presentations, Dr. Goetz pointed out that the analyses were both retrospective, and they did not take into account adherence to tamoxifen or the concomitant use of over-the-counter drugs. In addition, the analysis for hot flashes did not adjust for concomitant use of drugs that are prescribed to treat hot flashes, such as venlafaxine and gabapentin, he said.

Nevertheless, Dr. Goetz agreed with the recommendation from both presenters that CYP2D6 testing should not be used routinely.

However, he disagreed with the conclusion on drugs that inhibit CYP2D6, and recommended that physicians exercise caution in the concomitant use of such drugs in women taking tamoxifen.

The controversy surrounding this issue is unlikely to be resolved by retrospective analyses, given that CYP2D6 only partially explains the variability of responses to endoxifen, the active metabolite, Dr. Goetz said. He reported that his team is developing endoxifen as a drug in its own right, and that a clinical trial is planned to start in 2011.

The original ATAC trial was funded by AstraZeneca, the manufacturer of anastrozole; the original BIG 1-94 trial was funded by Novartis, the manufacturer of letrozole.

33rd Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts S1-7 and S1-8. Presented December 9, 2010.

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