CYP2D6 genotyping does not appear to predict the effectiveness of tamoxifen in preventing breast cancer recurrences, according to two large retrospective analyses.
While the findings are probably not the final word on the controversy surrounding CYP2D6 genotyping, they will probably bring an end to routine testing, researchers said here at the CTRC-AACR San Antonio Breast Cancer Symposium.
Tamoxifen is metabolized into its active metabolite endoxifen by the CYP2D6 enzyme in the liver, and previous research has shown that patients with reduced-function CYP2D6 polymorphisms are poor metabolizers of tamoxifen, explained study discussant Matthew P. Goetz, MD, Associate Professor of Oncology and Associate Professor of Pharmacology at the Mayo Clinic.
He noted that although there have been 14 separate studies since 2003 showing a positive association between CYP2D6 genotype or CYP2D6 inhibitor use and breast cancer outcomes, 15 other studies have found no such association.
For the first new study, researchers genotyped 588 of the 3116 women who had taken part in the ATAC (Aromatase [Arimidex], Tamoxifen, Alone or in, Combination) trial comparing tamoxifen and anastrozole.
The women were separated into three groups depending on whether they were poor, intermediate, or extensive metabolizers of tamoxifen.
The breast cancer recurrence rate was similar in all three groups, regardless of whether a woman was in the tamoxifen or the anastrozole arm, reported James M. Rae, PhD, Assistant Professor in the Department of Internal Medicine at the University of Michigan Health System.
He and his co-researchers then compared the 9% of women who were taking CYP2D6 inhibitors, with those not taking the drugs.
Studies have suggested that the use of CYP2D6 inhibitor drugs—such as certain selective serotonin reuptake inhibitors—lower plasma levels of endoxifen by 45% to 58%, Dr. Rae noted, explaining that this provides a biologic rationale for the hypothesis that breast cancer outcomes will be worse in women taking these drugs with tamoxifen.
The study found, however, that the use of potent CYP2D6 inhibitors did not affect the breast cancer relapse rate.
The bottom line, Dr. Rae said, is that there is not sufficient evidence to recommend either CYP2D6 genotyping or avoidance of CYP2D6 by women taking tamoxifen.
BIG 1-98 Also Negative
The other analysis, reported by Brian Leyland-Jones, MD, PhD, Professor of Hematology and Oncology at Emory Winship Cancer Institute, was based on data from the Breast International Group (BIG) 1-98 trial comparing tamoxifen and letrozole.
Among the 2,675 women who underwent genotyping, 9% were categorized as poor metabolizers of CYP2D6, 27% were intermediate metabolizers, and 59% were extensive metabolizers; the results were unclear in the remaining women.
Metabolizer status was found to have no impact on the primary endpoint of the breast-cancer-free interval in either the tamoxifen or letrozole groups.
Additionally, there was no association between CYP2D6 genotype and the severity or number of hot flashes, he said.
The researchers had hypothesized that the lower endoxifen levels among women who are poor metabolizers would manifest as fewer or less severe hot flashes. That's important, Dr. Leyland-Jones noted, since some doctors have viewed an absence of hot flashes as a sign that tamoxifen is not working. But based on the new data, CYP2D6 genotype testing is not justified, he said, and hot flashes should not be used as a marker of tamoxifen efficacy.
In his discussion, Dr. Goetz pointed to “the substantial controversy” regarding the pharmacokinetics of tamoxifen and CYP2D6 activity and said it is “unlikely to be resolved though retrospective analyses, given that CYP2D6 only partially explains the extensive variability in endoxifen pharmacokinetics.”
Among the drawbacks of the two new analyses are that they did not take into account adherence to tamoxifen, the duration of CYP2D6 inhibitor use, or use of over-the-counter drugs, he said.
Also, the hot flash analysis was not adjusted for concomitant use of drugs that are known to reduce the number and severity of hot flashes, Dr. Goetz said.
And while routine CYP2D6 testing is not justified, there may be certain patients, such as postmenopausal women with high-risk disease who prefer tamoxifen over aromatase inhibitors, in whom testing could be considered—“additionally, caregivers should exert caution and avoid potent CYP2D6 inhibitors in women being treated with tamoxifen,” he said.
Minetta C. Liu, MD, Director of Translational Breast Cancer Research at Georgetown Lombardi Comprehensive Cancer Center, although noting that retrospective analyses have limitations that can allow some experts to argue that various medications or other factors were not controlled for, said that “for most of us, this study does answer the question of whether CYP2D6 testing should be performed—it should not be used to guide therapy.”