Breast cancer patients who carry the wild-type gene required for tamoxifen metabolism may have comparable risk of recurrence when taking tamoxifen or an aromatase inhibitor, according to modeling data.
Cytochrome P450 2D6 (CYP2D6) converts tamoxifen into its metabolically active form called endoxifen. The enzymes encoded by different variants of the CYP2D6 gene metabolize tamoxifen at different rates. For example, women who carry two copies of the CYP2D6*4 allele have less endoxifen in their blood than women who carry two copies of the wild-type allele for CYP2D6. The lower serum concentration of endoxifen may make tamoxifen less effective for the women with the CYP2D6 *4 allele. However, two large randomized trials, which did not test women for their CYP2D6 genotype, showed that breast cancer survivors who take aromatase inhibitors reduce their risk of recurrence more than those taking tamoxifen.
To estimate whether women with wild-type CYP2D6 might derive more clinical benefit from tamoxifen than from aromatase inhibitors, Rinaa Punglia, M.D., of the Dana-Farber Cancer Institute in Boston and colleagues created a mathematical model. The researchers used estimates about the risk of recurrence from past randomized trials.
Punglia and colleagues calculated that women with wild-type CYP2D6 who take tamoxifen would have approximately the same reduction in the risk of recurrence as was seen for the whole population of women who took aromatase inhibitors in the clinical trial. Therefore, women with wild-type CYP2D6 genotype may derive as much benefit from tamoxifen as from aromatase inhibitors.
"Our model raises the possibility that tailored therapy based on pharmacogenomics could be considered for such women," the authors write.
In an accompanying editorial, Daniel Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in Ann Arbor and colleagues review what is known about tamoxifen metabolism and CYP2D6 allele types and their impact on the risk of recurrence for breast cancer patients.
The editorialists comment that the conclusions by Punglia and colleagues are important because they have brought the field of pharmacogenomics to the attention of breast cancer physicians. However, the analysis was based on limited data and on modeling assumptions and must be viewed with caution. "We do not recommend routine CYP2D6 genotyping for all patients who are considering tamoxifen, although we recognize that there are already selected circumstances in which such knowledge might be helpful," they write.
This research was reported April 29 in the Journal of the National Cancer Institute.
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