How does CYP2D6 allele status influence outcomes with tamoxifen?

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Among the most influential studies of the association between CYP2D6 genotype and tamoxifen effectiveness are the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98 trials, which together randomized more than 9000 patients to tamoxifen or to anastrozole or letrozole, respectively.^{[12, 13]}

In both assessments, CYP2D6 allele status had no effect on any outcomes, including disease recurrence, distant recurrence, and overall survival.^{[14, 15]}In addition, because it was thought that the presence of hot flashes might be an indicator of metabolic activity of tamoxifen, BIG 1-98 investigators also looked at whether the presence or absence of hot flashes might correlate with CYP2D6 allele status. Again, no difference was seen between the groups.^[15]

Nevertheless, the question of whether CYP2D6 allele status influences outcomes from tamoxifen still remains. Critics of these assessments have challenged the inconsistent use of somatic versus germline DNA in testing for genetic mutations and possible deviations from accepted statistical methodology.^[16]Indeed, a matched case-control study using data from the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that corrected for these factors found significant differences in disease recurrence in patients taking tamoxifen for 5 years, although the difference was not apparent in patients taking only 2-3 years of tamoxifen who were then switched to anastrozole.^[8]

It has been suggested that the current data may be suspect because of poor understanding of the metabolism of tamoxifen and endoxifen within the cytochrome P450 pathway.^[16]

Ongoing studies of patients with metastatic breast cancer that are incorporating genetic testing will add more information to the debate,^[17]but it is unclear whether they will fully resolve the question of how and whether CYP2D6 allele status influences outcomes from tamoxifen therapy given in the adjuvant setting.

The International Tamoxifen Pharmacogenomics Consortium (ITPC) is currently compiling comprehensive information on CYP2D6 and other genetic variants associated with metabolism and effects of tamoxifen in women treated with tamoxifen for breast cancer.^{[18, 19, 20, 21]}

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