Overview of the Action of CYP2D6
Since the early 1980s, systemic tamoxifen has been the standard approach to reducing risk of recurrence in women with estrogen receptor (ER)–positive early-stage breast cancer. Long-term data have demonstrated that the use of tamoxifen reduces recurrence and mortality by more than 30%, irrespective of the use of systemic chemotherapy.  Aromatase inhibitors (AIs), such as anastrozole (Arimidex) and letrozole (Femara), have been proven to be as effective as or superior to tamoxifen, but because of differing adverse-effect profiles, tamoxifen remains the treatment of choice for a large percentage of women.Tamoxifen is metabolized via CYP2D6 into endoxifen (4-OH-N-desmethyl-tamoxifen), its primary active metabolite. Multiple investigations have identified genetic variants of CYP2D6 that can affect its activity, which in turn affects the metabolism of tamoxifen.
The proficiency with which CYP2D6 metabolizes tamoxifen was assumed to be associated with the specific variant of the gene that an individual possesses, on the basis of studies that were conducted in breast cancer patients taking selective serotonin reuptake inhibitors (SSRIs) to relieve hot flashes. [2, 3, 4]
Specifically, because SSRIs inhibit CYP2D6, significantly lower endoxifen concentrations were also found in the studies’ patients. Further analysis identified 3 different groups of patients, based on genetic variants of CYP2D6: patients with 2 wild-type (wt), or normal, alleles; those with 1 non-wt allele; and those with 2 non-wt alleles. In a direct dose-gene effect, patients with 2 non-wt alleles had lower concentrations of endoxifen than did those with 1 non-wt allele, and patients with 2 wt alleles had endoxifen levels similar to those of poor metabolizers of tamoxifen who were not taking SSRIs. [3, 4]
Follow-up studies identified the *4 variant (1846G>A) as the most common allele associated with poor metabolism of tamoxifen. [5, 6] It is estimated that 7-10% of whites are poor metabolizers of tamoxifen based on specific CYP2D6 alleles. 
For more information, see Breast Cancer.
Clinical Implications of CYP2D6 Variants
A retrospective study conducted by Goetz et al showed that patients with the CYP2D6*4/*4 genotype had significantly shorter relapse-free time (RFT) and disease-free survival (DFS) time than did patients with *4/wt and wt/wt variants, although no difference was seen in overall survival.  In addition, patients who were poor metabolizers, defined as those with *4/*4 alleles or patients on strong CYP2D6 inhibitors for 2-3 years, had significantly shorter time to recurrence, significantly worse RFT, and significantly higher risk of relapse than did patients with wt alleles and those not on CYP2D6 inhibitors. 
A second retrospective study, by Schroth et al, confirmed these results,  but results from a third study of patients enrolled in a Stockholm Breast Cancer Group clinical trial showed that tamoxifen-treated patients with at least 1 CYP2D6*4 allele had a significantly better survival time than did those without the genetic variant. 
Additional, recent studies have also shown conflicting results, but all of the studies were retrospective, and most evaluated small numbers of patients.
In an attempt to settle this issue, investigators assessed data from the large, prospective Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98 trials that, in combination, had randomized more than 9000 patients to tamoxifen or to anastrozole or letrozole, respectively. [10, 11]
In both assessments, CYP2D6 allele status had no effect on any outcomes, including disease recurrence, distant recurrence, and overall survival. [12, 13] 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. 
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.  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 5 years of tamoxifen, although the difference was not apparent in patients taking only 2-3 years of tamoxifen who were then switched to anastrozole. 
Finally, some have suggested that all of the current data may be suspect because of the poor understanding of the metabolism of tamoxifen and endoxifen within the cytochrome P450 pathway. 
Ongoing studies of patients with metastatic breast cancer that are incorporating genetic testing will add more information to the debate,  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. [17, 18, 19, 20]
Recommendations and Further Research
Currently, the National Comprehensive Cancer Network (NCCN) does not recommend testing for CYP2D6 variants in patients considering tamoxifen in the adjuvant setting, which matches the recommendation from the American Society of Clinical Oncology about not testing for CYP2D6 variants in patients considering tamoxifen as a breast cancer risk reduction strategy. [21, 22] Further research is still needed to elucidate the potential effect of strong CYP2D6 inhibitors on tamoxifen metabolism. In the meantime, although NCCN recognizes that it is reasonable to avoid the use of potent CYP2D6-inhibiting SSRIs in patients taking tamoxifen,  there is no evidence to suggest that the use of such medications should influence the use of tamoxifen.