Table 1.

A summary of some of the factors associated with variability in the published CYP2D6 tamoxifen studies

Factor	Effect
Pharmacology factors
Variability in rates of adherence among different CYP2D6 genotypes	Higher rates of nonadherence in CYP2D6 EMs given the greater likelihood of side effects
Duration of tamoxifen administration	Duration must be consistent because tamoxifen is more effective with longer duration than shorter duration, and different durations could obscure any impact of CYP2D6
Dose (40 vs. 20 mg/day)	Increase in endoxifen Css in CYP2D6 PMs (but not EMs) with higher doses of tamoxifen, thereby decreasing the risk associated with the PM state14
Concurrent administration of potent CYP2D6 inhibitors	CYP2D6 EMs converted to PMs in the presence of CYP2D6 potent inhibitors
Clinical factors
Chemotherapy administered before or after tamoxifen	Fewer recurrences and fewer at-risk patients; loss of statistical power
Administration of aromatase inhibitor after tamoxifen	CYP2D6 is not responsible for the metabolism of aromatase inhibitors, and the effect of CYP2D6 metabolism is lost in patients switched to an aromatase inhibitor.8, Lack of knowledge regarding switching to an aromatase inhibitor can obscure CYP2D6 effect
Inclusion of ER-negative patients	Tamoxifen does not reduce the risk of recurrence of ER-negative breast cancer
Genotyping factors
Use of tumor cores for determination of CYP2D6 genotype	CYP2D6 genotype from tumor-derived DNA subject to error due to somatic loss of heterozygosity affecting the 22q13 CYP2D6 locus3,5,6,7
Limited CYP2D6 allele coverage (genotyping for only the *4 allele)	Misclassification of CYP2D6 PMs, thereby falsely assigning undetected PMs to the EM or IM groups5
Use of nonstandard genotyping techniques (60 PCR cycles)	Potential for genotyping error3

C_ss, steady-state concentration; EM, extensive metabolizer; ER, estrogen receptor; IM, intermediate metabolizer; PM, poor metabolizer.