Factors potentially affecting tamoxifen efficacy

Factor	Potential effect	Probability estimate	Comments
CYP2D6 inhibitors	Reduced production of endoxifen	Possible	Conflicting results; significant limitations in all studies
Genotype for reduced CYP2D6 function	Reduced production of endoxifen	Possible	Conflicting results; significant limitations in all studies
Genotype for higher ABCB1 activity	Increased efflux of endoxifen from cancer cells	Possible	Two studies suggesting increased breast cancer recurrence with higher ABCB1 activity
Genotype for higher ABCC2 activity	Increased efflux of endoxifen from cancer cells	Possible	Two studies suggesting increased breast cancer recurrence with higher ABCC2 activity
Enzyme inducers	Decreased production and/or increased elimination of endoxifen	Probable	Dramatic reduction in endoxifen concentrations. Evidence from rifampin, aminoglutethimide, and phenytoin.
Enzyme inducers	Increased activity of ABCB1 and ABCC2 with increased efflux of endoxifen from cancer cells	Unestablished	Theoretical, based on transport genotype studies and known inducer effects on transporters.
Lower CYP2D activity combined with higher ABCB1 activity (both genotypes)	Reduced production of endoxifen AND increased efflux of endoxifen from cancer cells	Unestablished	Preliminary results suggest a dramatic reduction in the time of breast cancer recurrence and metastasis [39]
Lower CYP2D activity combined with higher ABCC2 activity (both genotype)	Reduced production of endoxifen AND increased efflux of endoxifen from cancer cells	Unestablished	Preliminary results suggest a catastrophic increase in breast cancer recurrence (hazard ratio of over 45) with lowest CYP2D6 activity and highest ABCC2 activity [40]
CYP2D6 inhibitors AND enzyme inducers	(1) Reduced production of endoxifen (2) Possible increased elimination of endoxifen (3) Increased efflux of endoxifen from cancer cells	Unestablished	Although the possibility of an additive effect is primarily theoretical, it seems likely that it would occur and is likely to be more problematic than either CYP2D6 inhibitors or enzyme inducers alone