CYP2D6 inherited variation and inhibiting medication use in relation to adverse breast cancer outcomes after tamoxifen therapy

Tamoxifen (TAM) is widely used to reduce the risk of breast cancer (BC) recurrence and prolong disease-free survival among women with estrogen-sensitive breast cancers. TAM efficacy is thought to be attributable largely to the actions of its active metabolite, endoxifen, and must undergo biotransformation catalyzed by the cytochrome P450 enzyme, CYP2D6. Endogenous variation in CYP2D6 metabolic efficiency and use of medications that inhibit CYP2D6 activity are thought to increase the risk of adverse BC outcomes among women taking TAM. This cohort study of 960 women diagnosed with early-stage BC between 1993 and 1999 in the Seattle tri-county area examined the association between concomitant use of CYP2D6 inhibitors and adjuvant TAM and the risk of adverse BC outcomes, both overall and among women with specific CYP2D6 metabolic phenotypes. Six or more months of CYP2D6 inhibitor use concomitant with TAM was not associated with any appreciable change in risk of recurrence or second primary BC, regardless of a women’s metabolic phenotype. These results are consistent with a number of other studies that have found no increased risk of adverse BC outcomes associated with CYP2D6 inhibition.