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

Abstract

Purpose: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen.

Methods: The present cohort study of 960 women diagnosed with early-stage BC between 1993 and 1999 examined the association between concomitant use of CYP2D6 inhibitors and adjuvant tamoxifen and the risk of adverse BC outcomes (recurrence, second primary BC, BC mortality), both overall and according to CYP2D6 metabolic phenotype.

Results: Six or more months of CYP2D6 inhibitor use concomitant with tamoxifen was not associated with any appreciable increase in risk of recurrence or second primary BC or BC mortality, and there was no clear evidence of variation by CYP2D6 metabolic phenotype.

Conclusions: These results are consistent with the relatively few other large, population-based studies conducted to date that have not observed an increased risk of adverse BC outcomes associated with CYP2D6 inhibition.

Keywords: Breast cancer; CYP2D6; Pharmacogenetics; Survival; Tamoxifen.

Figure 1.

Identification of study cohorts, including inclusion and exclusion criteria for each analysis. Abbreviations: AA=African American, CARE=Women’s Contraceptive and Reproductive Experiences, EMF=Electromagnetic Fields and Risk of Breast Cancer,

Figure 2.

Crude Kaplan-Meier survival curves showing time to earliest recurrence or second primary breast cancer by time-varying TAM-CYP2D6 inhibitor concomitant use. Because exposure status was assessed in the first six months following diagnosis, no events in this analysis could occur during this period. Individuals were classified as nonusers prior to first record of concomitant use, at which point they become exposed for <6 months; after 6 or more months of cumulative concomitant use, they were considered exposed in the main analysis. Abbreviations: Mos.=months.