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

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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.

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Acknowledgments

This research was supported by the following National Cancer Institute grants issued to the Fred Hutch/University of Washington: CA173795, CA098858, CA015704, and CA009168. We are very grateful for the generous contributions of our study participants and research team.

Funding

This research was supported by NIH Grants R01 CA098858, R03 CA173795, and T32 CA009168. This research was also supported in part through the NIH/NCI Cancer Center Support Grant P30 CA015704.

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Authors and Affiliations

  1. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Sophie E. Mayer

  2. University of Washington, Seattle, WA, USA

    Sophie E. Mayer, Noel S. Weiss, Jessica Chubak & Kathleen E. Malone

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Noel S. Weiss, David R. Doody, Christopher S. Carlson, Michelle A. Wurscher & Kathleen E. Malone

  4. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    Jessica Chubak

  5. Bill & Melinda Gates Foundation, Seattle, WA, USA

    Karen W. Makar

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  1. Sophie E. Mayer
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  2. Noel S. Weiss
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Correspondence to Sophie E. Mayer.

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Mayer, S.E., Weiss, N.S., Chubak, J. et al. CYP2D6-inhibiting medication use and inherited CYP2D6 variation in relation to adverse breast cancer outcomes after tamoxifen therapy. Cancer Causes Control 30, 103–112 (2019). https://doi.org/10.1007/s10552-018-1117-x

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