Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep;27(9):3655-3663.
doi: 10.1007/s12094-025-03908-y. Epub 2025 Apr 11.

Influence of CYP2D6 polymorphisms on tamoxifen side effects in patients with breast cancer

Isabel Blancas  1   2   3 , Marina Linares-Rodríguez  4 , Carlos José Rodríguez-González  5 , Fernando Rodríguez-Serrano  6   7   8
Affiliations

Influence of CYP2D6 polymorphisms on tamoxifen side effects in patients with breast cancer

Isabel Blancas et al. Clin Transl Oncol. 2025 Sep.

Abstract

Purpose: CYP2D6 is a key enzyme involved in converting tamoxifen into its active metabolites. However, polymorphisms in CYP2D6 lead to variable enzymatic capacities. We aimed to examine the impact of CYP2D6 polymorphisms on tamoxifen-derived side effects in breast cancer patients.

Methods: Eighty-six patients with hormone receptor-positive breast cancer who received tamoxifen were classified as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM) metabolizers according to Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. All patients received 20 mg/day tamoxifen for 5 years, except PM, who were dose-escalated (20 mg/day for 4 months, 40 mg/day for 4 months, 60 mg/day for 4 months, then back to 20 mg/day). Adverse events-osteoarticular pain, hot flashes, asthenia, and uterine changes-were analyzed by Kaplan-Meier and Cox regression. A propensity score-matched (PSM) subgroup was also examined.

Results: Rapid metabolizers (RM: NM + UM) consistently showed fewer uterine changes compared to slow metabolizers (SM: PM + IM) in both the entire cohort (HR 0.20, p = 0.001) and the PSM subgroup (HR 0.07, p = 0.011). Excluding PM and UM, comparison of IM vs. NM showed similar differences (complete group: HR 0.20, p = 0.002; PSM subgroup: HR 0.23, p = 0.068). Other side effects (joint pain, hot flashes, asthenia) were not significantly associated with CYP2D6 phenotype.

Conclusion: Uterine alterations in breast cancer patients treated with tamoxifen appear linked to decreased CYP2D6 activity, although we observed no association between CYP2D6 and other toxicities. These findings suggest closer monitoring for uterine toxicity in individuals with impaired CYP2D6 metabolism.

Keywords: Breast cancer; CYP2D6; Side effects; Tamoxifen; Uterine changes.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of interest: Dr. Blancas declares having conflicts of interest that include grants and contracts from the institutions Roche, Agendia, Lilly, Pfizer, and AstraZeneca; consulting fees from AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Gilead, Grünenthal, Jazz Pharmaceutical, Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, and Veracyte; payments or honoraria for lectures, presentations, participation in speaker bureaus, manuscript writing, or educational events from AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Gilead, Grünenthal, GSK, Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, and Veracyte, as well as Medical Scientia Innovation Research (MEDSIR); support for attending meetings and/or travel from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Gilead, Lilly, Novartis, Pfizer, Pierre-Fabre, and Roche; and participation on Data Safety Monitoring Boards or Advisory Boards for AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Gilead, Grünenthal, GSK, Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen and Veracyte. Ethical approval and consent to participate: Informed, written consent was obtained from all participants involved in the study. Additionally, the research received approval from the Provincial Ethical Committee of Granada, ensuring adherence to ethical standards in the conduct of this research. The study was registered in the European Union Clinical Trials Register ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-002942-40/ES ). EudraCT Number: 2007–002942-40. Date on which this record was first entered in the EudraCT database: 2007–09-11.

Figures

Fig. 1
Fig. 1
Cumulative incidence of uterine changes stratified by (A) rapid metabolizers (RM) vs. slow metabolizers (SM) in the complete cohort, and (B) RM vs. SM in the PSM-matched subgroup
See this image and copyright information in PMC

References

    1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Global cancer statistics, et al. GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63. 10.3322/caac.21834. - PubMed
    1. Lumachi F, Santeufemia DA, Basso SM. Current medical treatment of estrogen receptor-positive breast cancer. World J Biol Chem. 2015;6:231–9. 10.4331/wjbc.v6.i3.231. - PMC - PubMed
    1. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339:1609–18. 10.1056/NEJM199811263392207. - PubMed
    1. Liu S, Chia SK, Mehl E, Leung S, Rajput A, Cheang MCU, et al. Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients. Breast Cancer Res Treat. 2010;119:53–61. 10.1007/s10549-009-0318-0. - PubMed
    1. Chan CWH, Law BMH, So WKW, Chow KM, Waye MMY. Pharmacogenomics of breast cancer: highlighting CYP2D6 and tamoxifen. J Cancer Res Clin Oncol. 2020;146:1395–404. 10.1007/s00432-020-03206-w. - PMC - PubMed

LinkOut - more resources