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. 2025 Apr 11.
doi: 10.1007/s12094-025-03908-y. Online ahead of print.

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. .

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.

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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.

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