Abstract
Tamoxifen’s pharmacokinetics are strongly influenced by the highly polymorphic CYP2D6, while the influence of other genetic variants has been inconclusive. To further delineate this genotypic-phenotypic impact, we conducted a multi-ancestry genome-wide association study in 636 hormone-receptor-positive (HR+) breast cancer (BC) patients treated with 20 mg tamoxifen daily for ≥8 weeks and validated these genetic determinants in another 869 patients. Association with clinical outcomes was examined in 1326 non-metastatic HR+ patients receiving adjuvant tamoxifen. A genome-wide significant association with Z-endoxifen levels was observed at the CYP2D6 locus on chromosome 22 and its downstream region of TCF20 rs932376 A > G. Both CYP2D6 metabolizer status and TCF20 rs932376 A > G were independent predictors of endoxifen levels in multivariable analysis. CYP2D6 metabolizer status accounted for greater variability of mean endoxifen levels compared to TCF20 rs932376 A > G (91.2% vs 48.8%). These findings were replicated in validation cohorts. Neither TCF20 rs932376 nor CYP2D6 metabolizer status was significantly associated with BC outcomes after adjustment for known prognostic factors. Our study confirmed that CYP2D6 metabolizer status remains as the prime predictor of steady-state Z-endoxifen levels, while TCF20 rs932376 A > G has a smaller, independent effect. Both genetic factors were not associated with BC clinical outcomes.
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Data supporting this study have been de-identified and only known to the respective research teams involved in patient recruitment. The data is not publicly available due to confidentiality of the research participants and is governed by the data sharing policies of the respective research institutions. Please contact the corresponding author (BC) for any request.
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Acknowledgements
This study was supported by grants from the National Medical Research Council Singapore (NMRC/1159/2008, NMRCB1011, NRFCG1516, NMRCG13163 and NMRC/CIRG/1423/2015, MOH-000377), the National Research Foundation of Singapore grant (NRF-NRFI2018-01); the Robert Bosch Foundation, Stuttgart, Germany and German Federal Ministry of Education and Research (BMBF; 01ZP0502, 01EK1509A); the Deutsche Foschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2180–390900677 and DFG grants SCHR 1323/2-1 and MU 1727/2-1; the German Cancer Consortium (DKTK), Partner Site Tübingen, 72074 Tübingen and the Interfaculty Center for Pharmacogenomics and Drug Research (ICEPHA), University of Tuebingen (no grant number). The funding sources had no involvement in the study design, collection, analysis and interpretation of data, writing of the manuscript and decision for publication. Additional funding for this study was provided by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore (no grant number). The funders had no role in the study design, collection, analysis and interpretation of data as well as drafting and submission of this manuscript.
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BC conceived and designed the study. EHL, EC, SC, TEM, JEA, NS, JSLL, SSL, CA, ZL, KSS, DME, WJT, TM, NKZ, SW, BG, LD, QG, CC, HME, LH, JD, RCHN, YSY, MW, FYW, NSW, PACS, RD, PK, UL, TL, AT, ES, ME, UH, PAF, MWB, FD, MWK, HBB, WS, WR, MS were involved in patient collection, conduct of study and data collection. CCK, WSO, TEM, HBB, MS, FT and BC contributed to data analysis and interpretation. CCK, WSO and BC drafted the manuscript. All authors participated in manuscript editing, review and approval of final revised manuscript.
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Carlos Caldas is a member of the AstraZeneca External Science Panel and has received research grants (administered by the University of Cambridge) from AstraZeneca, Genentech, Roche and Servier. Helena M. Earl has received research grants from Roche and Sanofi-Aventis (administered by Cambridge University Hospital Trust), honoraria and travel expenses from Daiichi-Sankyo, Astra Zeneca, Pfizer, Amgen and Prime Oncology all outside the submitted work. Jean E. Abraham has received research grants from AstraZeneca (administered by the Cambridge University Hospital Trust and the University of Cambridge, Dept of Oncology), honoraria and travel expenses from Astra Zeneca and Pfizer all outside the submitted work. All other authors declare no competing interests.
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Khor, C.C., Ong, W.S., Lim, E.H. et al. A multi-ancestry genome-wide study of tamoxifen metabolism and breast cancer recurrence. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00931-2
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DOI: https://doi.org/10.1038/s41523-026-00931-2
