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<p>Tamoxifen’s pharmacokinetics are strongly influenced by the highly polymorphic <i>CYP2D6,</i> 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 <i>CYP2D6</i> locus on chromosome 22 and its downstream region of <i>TCF20</i> rs932376 A &gt; G. Both <i>CYP2D6</i> metabolizer status and <i>TCF20</i> rs932376 A &gt; G were independent predictors of endoxifen levels in multivariable analysis. <i>CYP2D6</i> metabolizer status accounted for greater variability of mean endoxifen levels compared to <i>TCF20</i> rs932376 A &gt; G (91.2% vs 48.8%). These findings were replicated in validation cohorts. Neither <i>TCF20</i> rs932376 nor <i>CYP2D6</i> metabolizer status was significantly associated with BC outcomes after adjustment for known prognostic factors. Our study confirmed that <i>CYP2D6</i> metabolizer status remains as the prime predictor of steady-state Z-endoxifen levels, while <i>TCF20 rs932376 A</i> &gt; <i>G</i> has a smaller, independent effect. Both genetic factors were not associated with BC clinical outcomes.</p>

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A multi-ancestry genome-wide study of tamoxifen metabolism and breast cancer recurrence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月20日

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  • Chiea Chuen Khor,
  • Whee Sze Ong,
  • Elaine Hsuen Lim,
  • Etienne Chatelut,
  • Sylvia Chen,
  • Thomas E. Muerdter,
  • Jean E. Abraham,
  • Natalia Sutiman,
  • Joanne Siok Liu Lim,
  • Sze Sing Lee,
  • Cecile Arellano,
  • Zheng Li,
  • Kar Seng Sim,
  • Diana M. Eccles,
  • William J. Tapper,
  • Tom Maishman,
  • Nathalie K. Zgheib,
  • Stefan Winter,
  • Boian Ganchev,
  • Leila Dorling,
  • Qi Guo,
  • Carlos Caldas,
  • Helena M. Earl,
  • Louise Hiller,
  • Janet Dunn,
  • Raymond Chee Hui Ng,
  • Yoon Sim Yap,
  • Mabel Wong,
  • Fuh Yong Wong,
  • Nan Soon Wong,
  • Peter Cher Siang Ang,
  • Rebecca Dent,
  • Peter Krippl,
  • Uwe Langsenlehner,
  • Tanja Langsenlehner,
  • Arafat Tfayli,
  • Elke Schaeffeler,
  • Michel Eichelbaum,
  • Ute Hamann,
  • Peter A. Fasching,
  • Matthias W. Beckmann,
  • Florence Dalenc,
  • Melanie White-Koning,
  • Hiltrud B. Brauch,
  • Werner Schroth,
  • Wilfried Renner,
  • Matthias Schwab,
  • Fabienne Thomas,
  • Balram Chowbay

摘要

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.