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Metabolic pathway analysis and effectiveness of tamoxifen in Danish breast cancer patients

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  • Thomas P Ahern
  • Lindsay J Collin
  • James W Baurley, Bioinformatics and Data Science Research Center, Bina Nusantara University.
  • ,
  • Anders Kjærsgaard
  • Rebecca Nash, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA; Winship Cancer Institute, Emory University, Atlanta, USA.
  • ,
  • Maret L Maliniak, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA; Winship Cancer Institute, Emory University, Atlanta, USA.
  • ,
  • Per Damkier, Dept. of Clinical Biochemistry and Pharmacology, Odense University Hospital
  • ,
  • Michael E Zwick, Department of Human Genetics, Emory University School of Medicine.
  • ,
  • R Benjamin Isett, Emory University School of Medicine
  • ,
  • Peer M Christiansen
  • Bent Ejlertsen, DBCG secretariat, Dept. of Oncology, Rigshospitalet.
  • ,
  • Kristina L Lauridsen
  • Kristina Bang Christensen
  • Rebecca A Silliman, Section of Geriatrics, Boston University School of Medicine.
  • ,
  • Henrik Toft Sorensen
  • Trine Tramm
  • Stephen Hamilton-Dutoit
  • Timothy L Lash
  • Deirdre Cronin Fenton

BACKGROUND: Tamoxifen and its metabolites compete with estrogen to occupy the estrogen receptor. The conventional dose of adjuvant tamoxifen overwhelms estrogen in this competition, reducing breast cancer recurrence risk by nearly half. Phase 1 metabolism generates active tamoxifen metabolites and phase 2 metabolism deactivates them. No earlier pharmacogenetic study has comprehensively evaluated the metabolism and transport pathways, and no earlier study has included a large population of premenopausal women.

METHODS: We completed a cohort study of 5959 Danish nonmetastatic premenopausal breast cancer patients, in whom 938 recurrences occurred, and a case-control study of 541 recurrent cases in a cohort of Danish predominantly postmenopausal breast cancer patients, all followed for ten years. We collected formalin-fixed paraffin-embedded tumor blocks and genotyped 32 variants in 15 genes involved in tamoxifen metabolism or transport. We estimated conventional associations for each variant and used prior information about the tamoxifen metabolic path to evaluate the importance of metabolic and transporter pathways.

RESULTS: No individual variant was notably associated with risk of recurrence in either study population. Both studies showed weak evidence of the importance of phase 1 metabolism in the clinical response to adjuvant tamoxifen therapy.

CONCLUSIONS: Consistent with prior knowledge, our results support the role of phase 1 metabolic capacity in clinical response to tamoxifen. Nonetheless, no individual variant substantially explained the modest phase 1 effect on tamoxifen response.

IMPACT: These results are consistent with guidelines recommending against genotype-guided prescribing of tamoxifen, and for the first time provide evidence supporting these guidelines in premenopausal women.

Original languageEnglish
JournalCancer Epidemiology, Biomarkers & Prevention
Pages (from-to)582-590
Publication statusPublished - Mar 2020

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Copyright ©2020, American Association for Cancer Research.

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