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Breast Cancer Research and Treatment

, Volume 139, Issue 1, pp 95–105 | Cite as

CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy

  • Wendy A. Teft
  • Inna Y. Gong
  • Brian Dingle
  • Kylea Potvin
  • Jawaid Younus
  • Theodore A. Vandenberg
  • Muriel Brackstone
  • Francisco E. Perera
  • Yun-Hee Choi
  • Guangyong Zou
  • Robin M. Legan
  • Rommel G. Tirona
  • Richard B. KimEmail author
Clinical trial

Abstract

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

Keywords

Endoxifen CYP3A4 Vitamin D CYP2D6 Tamoxifen efficacy Therapeutic threshold 

Notes

Acknowledgments

Dr. Richard B. Kim holds the Wolfe Medical Research Chair in Pharmacogenomics at Western. We would like to thank Matilde Leon-Ponte, Cameron Ross, and Sara Mansell for their technical assistance and Julie Mayo for her administrative support. We would also like to thank the Breast Disease Site Team at the London Regional Cancer Program (LRCP). This study was funded by the Cancer Care Ontario (CCO) Research Chair Award (Tier-1) in Experimental Therapeutics (Richard B Kim) and the Ontario Institute for Cancer Research (OICR) Translational Research Team grant.

Conflict of interest

None.

Supplementary material

10549_2013_2511_MOESM1_ESM.docx (226 kb)
Supplementary material 1 (DOCX 226 kb)
10549_2013_2511_MOESM2_ESM.xlsx (19 kb)
Supplementary material 2 (XLSX 19 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Wendy A. Teft
    • 1
  • Inna Y. Gong
    • 1
    • 5
  • Brian Dingle
    • 2
  • Kylea Potvin
    • 2
  • Jawaid Younus
    • 2
  • Theodore A. Vandenberg
    • 2
  • Muriel Brackstone
    • 2
    • 3
  • Francisco E. Perera
    • 2
  • Yun-Hee Choi
    • 4
  • Guangyong Zou
    • 4
  • Robin M. Legan
    • 1
  • Rommel G. Tirona
    • 1
    • 5
  • Richard B. Kim
    • 1
    • 2
    • 5
    • 6
    Email author
  1. 1.Division of Clinical Pharmacology, Department of MedicineUniversity of Western OntarioLondonCanada
  2. 2.Department of OncologyUniversity of Western OntarioLondonCanada
  3. 3.Department of SurgeryUniversity of Western OntarioLondonCanada
  4. 4.Department of Epidemiology and BiostatisticsUniversity of Western OntarioLondonCanada
  5. 5.Department of Physiology and PharmacologyUniversity of Western OntarioLondonCanada
  6. 6.Department of MedicineLHSC-University HospitalLondonCanada

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