title: CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.
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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Teft
authors.forename: Inna Y
authors.initials: IY
authors.lastname: Gong
authors.forename: Brian
authors.initials: B
authors.lastname: Dingle
authors.forename: Kylea
authors.initials: K
authors.lastname: Potvin
authors.forename: Jawaid
authors.initials: J
authors.lastname: Younus
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Vandenberg
authors.forename: Muriel
authors.initials: M
authors.lastname: Brackstone
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Perera
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Guangyong
authors.initials: G
authors.lastname: Zou
authors.forename: Robin M
authors.initials: RM
authors.lastname: Legan
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D012621:Seasons; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D014807:Vitamin D / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; D013629:Tamoxifen; D014807:Vitamin D; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human