Vitamin D levels linked to Tamoxifen response
Breast Cancer Res Treat.
2013 Apr 12. [Epub ahead of print]
CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.
, Gong IY
, Dingle B
, Potvin K
, Younus J
, Vandenberg TA
, Brackstone M
, Perera FE
, Choi YH
, Zou G
, Legan RM
, Tirona RG
, Kim RB
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, ON, Canada.
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.
PMID:23580071 [PubMed - as supplied by publisher]
Male Breast Cancer, DX 5/15/09, IDC, STAGE 1, 1.7 cm, HER2+++, ER+(95%)/PR+(75%), Ki67 40%, grade 3, 0/5 nodes, TX: mastectomy, TCH finished 7/19/10, radiation 6 wks., Tamoxifen on going, bisphosphonate 24 mos.