1rarebird
04-15-2013, 10:16 AM
Breast Cancer Res Treat. (http://www.ncbi.nlm.nih.gov/pubmed/23580071?dopt=Abstract#) 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.
Teft WA (http://www.ncbi.nlm.nih.gov/pubmed?term=Teft%20WA%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Gong IY (http://www.ncbi.nlm.nih.gov/pubmed?term=Gong%20IY%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Dingle B (http://www.ncbi.nlm.nih.gov/pubmed?term=Dingle%20B%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Potvin K (http://www.ncbi.nlm.nih.gov/pubmed?term=Potvin%20K%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Younus J (http://www.ncbi.nlm.nih.gov/pubmed?term=Younus%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Vandenberg TA (http://www.ncbi.nlm.nih.gov/pubmed?term=Vandenberg%20TA%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Brackstone M (http://www.ncbi.nlm.nih.gov/pubmed?term=Brackstone%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Perera FE (http://www.ncbi.nlm.nih.gov/pubmed?term=Perera%20FE%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Choi YH (http://www.ncbi.nlm.nih.gov/pubmed?term=Choi%20YH%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Zou G (http://www.ncbi.nlm.nih.gov/pubmed?term=Zou%20G%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Legan RM (http://www.ncbi.nlm.nih.gov/pubmed?term=Legan%20RM%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Tirona RG (http://www.ncbi.nlm.nih.gov/pubmed?term=Tirona%20RG%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Kim RB (http://www.ncbi.nlm.nih.gov/pubmed?term=Kim%20RB%5BAuthor%5D&cauthor=true&cauthor_uid=23580071).
Source
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, ON, Canada.
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.
PMID:23580071 [PubMed - as supplied by publisher]
CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.
Teft WA (http://www.ncbi.nlm.nih.gov/pubmed?term=Teft%20WA%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Gong IY (http://www.ncbi.nlm.nih.gov/pubmed?term=Gong%20IY%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Dingle B (http://www.ncbi.nlm.nih.gov/pubmed?term=Dingle%20B%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Potvin K (http://www.ncbi.nlm.nih.gov/pubmed?term=Potvin%20K%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Younus J (http://www.ncbi.nlm.nih.gov/pubmed?term=Younus%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Vandenberg TA (http://www.ncbi.nlm.nih.gov/pubmed?term=Vandenberg%20TA%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Brackstone M (http://www.ncbi.nlm.nih.gov/pubmed?term=Brackstone%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Perera FE (http://www.ncbi.nlm.nih.gov/pubmed?term=Perera%20FE%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Choi YH (http://www.ncbi.nlm.nih.gov/pubmed?term=Choi%20YH%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Zou G (http://www.ncbi.nlm.nih.gov/pubmed?term=Zou%20G%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Legan RM (http://www.ncbi.nlm.nih.gov/pubmed?term=Legan%20RM%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Tirona RG (http://www.ncbi.nlm.nih.gov/pubmed?term=Tirona%20RG%5BAuthor%5D&cauthor=true&cauthor_uid=23580071), Kim RB (http://www.ncbi.nlm.nih.gov/pubmed?term=Kim%20RB%5BAuthor%5D&cauthor=true&cauthor_uid=23580071).
Source
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, ON, Canada.
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.
PMID:23580071 [PubMed - as supplied by publisher]