Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score
Tamoxifen (Tam), the major drug for estrogen receptor (ER)‐positive breast cancer, is converted to its active metabolites, Z‐ and Z′‐endoxifen and 4‐OH‐Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20 mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma le...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2011-10, Vol.90 (4), p.605-611 |
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| creator | Barginear, M F Jaremko, M Peter, I Yu, C Kasai, Y Kemeny, M Raptis, G Desnick, R J |
| description | Tamoxifen (Tam), the major drug for estrogen receptor (ER)‐positive breast cancer, is converted to its active metabolites, Z‐ and Z′‐endoxifen and 4‐OH‐Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20 mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z‐endoxifen levels increased while Z′‐endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P ≤ 0.0004). The dosage in patients with endoxifen |
| doi_str_mv | 10.1038/clpt.2011.153 |
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Clinical Pharmacology & Therapeutics (2011) 90 4, 605–611. doi:10.1038/clpt.2011.153</description><subject>Adult</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cytochrome P-450 CYP2D6 - genetics</subject><subject>Dose-Response Relationship, Drug</subject><subject>Estrogen Antagonists - administration & dosage</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Genotype</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Prospective Studies</subject><subject>Tamoxifen - administration & dosage</subject><subject>Tamoxifen - analogs & derivatives</subject><subject>Tamoxifen - metabolism</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFv0zAYhi0EYt3gyBWZ004pn504ibl1WRmViqhELpwix_kyjFK72O6gP4r_uETpduRi65Of5_0svYS8Y7BkkJYf9XCISw6MLZlIX5DFePIkF6l4SRYAIBPJ0_yCXIbwaxwzWZavyQVnEqCUsCD_NlZ7VMHYe1qrvftrerT01gWkxtKb6SnSSlmNnu5UNGhjoDcqYEedpdWPHb_N6R1aF08HDFTZjq5td47Z4gMO4RNd9z3qOAkrHc0D0q8YVesGE5Fugtujn834E-nKjktC9O4erdGzYOKJftfO4xvyqldDwLfn-4rUn9d19SXZfrvbVKttorMiTRPRZ7pDXrAi020OjOfQ9RlIBZC2EoQG0CLruRBa5SWwvEChtSwZoizbLL0i13Pswbvfx_E3zd4EjcOgLLpjaEqZFhxKLkYymUntXQge--bgzV75U8Ogmfpppn6aqZ9mbGbk35-Tj-0eu2f6qZARkDPwxwx4-n9aU-3qarurp3kO_zC7VsWjx2d5kp6YR7mEqgE</recordid><startdate>201110</startdate><enddate>201110</enddate><creator>Barginear, M F</creator><creator>Jaremko, M</creator><creator>Peter, I</creator><creator>Yu, C</creator><creator>Kasai, Y</creator><creator>Kemeny, M</creator><creator>Raptis, G</creator><creator>Desnick, R J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201110</creationdate><title>Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score</title><author>Barginear, M F ; Jaremko, M ; Peter, I ; Yu, C ; Kasai, Y ; Kemeny, M ; Raptis, G ; Desnick, R J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4733-5f4cde27174cb601260df409a003b905c00c54f255ca680167e5cc981ee98b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adult</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cytochrome P-450 CYP2D6 - genetics</topic><topic>Dose-Response Relationship, Drug</topic><topic>Estrogen Antagonists - administration & dosage</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Genotype</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Prospective Studies</topic><topic>Tamoxifen - administration & dosage</topic><topic>Tamoxifen - analogs & derivatives</topic><topic>Tamoxifen - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barginear, M F</creatorcontrib><creatorcontrib>Jaremko, M</creatorcontrib><creatorcontrib>Peter, I</creatorcontrib><creatorcontrib>Yu, C</creatorcontrib><creatorcontrib>Kasai, Y</creatorcontrib><creatorcontrib>Kemeny, M</creatorcontrib><creatorcontrib>Raptis, G</creatorcontrib><creatorcontrib>Desnick, R J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barginear, M F</au><au>Jaremko, M</au><au>Peter, I</au><au>Yu, C</au><au>Kasai, Y</au><au>Kemeny, M</au><au>Raptis, G</au><au>Desnick, R J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2011-10</date><risdate>2011</risdate><volume>90</volume><issue>4</issue><spage>605</spage><epage>611</epage><pages>605-611</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><abstract>Tamoxifen (Tam), the major drug for estrogen receptor (ER)‐positive breast cancer, is converted to its active metabolites, Z‐ and Z′‐endoxifen and 4‐OH‐Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20 mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z‐endoxifen levels increased while Z′‐endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P ≤ 0.0004). The dosage in patients with endoxifen <40 nmol/l and/or CYP2D6 MPA scores of 0 was increased to 30 mg/day and their metabolite isomers were monitored for up to 90 days. Of the 24 patients on the increased dose, 90% showed an increase in active isomers by day 60; the rate of increase correlated with the MPA score. Notably, their antiestrogenic activity scores (AASs), which estimate total isomer biologic activity, increased from a baseline median of 17 to 26 at day 60. Further studies involving increasing/decreasing the Tam dosage based on the AAS may determine whether dose adjustment can optimize treatment and improve long‐term survival.
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| subjects | Adult Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Cytochrome P-450 CYP2D6 - genetics Dose-Response Relationship, Drug Estrogen Antagonists - administration & dosage Female Follow-Up Studies Genotype Humans Male Middle Aged Prospective Studies Tamoxifen - administration & dosage Tamoxifen - analogs & derivatives Tamoxifen - metabolism |
| title | Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score |
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