The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Research Abstract Details 

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The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Abstract Text:

Matthew P Goetz,Stacey K Knox,Vera J Suman,James M Rae,Stephanie L Safgren,Matthew M Ames,Daniel W Visscher,Carol Reynolds,Fergus J Couch,Wilma L Lingle,Richard M Weinshilboum,Emily G Barr Fritcher,Andrea M Nibbe,Zeruesenay Desta,Anne Nguyen,David A Flockhart,Edith A Perez,James N Ingle,

BACKGROUND: Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death. METHODS: Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling. RESULTS: Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007). CONCLUSION: CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Publishing Authors By Initials

MP Goetz,SK Knox,VJ Suman,JM Rae,SL Safgren,MM Ames,DW Visscher,C Reynolds,FJ Couch,WL Lingle,RM Weinshilboum,EG Fritcher,AM Nibbe,Z Desta,A Nguyen,DA Flockhart,EA Perez,JN Ingle,

For similar diagnosis: prognosis: treatment outcome research abstracts see: diagnosis: prognosis: treatment outcome research

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MEDLINE DATE:

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Breast cancer research and treatment

VOLUME: 101

Page Numbers: 113-21

Journal Abbreviation: Breast Cancer Res. Treat.

ISSN: 0167-6806

DAY: 18

MONTH: 11

YEAR: 2006

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8111104

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Keywords Mesh Terms:

KEYWORDS: Treatment Outcome

MESH TERMS: therapeutic use

Chemical & Substance for Abstract: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Information

Substance Name: Cytochrome P-450 CYP2D6

Registry Number: EC 1.14.14.1

Grant and Affiliation Information for The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.

AFFILIATION: Department of Oncology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN , 55905, USA, goetz.matthew@mayo.edu.

Country: Netherlands

AGENCY: United States NIGMS

GRANT: U-01 GM61373

ACRONYM: GM

MEDLINETA: Breast Cancer Res Treat

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