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

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

Research output: Contribution to journalArticle

471 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)113-121
Number of pages9
JournalBreast Cancer Research and Treatment
Volume101
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Cytochrome P-450 CYP2D6
Tamoxifen
Breast Neoplasms
Recurrence
Alleles
Genotype
Enzyme Inhibitors
Enzymes
Cytochrome P-450 Enzyme System
Medical Records
Estrogens
Multivariate Analysis
Cytochrome P-450 CYP2D6 Inhibitors

Keywords

  • Breast cancer
  • Cytochrome P450 2D6
  • Pharmacogenetics
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Goetz, M. P., Knox, S. K., Suman, V. J., Rae, J. M., Safgren, S. L., Ames, M. M., ... Ingle, J. N. (2007). The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Research and Treatment, 101(1), 113-121. https://doi.org/10.1007/s10549-006-9428-0

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. / Goetz, Matthew P.; Knox, Stacey K.; Suman, Vera J.; Rae, James M.; Safgren, Stephanie L.; Ames, Matthew M.; Visscher, Daniel W.; Reynolds, Carol; Couch, Fergus J.; Lingle, Wilma L.; Weinshilboum, Richard M.; Fritcher, Emily G Barr; Nibbe, Andrea M.; Desta, Zeruesenay; Nguyen, Anne; Flockhart, David A.; Perez, Edith A.; Ingle, James N.

In: Breast Cancer Research and Treatment, Vol. 101, No. 1, 01.01.2007, p. 113-121.

Research output: Contribution to journalArticle

Goetz, MP, Knox, SK, Suman, VJ, Rae, JM, Safgren, SL, Ames, MM, Visscher, DW, Reynolds, C, Couch, FJ, Lingle, WL, Weinshilboum, RM, Fritcher, EGB, Nibbe, AM, Desta, Z, Nguyen, A, Flockhart, DA, Perez, EA & Ingle, JN 2007, 'The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen', Breast Cancer Research and Treatment, vol. 101, no. 1, pp. 113-121. https://doi.org/10.1007/s10549-006-9428-0
Goetz, Matthew P. ; Knox, Stacey K. ; Suman, Vera J. ; Rae, James M. ; Safgren, Stephanie L. ; Ames, Matthew M. ; Visscher, Daniel W. ; Reynolds, Carol ; Couch, Fergus J. ; Lingle, Wilma L. ; Weinshilboum, Richard M. ; Fritcher, Emily G Barr ; Nibbe, Andrea M. ; Desta, Zeruesenay ; Nguyen, Anne ; Flockhart, David A. ; Perez, Edith A. ; Ingle, James N. / The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. In: Breast Cancer Research and Treatment. 2007 ; Vol. 101, No. 1. pp. 113-121.
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abstract = "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.",
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author = "Goetz, {Matthew P.} and Knox, {Stacey K.} and Suman, {Vera J.} and Rae, {James M.} and Safgren, {Stephanie L.} and Ames, {Matthew M.} and Visscher, {Daniel W.} and Carol Reynolds and Couch, {Fergus J.} and Lingle, {Wilma L.} and Weinshilboum, {Richard M.} and Fritcher, {Emily G Barr} and Nibbe, {Andrea M.} and Zeruesenay Desta and Anne Nguyen and Flockhart, {David A.} and Perez, {Edith A.} and Ingle, {James N.}",
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T1 - The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen

AU - Goetz, Matthew P.

AU - Knox, Stacey K.

AU - Suman, Vera J.

AU - Rae, James M.

AU - Safgren, Stephanie L.

AU - Ames, Matthew M.

AU - Visscher, Daniel W.

AU - Reynolds, Carol

AU - Couch, Fergus J.

AU - Lingle, Wilma L.

AU - Weinshilboum, Richard M.

AU - Fritcher, Emily G Barr

AU - Nibbe, Andrea M.

AU - Desta, Zeruesenay

AU - Nguyen, Anne

AU - Flockhart, David A.

AU - Perez, Edith A.

AU - Ingle, James N.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Cytochrome P450 2D6

KW - Pharmacogenetics

KW - Tamoxifen

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