CYP2D6 Genotype and Adjuvant Tamoxifen

Meta-Analysis of Heterogeneous Study Populations

Michael A. Province, M. P. Goetz, H. Brauch, D. A. Flockhart, J. M. Hebert, R. Whaley, V. J. Suman, W. Schroth, S. Winter, H. Zembutsu, Taisei Mushiroda, W. G. Newman, M. T.M. Lee, C. B. Ambrosone, M. W. Beckmann, J. Y. Choi, A. S. Dieudonné, P. A. Fasching, R. Ferraldeschi, L. Gong & 44 others E. Haschke-Becher, A. Howell, L. B. Jordan, U. Hamann, K. Kiyotani, P. Krippl, D. Lambrechts, A. Latif, U. Langsenlehner, W. Lorizio, P. Neven, A. T. Nguyen, Byeongwoo Park, C. A. Purdie, P. Quinlan, W. Renner, M. Schmidt, M. Schwab, J. G. Shin, J. C. Stingl, P. Wegman, Sten Wingren, A. H.B. Wu, E. Ziv, G. Zirpoli, A. M. Thompson, V. C. Jordan, Y. Nakamura, R. B. Altman, M. M. Ames, R. M. Weinshilboum, M. Eichelbaum, J. N. Ingle, T. E. Klein, Julia Boländer, Hans Ulrich Ulmer, Margarete Fischer-Bosch, Peter Fritz, Wolfgang Simon, Y. Bryan, Reiner Strick, Heinz Koelbl, Christine A. Ambrosone, Elad Ziv H

Research output: Contribution to journalArticle

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Abstract

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Original languageEnglish
Pages (from-to)216-227
Number of pages12
JournalClinical Pharmacology and Therapeutics
Volume95
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

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Cytochrome P-450 CYP2D6
Tamoxifen
Meta-Analysis
Genotype
Population
Pharmacogenetics
Estrogen Receptors
Disease-Free Survival
Prospective Studies
Confidence Intervals
Breast Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Province, M. A., Goetz, M. P., Brauch, H., Flockhart, D. A., Hebert, J. M., Whaley, R., ... H, E. Z. (2014). CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations. Clinical Pharmacology and Therapeutics, 95(2), 216-227. https://doi.org/10.1038/clpt.2013.186
Province, Michael A. ; Goetz, M. P. ; Brauch, H. ; Flockhart, D. A. ; Hebert, J. M. ; Whaley, R. ; Suman, V. J. ; Schroth, W. ; Winter, S. ; Zembutsu, H. ; Mushiroda, Taisei ; Newman, W. G. ; Lee, M. T.M. ; Ambrosone, C. B. ; Beckmann, M. W. ; Choi, J. Y. ; Dieudonné, A. S. ; Fasching, P. A. ; Ferraldeschi, R. ; Gong, L. ; Haschke-Becher, E. ; Howell, A. ; Jordan, L. B. ; Hamann, U. ; Kiyotani, K. ; Krippl, P. ; Lambrechts, D. ; Latif, A. ; Langsenlehner, U. ; Lorizio, W. ; Neven, P. ; Nguyen, A. T. ; Park, Byeongwoo ; Purdie, C. A. ; Quinlan, P. ; Renner, W. ; Schmidt, M. ; Schwab, M. ; Shin, J. G. ; Stingl, J. C. ; Wegman, P. ; Wingren, Sten ; Wu, A. H.B. ; Ziv, E. ; Zirpoli, G. ; Thompson, A. M. ; Jordan, V. C. ; Nakamura, Y. ; Altman, R. B. ; Ames, M. M. ; Weinshilboum, R. M. ; Eichelbaum, M. ; Ingle, J. N. ; Klein, T. E. ; Boländer, Julia ; Ulmer, Hans Ulrich ; Fischer-Bosch, Margarete ; Fritz, Peter ; Simon, Wolfgang ; Bryan, Y. ; Strick, Reiner ; Koelbl, Heinz ; Ambrosone, Christine A. ; H, Elad Ziv. / CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations. In: Clinical Pharmacology and Therapeutics. 2014 ; Vol. 95, No. 2. pp. 216-227.
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abstract = "The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95{\%} confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.",
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Province, MA, Goetz, MP, Brauch, H, Flockhart, DA, Hebert, JM, Whaley, R, Suman, VJ, Schroth, W, Winter, S, Zembutsu, H, Mushiroda, T, Newman, WG, Lee, MTM, Ambrosone, CB, Beckmann, MW, Choi, JY, Dieudonné, AS, Fasching, PA, Ferraldeschi, R, Gong, L, Haschke-Becher, E, Howell, A, Jordan, LB, Hamann, U, Kiyotani, K, Krippl, P, Lambrechts, D, Latif, A, Langsenlehner, U, Lorizio, W, Neven, P, Nguyen, AT, Park, B, Purdie, CA, Quinlan, P, Renner, W, Schmidt, M, Schwab, M, Shin, JG, Stingl, JC, Wegman, P, Wingren, S, Wu, AHB, Ziv, E, Zirpoli, G, Thompson, AM, Jordan, VC, Nakamura, Y, Altman, RB, Ames, MM, Weinshilboum, RM, Eichelbaum, M, Ingle, JN, Klein, TE, Boländer, J, Ulmer, HU, Fischer-Bosch, M, Fritz, P, Simon, W, Bryan, Y, Strick, R, Koelbl, H, Ambrosone, CA & H, EZ 2014, 'CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations', Clinical Pharmacology and Therapeutics, vol. 95, no. 2, pp. 216-227. https://doi.org/10.1038/clpt.2013.186

CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations. / Province, Michael A.; Goetz, M. P.; Brauch, H.; Flockhart, D. A.; Hebert, J. M.; Whaley, R.; Suman, V. J.; Schroth, W.; Winter, S.; Zembutsu, H.; Mushiroda, Taisei; Newman, W. G.; Lee, M. T.M.; Ambrosone, C. B.; Beckmann, M. W.; Choi, J. Y.; Dieudonné, A. S.; Fasching, P. A.; Ferraldeschi, R.; Gong, L.; Haschke-Becher, E.; Howell, A.; Jordan, L. B.; Hamann, U.; Kiyotani, K.; Krippl, P.; Lambrechts, D.; Latif, A.; Langsenlehner, U.; Lorizio, W.; Neven, P.; Nguyen, A. T.; Park, Byeongwoo; Purdie, C. A.; Quinlan, P.; Renner, W.; Schmidt, M.; Schwab, M.; Shin, J. G.; Stingl, J. C.; Wegman, P.; Wingren, Sten; Wu, A. H.B.; Ziv, E.; Zirpoli, G.; Thompson, A. M.; Jordan, V. C.; Nakamura, Y.; Altman, R. B.; Ames, M. M.; Weinshilboum, R. M.; Eichelbaum, M.; Ingle, J. N.; Klein, T. E.; Boländer, Julia; Ulmer, Hans Ulrich; Fischer-Bosch, Margarete; Fritz, Peter; Simon, Wolfgang; Bryan, Y.; Strick, Reiner; Koelbl, Heinz; Ambrosone, Christine A.; H, Elad Ziv.

In: Clinical Pharmacology and Therapeutics, Vol. 95, No. 2, 01.02.2014, p. 216-227.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CYP2D6 Genotype and Adjuvant Tamoxifen

T2 - Meta-Analysis of Heterogeneous Study Populations

AU - Province, Michael A.

AU - Goetz, M. P.

AU - Brauch, H.

AU - Flockhart, D. A.

AU - Hebert, J. M.

AU - Whaley, R.

AU - Suman, V. J.

AU - Schroth, W.

AU - Winter, S.

AU - Zembutsu, H.

AU - Mushiroda, Taisei

AU - Newman, W. G.

AU - Lee, M. T.M.

AU - Ambrosone, C. B.

AU - Beckmann, M. W.

AU - Choi, J. Y.

AU - Dieudonné, A. S.

AU - Fasching, P. A.

AU - Ferraldeschi, R.

AU - Gong, L.

AU - Haschke-Becher, E.

AU - Howell, A.

AU - Jordan, L. B.

AU - Hamann, U.

AU - Kiyotani, K.

AU - Krippl, P.

AU - Lambrechts, D.

AU - Latif, A.

AU - Langsenlehner, U.

AU - Lorizio, W.

AU - Neven, P.

AU - Nguyen, A. T.

AU - Park, Byeongwoo

AU - Purdie, C. A.

AU - Quinlan, P.

AU - Renner, W.

AU - Schmidt, M.

AU - Schwab, M.

AU - Shin, J. G.

AU - Stingl, J. C.

AU - Wegman, P.

AU - Wingren, Sten

AU - Wu, A. H.B.

AU - Ziv, E.

AU - Zirpoli, G.

AU - Thompson, A. M.

AU - Jordan, V. C.

AU - Nakamura, Y.

AU - Altman, R. B.

AU - Ames, M. M.

AU - Weinshilboum, R. M.

AU - Eichelbaum, M.

AU - Ingle, J. N.

AU - Klein, T. E.

AU - Boländer, Julia

AU - Ulmer, Hans Ulrich

AU - Fischer-Bosch, Margarete

AU - Fritz, Peter

AU - Simon, Wolfgang

AU - Bryan, Y.

AU - Strick, Reiner

AU - Koelbl, Heinz

AU - Ambrosone, Christine A.

AU - H, Elad Ziv

PY - 2014/2/1

Y1 - 2014/2/1

N2 - The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

AB - The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

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