CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations

M. A. Province, M. P. Goetz, H. Brauch, D. A. Flockhart, J. M. Hebert, R. Whaley, V. J. Suman, W. Schroth, S. Winter, H. Zembutsu, T. 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. GongE. 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, B. W. Park, C. A. Purdie, P. Quinlan, W. Renner, M. Schmidt, M. Schwab, J. G. Shin, J. C. Stingl, P. Wegman, S. 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, Ute Hamann, Julia Boländer, Hans Ulrich Ulmer, Margarete Fischer-Bosch, Hiltrud Brauch, Werner Schroth, Matthias Schwab, Stefan Winter, Michel Eichelbaum, Peter Fritz, Wolfgang Simon, Julia C. Stingl, David A. Flockhart, Anne T. Nguyen, Jae Gook Shin, Ji Yeob Choi, Matthew P. Goetz, James N. Ingle, Vera J. Suman, Richard M. Weinshilboum, Colin A. Purdie, Lee B. Jordan, Pia Wegman, Hitoshi Zembutsu, Taisei Mushiroda, Kazuma Kiyotani, Christine B. Ambrosone, Peter A. Fasching, Reiner Strick, Matthias W. Beckmann, Patrick Neven, Anne Sophie Dieudonné, Elisabeth Haschke-Becher, Alan H B Wu, Wendy Lorizio, Elad Ziv, Philip Quinlan, Marcus Schmidt, Heinz Koelbl, William G. Newman, Roberta Ferraldeschi, Anthony Howell, Ayse Latif, Diether Lambrechts, Byeong Woo Park, Teri E. Klein, Ryan Whaley, Michael A. Province, Joan M. Hebert, Li Gong, Russ B. Altman, Christine A. Ambrosone, Alastair M. Thompson, Sten Wingren, Elad Ziv H

Research output: Contribution to journalArticle

109 Citations (Scopus)

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 (US)
Pages (from-to)216-227
Number of pages12
JournalClinical Pharmacology and Therapeutics
Volume95
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

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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

ASJC Scopus subject areas

  • 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

CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations. / Province, M. A.; Goetz, M. P.; Brauch, H.; Flockhart, D. A.; Hebert, J. M.; Whaley, R.; Suman, V. J.; Schroth, W.; Winter, S.; Zembutsu, H.; Mushiroda, T.; 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, B. W.; Purdie, C. A.; Quinlan, P.; Renner, W.; Schmidt, M.; Schwab, M.; Shin, J. G.; Stingl, J. C.; Wegman, P.; Wingren, S.; 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.; Hamann, Ute; Boländer, Julia; Ulmer, Hans Ulrich; Fischer-Bosch, Margarete; Brauch, Hiltrud; Schroth, Werner; Schwab, Matthias; Winter, Stefan; Eichelbaum, Michel; Fritz, Peter; Simon, Wolfgang; Stingl, Julia C.; Flockhart, David A.; Nguyen, Anne T.; Shin, Jae Gook; Choi, Ji Yeob; Goetz, Matthew P.; Ingle, James N.; Suman, Vera J.; Weinshilboum, Richard M.; Purdie, Colin A.; Jordan, Lee B.; Wegman, Pia; Zembutsu, Hitoshi; Mushiroda, Taisei; Kiyotani, Kazuma; Ambrosone, Christine B.; Fasching, Peter A.; Strick, Reiner; Beckmann, Matthias W.; Neven, Patrick; Dieudonné, Anne Sophie; Haschke-Becher, Elisabeth; Wu, Alan H B; Lorizio, Wendy; Ziv, Elad; Quinlan, Philip; Schmidt, Marcus; Koelbl, Heinz; Newman, William G.; Ferraldeschi, Roberta; Howell, Anthony; Latif, Ayse; Lambrechts, Diether; Park, Byeong Woo; Klein, Teri E.; Whaley, Ryan; Province, Michael A.; Hebert, Joan M.; Gong, Li; Altman, Russ B.; Ambrosone, Christine A.; Thompson, Alastair M.; Wingren, Sten; H, Elad Ziv.

In: Clinical Pharmacology and Therapeutics, Vol. 95, No. 2, 02.2014, p. 216-227.

Research output: Contribution to journalArticle

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, BW, 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, Hamann, U, Boländer, J, Ulmer, HU, Fischer-Bosch, M, Brauch, H, Schroth, W, Schwab, M, Winter, S, Eichelbaum, M, Fritz, P, Simon, W, Stingl, JC, Flockhart, DA, Nguyen, AT, Shin, JG, Choi, JY, Goetz, MP, Ingle, JN, Suman, VJ, Weinshilboum, RM, Purdie, CA, Jordan, LB, Wegman, P, Zembutsu, H, Mushiroda, T, Kiyotani, K, Ambrosone, CB, Fasching, PA, Strick, R, Beckmann, MW, Neven, P, Dieudonné, AS, Haschke-Becher, E, Wu, AHB, Lorizio, W, Ziv, E, Quinlan, P, Schmidt, M, Koelbl, H, Newman, WG, Ferraldeschi, R, Howell, A, Latif, A, Lambrechts, D, Park, BW, Klein, TE, Whaley, R, Province, MA, Hebert, JM, Gong, L, Altman, RB, Ambrosone, CA, Thompson, AM, Wingren, S & 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
Province, M. A. ; Goetz, M. P. ; Brauch, H. ; Flockhart, D. A. ; Hebert, J. M. ; Whaley, R. ; Suman, V. J. ; Schroth, W. ; Winter, S. ; Zembutsu, H. ; Mushiroda, T. ; 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, B. W. ; Purdie, C. A. ; Quinlan, P. ; Renner, W. ; Schmidt, M. ; Schwab, M. ; Shin, J. G. ; Stingl, J. C. ; Wegman, P. ; Wingren, S. ; 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. ; Hamann, Ute ; Boländer, Julia ; Ulmer, Hans Ulrich ; Fischer-Bosch, Margarete ; Brauch, Hiltrud ; Schroth, Werner ; Schwab, Matthias ; Winter, Stefan ; Eichelbaum, Michel ; Fritz, Peter ; Simon, Wolfgang ; Stingl, Julia C. ; Flockhart, David A. ; Nguyen, Anne T. ; Shin, Jae Gook ; Choi, Ji Yeob ; Goetz, Matthew P. ; Ingle, James N. ; Suman, Vera J. ; Weinshilboum, Richard M. ; Purdie, Colin A. ; Jordan, Lee B. ; Wegman, Pia ; Zembutsu, Hitoshi ; Mushiroda, Taisei ; Kiyotani, Kazuma ; Ambrosone, Christine B. ; Fasching, Peter A. ; Strick, Reiner ; Beckmann, Matthias W. ; Neven, Patrick ; Dieudonné, Anne Sophie ; Haschke-Becher, Elisabeth ; Wu, Alan H B ; Lorizio, Wendy ; Ziv, Elad ; Quinlan, Philip ; Schmidt, Marcus ; Koelbl, Heinz ; Newman, William G. ; Ferraldeschi, Roberta ; Howell, Anthony ; Latif, Ayse ; Lambrechts, Diether ; Park, Byeong Woo ; Klein, Teri E. ; Whaley, Ryan ; Province, Michael A. ; Hebert, Joan M. ; Gong, Li ; Altman, Russ B. ; Ambrosone, Christine A. ; Thompson, Alastair M. ; Wingren, Sten ; 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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TY - JOUR

T1 - CYP2D6 Genotype and Adjuvant Tamoxifen

T2 - Meta-Analysis of Heterogeneous Study Populations

AU - Province, M. 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, T.

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, B. W.

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, S.

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 - Hamann, Ute

AU - Boländer, Julia

AU - Ulmer, Hans Ulrich

AU - Fischer-Bosch, Margarete

AU - Brauch, Hiltrud

AU - Schroth, Werner

AU - Schwab, Matthias

AU - Winter, Stefan

AU - Eichelbaum, Michel

AU - Fritz, Peter

AU - Simon, Wolfgang

AU - Stingl, Julia C.

AU - Flockhart, David A.

AU - Nguyen, Anne T.

AU - Shin, Jae Gook

AU - Choi, Ji Yeob

AU - Goetz, Matthew P.

AU - Ingle, James N.

AU - Suman, Vera J.

AU - Weinshilboum, Richard M.

AU - Purdie, Colin A.

AU - Jordan, Lee B.

AU - Wegman, Pia

AU - Zembutsu, Hitoshi

AU - Mushiroda, Taisei

AU - Kiyotani, Kazuma

AU - Ambrosone, Christine B.

AU - Fasching, Peter A.

AU - Strick, Reiner

AU - Beckmann, Matthias W.

AU - Neven, Patrick

AU - Dieudonné, Anne Sophie

AU - Haschke-Becher, Elisabeth

AU - Wu, Alan H B

AU - Lorizio, Wendy

AU - Ziv, Elad

AU - Quinlan, Philip

AU - Schmidt, Marcus

AU - Koelbl, Heinz

AU - Newman, William G.

AU - Ferraldeschi, Roberta

AU - Howell, Anthony

AU - Latif, Ayse

AU - Lambrechts, Diether

AU - Park, Byeong Woo

AU - Klein, Teri E.

AU - Whaley, Ryan

AU - Province, Michael A.

AU - Hebert, Joan M.

AU - Gong, Li

AU - Altman, Russ B.

AU - Ambrosone, Christine A.

AU - Thompson, Alastair M.

AU - Wingren, Sten

AU - H, Elad Ziv

PY - 2014/2

Y1 - 2014/2

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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U2 - 10.1038/clpt.2013.186

DO - 10.1038/clpt.2013.186

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