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. Gong; E. Haschke-Becher; 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

doi:10.1038/clpt.2013.186

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, 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 journal › Article › peer-review

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 language	English
Pages (from-to)	216-227
Number of pages	11
Journal	Clinical Pharmacology and Therapeutics
Volume	95
Issue number	2
DOIs	https://doi.org/10.1038/clpt.2013.186
Publication status	Published - Feb 2014

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10.1038/clpt.2013.186

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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., ... 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

@article{151c09466499429bbe92c028c137aa6b,

title = "CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations",

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.",

author = "Province, {M. A.} and Goetz, {M. P.} and H. Brauch and Flockhart, {D. A.} and Hebert, {J. M.} and R. Whaley and Suman, {V. J.} and W. Schroth and S. Winter and H. Zembutsu and T. Mushiroda and Newman, {W. G.} and Lee, {M. T M} and Ambrosone, {C. B.} and Beckmann, {M. W.} and Choi, {J. Y.} and Dieudonn{\'e}, {A. S.} and Fasching, {P. A.} and R. Ferraldeschi and L. Gong and E. Haschke-Becher and Jordan, {L. B.} and U. Hamann and K. Kiyotani and P. Krippl and D. Lambrechts and A. Latif and U. Langsenlehner and W. Lorizio and P. Neven and Nguyen, {A. T.} and Park, {B. W.} and Purdie, {C. A.} and P. Quinlan and W. Renner and M. Schmidt and M. Schwab and Shin, {J. G.} and Stingl, {J. C.} and P. Wegman and S. Wingren and Wu, {A. H B} and E. Ziv and G. Zirpoli and Thompson, {A. M.} and Jordan, {V. C.} and Y. Nakamura and Altman, {R. B.} and Ames, {M. M.} and Weinshilboum, {R. M.} and M. Eichelbaum and Ingle, {J. N.} and Klein, {T. E.} and Ute Hamann and Julia Bol{\"a}nder and Ulmer, {Hans Ulrich} and Margarete Fischer-Bosch and Hiltrud Brauch and Werner Schroth and Matthias Schwab and Stefan Winter and Michel Eichelbaum and Peter Fritz and Wolfgang Simon and Stingl, {Julia C.} and Flockhart, {David A.} and Nguyen, {Anne T.} and Shin, {Jae Gook} and Choi, {Ji Yeob} and Goetz, {Matthew P.} and Ingle, {James N.} and Suman, {Vera J.} and Weinshilboum, {Richard M.} and Purdie, {Colin A.} and Jordan, {Lee B.} and Pia Wegman and Hitoshi Zembutsu and Taisei Mushiroda and Kazuma Kiyotani and Ambrosone, {Christine B.} and Fasching, {Peter A.} and Reiner Strick and Beckmann, {Matthias W.} and Patrick Neven and Dieudonn{\'e}, {Anne Sophie} and Elisabeth Haschke-Becher and Wu, {Alan H B} and Wendy Lorizio and Elad Ziv and Philip Quinlan and Marcus Schmidt and Heinz Koelbl and Newman, {William G.} and Roberta Ferraldeschi and Anthony Howell and Ayse Latif and Diether Lambrechts and Park, {Byeong Woo} and Klein, {Teri E.} and Ryan Whaley and Province, {Michael A.} and Hebert, {Joan M.} and Li Gong and Altman, {Russ B.} and Ambrosone, {Christine A.} and Thompson, {Alastair M.} and Sten Wingren and H, {Elad Ziv}",

year = "2014",

month = feb,

doi = "10.1038/clpt.2013.186",

language = "English",

volume = "95",

pages = "216--227",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

publisher = "Springer Nature",

number = "2",

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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, 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

TY - JOUR

T1 - CYP2D6 Genotype and Adjuvant Tamoxifen: 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 - 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.

U2 - 10.1038/clpt.2013.186

DO - 10.1038/clpt.2013.186

M3 - Article

C2 - 24060820

SN - 0009-9236

VL - 95

SP - 216

EP - 227

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 2

ER -

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

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