Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen

Werner Schroth, Matthew Philip Goetz, Ute Hamann, Peter A. Fasching, Marcus Schmidt, Stefan Winter, Peter Fritz, Wolfgang Simon, Vera Jean Suman, Matthew M. Ames, Stephanie L. Safgren, Mary J. Kuffel, Hans Ulrich Ulmer, Julia Boländer, Reiner Strick, Matthias W. Beckmann, Heinz Koelbl, Richard M Weinshilboum, James N. Ingle, Michel Eichelbaum & 2 others Matthias Schwab, Hiltrud Brauch

Research output: Contribution to journalArticle

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Abstract

Context: The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Objective: To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. Design, Setting, and Patients: Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. Main Outcome Measures: Time to recurrence, event-free survival, disease-free survival, and overall survival. Results: Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and29.0%for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). Conclusion: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

Original languageEnglish (US)
Pages (from-to)1429-1436
Number of pages8
JournalJAMA - Journal of the American Medical Association
Volume302
Issue number13
DOIs
StatePublished - 2009

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Cytochrome P-450 CYP2D6
Tamoxifen
Breast Neoplasms
Disease-Free Survival
Confidence Intervals
Recurrence
Alleles
Hormones
Survival
Cytochrome P-450 Enzyme System
Outcome Assessment (Health Care)
Drug Therapy
Mortality
DNA
Enzymes
Therapeutics
Growth

ASJC Scopus subject areas

  • Medicine(all)

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Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. / Schroth, Werner; Goetz, Matthew Philip; Hamann, Ute; Fasching, Peter A.; Schmidt, Marcus; Winter, Stefan; Fritz, Peter; Simon, Wolfgang; Suman, Vera Jean; Ames, Matthew M.; Safgren, Stephanie L.; Kuffel, Mary J.; Ulmer, Hans Ulrich; Boländer, Julia; Strick, Reiner; Beckmann, Matthias W.; Koelbl, Heinz; Weinshilboum, Richard M; Ingle, James N.; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud.

In: JAMA - Journal of the American Medical Association, Vol. 302, No. 13, 2009, p. 1429-1436.

Research output: Contribution to journalArticle

Schroth, W, Goetz, MP, Hamann, U, Fasching, PA, Schmidt, M, Winter, S, Fritz, P, Simon, W, Suman, VJ, Ames, MM, Safgren, SL, Kuffel, MJ, Ulmer, HU, Boländer, J, Strick, R, Beckmann, MW, Koelbl, H, Weinshilboum, RM, Ingle, JN, Eichelbaum, M, Schwab, M & Brauch, H 2009, 'Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen', JAMA - Journal of the American Medical Association, vol. 302, no. 13, pp. 1429-1436. https://doi.org/10.1001/jama.2009.1420
Schroth, Werner ; Goetz, Matthew Philip ; Hamann, Ute ; Fasching, Peter A. ; Schmidt, Marcus ; Winter, Stefan ; Fritz, Peter ; Simon, Wolfgang ; Suman, Vera Jean ; Ames, Matthew M. ; Safgren, Stephanie L. ; Kuffel, Mary J. ; Ulmer, Hans Ulrich ; Boländer, Julia ; Strick, Reiner ; Beckmann, Matthias W. ; Koelbl, Heinz ; Weinshilboum, Richard M ; Ingle, James N. ; Eichelbaum, Michel ; Schwab, Matthias ; Brauch, Hiltrud. / Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. In: JAMA - Journal of the American Medical Association. 2009 ; Vol. 302, No. 13. pp. 1429-1436.
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title = "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen",
abstract = "Context: The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Objective: To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. Design, Setting, and Patients: Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4{\%}). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. Main Outcome Measures: Time to recurrence, event-free survival, disease-free survival, and overall survival. Results: Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9{\%} for extensive metabolizers, 20.9{\%} for heterozygous extensive/intermediate metabolizers, and29.0{\%}for poor metabolizers, and all-cause mortality rates were 16.7{\%}, 18.0{\%}, and 22.8{\%}, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95{\%} confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95{\%} CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95{\%} CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95{\%} CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95{\%} CI, 0.88-1.51). Conclusion: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.",
author = "Werner Schroth and Goetz, {Matthew Philip} and Ute Hamann and Fasching, {Peter A.} and Marcus Schmidt and Stefan Winter and Peter Fritz and Wolfgang Simon and Suman, {Vera Jean} and Ames, {Matthew M.} and Safgren, {Stephanie L.} and Kuffel, {Mary J.} and Ulmer, {Hans Ulrich} and Julia Bol{\"a}nder and Reiner Strick and Beckmann, {Matthias W.} and Heinz Koelbl and Weinshilboum, {Richard M} and Ingle, {James N.} and Michel Eichelbaum and Matthias Schwab and Hiltrud Brauch",
year = "2009",
doi = "10.1001/jama.2009.1420",
language = "English (US)",
volume = "302",
pages = "1429--1436",
journal = "JAMA - Journal of the American Medical Association",
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TY - JOUR

T1 - Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen

AU - Schroth, Werner

AU - Goetz, Matthew Philip

AU - Hamann, Ute

AU - Fasching, Peter A.

AU - Schmidt, Marcus

AU - Winter, Stefan

AU - Fritz, Peter

AU - Simon, Wolfgang

AU - Suman, Vera Jean

AU - Ames, Matthew M.

AU - Safgren, Stephanie L.

AU - Kuffel, Mary J.

AU - Ulmer, Hans Ulrich

AU - Boländer, Julia

AU - Strick, Reiner

AU - Beckmann, Matthias W.

AU - Koelbl, Heinz

AU - Weinshilboum, Richard M

AU - Ingle, James N.

AU - Eichelbaum, Michel

AU - Schwab, Matthias

AU - Brauch, Hiltrud

PY - 2009

Y1 - 2009

N2 - Context: The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Objective: To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. Design, Setting, and Patients: Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. Main Outcome Measures: Time to recurrence, event-free survival, disease-free survival, and overall survival. Results: Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and29.0%for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). Conclusion: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

AB - Context: The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Objective: To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. Design, Setting, and Patients: Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. Main Outcome Measures: Time to recurrence, event-free survival, disease-free survival, and overall survival. Results: Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and29.0%for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). Conclusion: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

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U2 - 10.1001/jama.2009.1420

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