Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention: Results from the NSABP P1 and P2 clinical trials

Matthew P. Goetz, Daniel J. Schaid, D. Lawrence Wickerham, Stephanie Safgren, Taisei Mushiroda, Michiaki Kubo, Anthony Batzler, Joseph P. Costantino, Victor G. Vogel, Soonmyung Paik, Erin E. Carlson, David A. Flockhart, Norman Wolmark, Yusuke Nakamura, Richard M. Weinshilboum, James N. Ingle, Matthew M. Ames

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. Methods: We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3,*4,*5, and*6), reduced (*10,*17, and*41), and increased (*1XN and*2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. Results: A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. Conclusion: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.

Original languageEnglish
Pages (from-to)6944-6951
Number of pages8
JournalClinical Cancer Research
Volume17
Issue number21
DOIs
Publication statusPublished - 01-11-2011

Fingerprint

Cytochrome P-450 CYP2D6
Chemoprevention
Tamoxifen
Clinical Trials
Breast Neoplasms
Genotype
Selective Estrogen Receptor Modulators
Raloxifene Hydrochloride
Enzymes
Primary Prevention
Case-Control Studies
Alleles
Cytochrome P-450 CYP2D6 Inhibitors
DNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Goetz, Matthew P. ; Schaid, Daniel J. ; Wickerham, D. Lawrence ; Safgren, Stephanie ; Mushiroda, Taisei ; Kubo, Michiaki ; Batzler, Anthony ; Costantino, Joseph P. ; Vogel, Victor G. ; Paik, Soonmyung ; Carlson, Erin E. ; Flockhart, David A. ; Wolmark, Norman ; Nakamura, Yusuke ; Weinshilboum, Richard M. ; Ingle, James N. ; Ames, Matthew M. / Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention : Results from the NSABP P1 and P2 clinical trials. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 21. pp. 6944-6951.
@article{540e98435f4d4573b1ec327057653921,
title = "Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention: Results from the NSABP P1 and P2 clinical trials",
abstract = "Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. Methods: We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3,*4,*5, and*6), reduced (*10,*17, and*41), and increased (*1XN and*2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. Results: A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97{\%}. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95{\%} CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95{\%} CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95{\%} CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. Conclusion: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.",
author = "Goetz, {Matthew P.} and Schaid, {Daniel J.} and Wickerham, {D. Lawrence} and Stephanie Safgren and Taisei Mushiroda and Michiaki Kubo and Anthony Batzler and Costantino, {Joseph P.} and Vogel, {Victor G.} and Soonmyung Paik and Carlson, {Erin E.} and Flockhart, {David A.} and Norman Wolmark and Yusuke Nakamura and Weinshilboum, {Richard M.} and Ingle, {James N.} and Ames, {Matthew M.}",
year = "2011",
month = "11",
day = "1",
doi = "10.1158/1078-0432.CCR-11-0860",
language = "English",
volume = "17",
pages = "6944--6951",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "21",

}

Goetz, MP, Schaid, DJ, Wickerham, DL, Safgren, S, Mushiroda, T, Kubo, M, Batzler, A, Costantino, JP, Vogel, VG, Paik, S, Carlson, EE, Flockhart, DA, Wolmark, N, Nakamura, Y, Weinshilboum, RM, Ingle, JN & Ames, MM 2011, 'Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention: Results from the NSABP P1 and P2 clinical trials', Clinical Cancer Research, vol. 17, no. 21, pp. 6944-6951. https://doi.org/10.1158/1078-0432.CCR-11-0860

Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention : Results from the NSABP P1 and P2 clinical trials. / Goetz, Matthew P.; Schaid, Daniel J.; Wickerham, D. Lawrence; Safgren, Stephanie; Mushiroda, Taisei; Kubo, Michiaki; Batzler, Anthony; Costantino, Joseph P.; Vogel, Victor G.; Paik, Soonmyung; Carlson, Erin E.; Flockhart, David A.; Wolmark, Norman; Nakamura, Yusuke; Weinshilboum, Richard M.; Ingle, James N.; Ames, Matthew M.

In: Clinical Cancer Research, Vol. 17, No. 21, 01.11.2011, p. 6944-6951.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention

T2 - Results from the NSABP P1 and P2 clinical trials

AU - Goetz, Matthew P.

AU - Schaid, Daniel J.

AU - Wickerham, D. Lawrence

AU - Safgren, Stephanie

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Batzler, Anthony

AU - Costantino, Joseph P.

AU - Vogel, Victor G.

AU - Paik, Soonmyung

AU - Carlson, Erin E.

AU - Flockhart, David A.

AU - Wolmark, Norman

AU - Nakamura, Yusuke

AU - Weinshilboum, Richard M.

AU - Ingle, James N.

AU - Ames, Matthew M.

PY - 2011/11/1

Y1 - 2011/11/1

N2 - Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. Methods: We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3,*4,*5, and*6), reduced (*10,*17, and*41), and increased (*1XN and*2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. Results: A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. Conclusion: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.

AB - Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. Methods: We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3,*4,*5, and*6), reduced (*10,*17, and*41), and increased (*1XN and*2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. Results: A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. Conclusion: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.

UR - http://www.scopus.com/inward/record.url?scp=80455168584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80455168584&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-11-0860

DO - 10.1158/1078-0432.CCR-11-0860

M3 - Article

C2 - 21880792

AN - SCOPUS:80455168584

VL - 17

SP - 6944

EP - 6951

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 21

ER -