CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study

D. L. Hertz, K. M. Kidwell, S. G. Hilsenbeck, S. Oesterreich, C. K. Osborne, S. Philips, C. Chenault, R. J. Hartmaier, Todd Skaar, M. J. Sikora, J. M. Rae

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00–2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

Original languageEnglish (US)
Pages (from-to)277-287
Number of pages11
JournalBreast Cancer Research and Treatment
Volume166
Issue number1
DOIs
StatePublished - Nov 1 2017

Fingerprint

Cytochrome P-450 CYP2D6
Tamoxifen
Genotype
Breast Neoplasms
Survival
Population
Recurrence
Neoplasms
Survival Analysis
Estrogen Receptors
Meta-Analysis
Therapeutics
Confidence Intervals
Phenotype
DNA

Keywords

  • CYP2D6
  • Pharmacogenetic
  • Predictive
  • Prognostic
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen : results from a population-based study. / Hertz, D. L.; Kidwell, K. M.; Hilsenbeck, S. G.; Oesterreich, S.; Osborne, C. K.; Philips, S.; Chenault, C.; Hartmaier, R. J.; Skaar, Todd; Sikora, M. J.; Rae, J. M.

In: Breast Cancer Research and Treatment, Vol. 166, No. 1, 01.11.2017, p. 277-287.

Research output: Contribution to journalArticle

Hertz, DL, Kidwell, KM, Hilsenbeck, SG, Oesterreich, S, Osborne, CK, Philips, S, Chenault, C, Hartmaier, RJ, Skaar, T, Sikora, MJ & Rae, JM 2017, 'CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study', Breast Cancer Research and Treatment, vol. 166, no. 1, pp. 277-287. https://doi.org/10.1007/s10549-017-4400-8
Hertz, D. L. ; Kidwell, K. M. ; Hilsenbeck, S. G. ; Oesterreich, S. ; Osborne, C. K. ; Philips, S. ; Chenault, C. ; Hartmaier, R. J. ; Skaar, Todd ; Sikora, M. J. ; Rae, J. M. / CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen : results from a population-based study. In: Breast Cancer Research and Treatment. 2017 ; Vol. 166, No. 1. pp. 277-287.
@article{9ad54343bd1140938a0a493852bc4a1b,
title = "CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study",
abstract = "Purpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95{\%} confidence interval 1.00–2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.",
keywords = "CYP2D6, Pharmacogenetic, Predictive, Prognostic, Tamoxifen",
author = "Hertz, {D. L.} and Kidwell, {K. M.} and Hilsenbeck, {S. G.} and S. Oesterreich and Osborne, {C. K.} and S. Philips and C. Chenault and Hartmaier, {R. J.} and Todd Skaar and Sikora, {M. J.} and Rae, {J. M.}",
year = "2017",
month = "11",
day = "1",
doi = "10.1007/s10549-017-4400-8",
language = "English (US)",
volume = "166",
pages = "277--287",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen

T2 - results from a population-based study

AU - Hertz, D. L.

AU - Kidwell, K. M.

AU - Hilsenbeck, S. G.

AU - Oesterreich, S.

AU - Osborne, C. K.

AU - Philips, S.

AU - Chenault, C.

AU - Hartmaier, R. J.

AU - Skaar, Todd

AU - Sikora, M. J.

AU - Rae, J. M.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Purpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00–2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

AB - Purpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00–2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

KW - CYP2D6

KW - Pharmacogenetic

KW - Predictive

KW - Prognostic

KW - Tamoxifen

UR - http://www.scopus.com/inward/record.url?scp=85025130119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85025130119&partnerID=8YFLogxK

U2 - 10.1007/s10549-017-4400-8

DO - 10.1007/s10549-017-4400-8

M3 - Article

C2 - 28730340

AN - SCOPUS:85025130119

VL - 166

SP - 277

EP - 287

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -