Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes

Matthew P. Goetz, James M. Rae, Vera J. Suman, Stephanie L. Safgren, Matthew M. Ames, Daniel W. Visscher, Carol Reynolds, Fergus J. Couch, Wilma L. Lingle, David A. Flockhart, Zeruesenay Desta, Edith A. Perez, James N. Ingle

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Abstract

Purpose: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. Methods: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells diving patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. Results: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 M/M genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. Conclusion: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.

Original languageEnglish
Pages (from-to)9312-9318
Number of pages7
JournalJournal of Clinical Oncology
Volume23
Issue number36
DOIs
StatePublished - 2005

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Hot Flashes
Pharmacogenetics
Cytochrome P-450 CYP2D6
Tamoxifen
Biotransformation
Genotype
Cytochrome P-450 CYP3A
Cheek
Paraffin
Recurrence
Neoplasms
Diving
Disease-Free Survival
Multivariate Analysis
Alleles
Breast Neoplasms
Survival
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Goetz, M. P., Rae, J. M., Suman, V. J., Safgren, S. L., Ames, M. M., Visscher, D. W., ... Ingle, J. N. (2005). Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. Journal of Clinical Oncology, 23(36), 9312-9318. https://doi.org/10.1200/JCO.2005.03.3266

Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. / Goetz, Matthew P.; Rae, James M.; Suman, Vera J.; Safgren, Stephanie L.; Ames, Matthew M.; Visscher, Daniel W.; Reynolds, Carol; Couch, Fergus J.; Lingle, Wilma L.; Flockhart, David A.; Desta, Zeruesenay; Perez, Edith A.; Ingle, James N.

In: Journal of Clinical Oncology, Vol. 23, No. 36, 2005, p. 9312-9318.

Research output: Contribution to journalArticle

Goetz, MP, Rae, JM, Suman, VJ, Safgren, SL, Ames, MM, Visscher, DW, Reynolds, C, Couch, FJ, Lingle, WL, Flockhart, DA, Desta, Z, Perez, EA & Ingle, JN 2005, 'Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes', Journal of Clinical Oncology, vol. 23, no. 36, pp. 9312-9318. https://doi.org/10.1200/JCO.2005.03.3266
Goetz, Matthew P. ; Rae, James M. ; Suman, Vera J. ; Safgren, Stephanie L. ; Ames, Matthew M. ; Visscher, Daniel W. ; Reynolds, Carol ; Couch, Fergus J. ; Lingle, Wilma L. ; Flockhart, David A. ; Desta, Zeruesenay ; Perez, Edith A. ; Ingle, James N. / Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 36. pp. 9312-9318.
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abstract = "Purpose: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. Methods: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells diving patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. Results: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100{\%}. Women with the CYP2D6 M/M genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. Conclusion: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.",
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AU - Goetz, Matthew P.

AU - Rae, James M.

AU - Suman, Vera J.

AU - Safgren, Stephanie L.

AU - Ames, Matthew M.

AU - Visscher, Daniel W.

AU - Reynolds, Carol

AU - Couch, Fergus J.

AU - Lingle, Wilma L.

AU - Flockhart, David A.

AU - Desta, Zeruesenay

AU - Perez, Edith A.

AU - Ingle, James N.

PY - 2005

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N2 - Purpose: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. Methods: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells diving patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. Results: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 M/M genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. Conclusion: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.

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