Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor

Combining inherited and tumor gene markers for prediction of tamoxifen resistance

Matthew P. Goetz, Vera J. Suman, Fergus J. Couch, Matthew M. Ames, James M. Rae, Mark G. Erlander, Xiao Jun Ma, Dennis C. Sgroi, Carol A. Reynolds, Wilma L. Lingle, Richard M. Weinshilboum, David A. Flockhart, Zeruesenay Desta, Edith A. Perez, James N. Ingle

Research output: Contribution to journalArticle

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Abstract

Purpose: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (H0XB13) to interteukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer. Experimental Design. Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central CancerTreatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6'4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling. Results: CYP2D6 metabolism and HOXB13IIL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13IIL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% Cl, 1.17-8.52; P = 0.024). Conclusions: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.

Original languageEnglish
Pages (from-to)5864-5868
Number of pages5
JournalClinical Cancer Research
Volume14
Issue number18
DOIs
StatePublished - Sep 15 2008

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Interleukin Receptors
Cytochrome P-450 CYP2D6
Interleukin-17
Homeobox Genes
Tamoxifen
Tumor Biomarkers
Genes
Disease-Free Survival
Survival
Breast Neoplasms
Reverse Transcription

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor : Combining inherited and tumor gene markers for prediction of tamoxifen resistance. / Goetz, Matthew P.; Suman, Vera J.; Couch, Fergus J.; Ames, Matthew M.; Rae, James M.; Erlander, Mark G.; Ma, Xiao Jun; Sgroi, Dennis C.; Reynolds, Carol A.; Lingle, Wilma L.; Weinshilboum, Richard M.; Flockhart, David A.; Desta, Zeruesenay; Perez, Edith A.; Ingle, James N.

In: Clinical Cancer Research, Vol. 14, No. 18, 15.09.2008, p. 5864-5868.

Research output: Contribution to journalArticle

Goetz, MP, Suman, VJ, Couch, FJ, Ames, MM, Rae, JM, Erlander, MG, Ma, XJ, Sgroi, DC, Reynolds, CA, Lingle, WL, Weinshilboum, RM, Flockhart, DA, Desta, Z, Perez, EA & Ingle, JN 2008, 'Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor: Combining inherited and tumor gene markers for prediction of tamoxifen resistance', Clinical Cancer Research, vol. 14, no. 18, pp. 5864-5868. https://doi.org/10.1158/1078-0432.CCR-08-0619
Goetz, Matthew P. ; Suman, Vera J. ; Couch, Fergus J. ; Ames, Matthew M. ; Rae, James M. ; Erlander, Mark G. ; Ma, Xiao Jun ; Sgroi, Dennis C. ; Reynolds, Carol A. ; Lingle, Wilma L. ; Weinshilboum, Richard M. ; Flockhart, David A. ; Desta, Zeruesenay ; Perez, Edith A. ; Ingle, James N. / Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor : Combining inherited and tumor gene markers for prediction of tamoxifen resistance. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 18. pp. 5864-5868.
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abstract = "Purpose: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (H0XB13) to interteukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer. Experimental Design. Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central CancerTreatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6'4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling. Results: CYP2D6 metabolism and HOXB13IIL17BR gene ratio was available in 110 of 160 (69{\%}) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13IIL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95{\%} confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95{\%} Cl, 1.17-8.52; P = 0.024). Conclusions: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.",
author = "Goetz, {Matthew P.} and Suman, {Vera J.} and Couch, {Fergus J.} and Ames, {Matthew M.} and Rae, {James M.} and Erlander, {Mark G.} and Ma, {Xiao Jun} and Sgroi, {Dennis C.} and Reynolds, {Carol A.} and Lingle, {Wilma L.} and Weinshilboum, {Richard M.} and Flockhart, {David A.} and Zeruesenay Desta and Perez, {Edith A.} and Ingle, {James N.}",
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T1 - Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor

T2 - Combining inherited and tumor gene markers for prediction of tamoxifen resistance

AU - Goetz, Matthew P.

AU - Suman, Vera J.

AU - Couch, Fergus J.

AU - Ames, Matthew M.

AU - Rae, James M.

AU - Erlander, Mark G.

AU - Ma, Xiao Jun

AU - Sgroi, Dennis C.

AU - Reynolds, Carol A.

AU - Lingle, Wilma L.

AU - Weinshilboum, Richard M.

AU - Flockhart, David A.

AU - Desta, Zeruesenay

AU - Perez, Edith A.

AU - Ingle, James N.

PY - 2008/9/15

Y1 - 2008/9/15

N2 - Purpose: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (H0XB13) to interteukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer. Experimental Design. Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central CancerTreatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6'4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling. Results: CYP2D6 metabolism and HOXB13IIL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13IIL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% Cl, 1.17-8.52; P = 0.024). Conclusions: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.

AB - Purpose: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (H0XB13) to interteukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer. Experimental Design. Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central CancerTreatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6'4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling. Results: CYP2D6 metabolism and HOXB13IIL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13IIL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% Cl, 1.17-8.52; P = 0.024). Conclusions: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.

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