Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor: combining inherited and tumor gene markers for prediction of tamoxifen resistance.
Clin Cancer Res
; 14(18): 5864-8, 2008 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-18794098
ABSTRACT
PURPOSE:
Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-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. EXPERIMENTALDESIGN:
Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central Cancer Treatment 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 (CYP2D6HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling.RESULTS:
CYP2D6 metabolism and HOXB13/IL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6HOXB13/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 HOXB13/IL17BR 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% CI, 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Receptores de Interleucina
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Proteínas de Homeodomínio
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Citocromo P-450 CYP2D6
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos