title: Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor: combining inherited and tumor gene markers for prediction of tamoxifen resistance.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 (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 HOXB13/IL17BR 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 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.
authors.affiliation: Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. goetz.matthew@mayo.edu
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Ma
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: Wilma L
authors.initials: WL
authors.lastname: Lingle
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005819:Genetic Markers; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D053722:Receptors, Interleukin-17; D012189:Retrospective Studies; D012307:Risk Factors; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D005819:Genetic Markers; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; C408922:IL17RB protein, human; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6
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