title: Thalidomide in total therapy 2 overcomes inferior prognosis of myeloma with low expression of the glucocorticoid receptor gene NR3C1.
abstract: OBJECTIVE
  Because dexamethasone remains a key component of myeloma therapy, we wished to examine the impact of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 on survival outcomes in the context of treatment with or without thalidomide.
  
  
  METHODS
  We investigated the clinical impact of gene expression profiling (GEP)-derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to total therapy 2 (TT2).
  
  
  RESULTS
  Low NR3C1 expression levels had a negative impact on progression-free survival (PFS; HR, 1.47; P = 0.030) and overall survival (OS; HR, 1.90; P = 0.002) in the no-thalidomide arm. Conversely, there was a significant clinical benefit of thalidomide for patients with low receptor levels (OS: HR, 0.54; P = 0.015; PFS: HR, 0.54; P = 0.004), mediated most likely by thalidomide's upregulation of NR3C1. In the context of both baseline and relapse parameters, post-relapse survival (PRS) was adversely affected by low NR3C1 levels at relapse in a multivariate analysis (HR, 2.61; P = 0.012).
  
  
  CONCLUSIONS
  These findings justify the inclusion of NR3C1 expression data in the work-up of patients with myeloma as it can significantly influence the choice of therapy and, ultimately, OS. The identification of an interaction term between thalidomide and NR3C1 underscores the importance of pharmacogenomic studies in the systematic study of new drugs.
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, AR, USA. cjheuck@uams.edu
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Heuck
authors.forename: Jackie
authors.initials: J
authors.lastname: Szymonifka
authors.forename: Emily
authors.initials: E
authors.lastname: Hansen
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Saad Z
authors.initials: SZ
authors.lastname: Usmani
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Bijay
authors.initials: B
authors.lastname: Nair
authors.forename: Sarah
authors.initials: S
authors.lastname: Waheed
authors.forename: Yazan
authors.initials: Y
authors.lastname: Alsayed
authors.forename: Nathan
authors.initials: N
authors.lastname: Petty
authors.forename: Clyde
authors.initials: C
authors.lastname: Bailey
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
mesh_terms: D000368:Aged; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018209:Myelolipoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016016:Proportional Hazards Models; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D013792:Thalidomide / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D013792:Thalidomide