title: Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer.
abstract: OBJECTIVE
  Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors.
  
  
  METHODS
  We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials.
  
  
  RESULTS
  In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression.
  
  
  CONCLUSIONS
  These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project, Division of Pathology, 1307 Federal St, Pittsburgh, PA 15212, USA.
authors.forename: Chungyeul
authors.initials: C
authors.lastname: Kim
authors.forename: Gong
authors.initials: G
authors.lastname: Tang
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Pogue-Geile
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Costantino
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Baehner
authors.forename: Joffre
authors.initials: J
authors.lastname: Baker
authors.forename: Maureen T
authors.initials: MT
authors.lastname: Cronin
authors.forename: Drew
authors.initials: D
authors.lastname: Watson
authors.forename: Steven
authors.initials: S
authors.lastname: Shak
authors.forename: Olga L
authors.initials: OL
authors.lastname: Bohn
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Ahwon
authors.initials: A
authors.lastname: Lee
authors.forename: Megan L
authors.initials: ML
authors.lastname: Reilly
authors.forename: Victor G
authors.initials: VG
authors.lastname: Vogel
authors.forename: Worta
authors.initials: W
authors.lastname: McCaskill-Stevens
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Ford
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
authors.forename: D Lawrence
authors.initials: DL
authors.lastname: Wickerham
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000517:prevention & control*; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy* / Q000517:prevention & control*; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D013629:Tamoxifen