title: Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance.
abstract: OBJECTIVE
  Estrogen withdrawal by treatment with aromatase inhibitors is the most effective form of endocrine therapy for postmenopausal estrogen receptor-positive (ER+) breast cancer. However, response to therapy varies markedly and understanding of the precise molecular effects of aromatase inhibitors and causes of resistance is limited. We aimed to identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of AI treatment.
  
  
  METHODS
  Baseline and 2-week posttreatment biopsies were obtained from 112 postmenopausal women with ER+ breast cancer receiving neoadjuvant anastrozole. Gene expression data were obtained from 81 baseline and 2-week paired samples. Pathway analysis identified (i) the most prevalent changes in expression and (ii) the pretreatment genes/pathways most related to poor antiproliferative response.
  
  
  RESULTS
  A total of 1,327 genes were differentially expressed after 2-week treatment (false discovery rate < 0.01). Proliferation-associated genes and classical estrogen-dependent genes were strongly downregulated whereas collagens and chemokines were upregulated. Pretreatment expression of an inflammatory signature correlated with antiproliferative response to anastrozole and this observation was validated in an independent study. Higher expression of immune-related genes such as SLAMF8 and TNF as well as lymphocytic infiltration were associated with poorer response (P < 0.001) and validated in an independent cohort.
  
  
  CONCLUSIONS
  The molecular response to aromatase inhibitor treatment varies greatly between patients consistent with the variable clinical benefit from aromatase inhibitor treatment. Higher baseline expression of an inflammatory signature is associated with poor antiproliferative response and should be assessed further as a novel biomarker and potential target for aromatase inhibitor-treated patients.
authors.affiliation: Royal Marsden Hospital, London, United Kingdom. anita.dunbier@otago.ac.nz
authors.forename: Anita K
authors.initials: AK
authors.lastname: Dunbier
authors.forename: Zara
authors.initials: Z
authors.lastname: Ghazoui
authors.forename: Helen
authors.initials: H
authors.lastname: Anderson
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Nerurkar
authors.forename: Peter
authors.initials: P
authors.lastname: Osin
authors.forename: Roger
authors.initials: R
authors.lastname: A'hern
authors.forename: William R
authors.initials: WR
authors.lastname: Miller
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000368:Aged; D000077384:Anastrozole; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001706:Biopsy; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007109:Immunity / Q000235:genetics; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D047072:Aromatase Inhibitors; D019394:Ki-67 Antigen; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole