title: Biomarker changes associated with the development of resistance to aromatase inhibitors (AIs) in estrogen receptor-positive breast cancer.
abstract: BACKGROUND
  The purpose of this study was to identify any differences in key biomarkers associated with estrogen action between biopsies taken at diagnosis and at recurrence or progression during treatment with an aromatase inhibitor (AI).
  
  
  METHODS
  Patients were retrospectively identified from a clinical database as having relapsed or progressed during AI treatment. Immunohistochemistry was carried out against estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), insulin-like growth factor type-1 receptor (IGF1R), insulin receptor substrate-1 (IRS-1), stathmin, phosphatase and tensin homolog and Ki67.
  
  
  RESULTS
  Fifty-five pairs of samples were identified with ER- and/or PgR-positive diseases. Four (7%) patients were ER-negative at progression. Overall, PgR levels were lower in the recurrence sample, but 35% of cases remained positive. IGF1R levels decreased significantly. There were no substantial changes in HER2, IRS-1 or stathmin levels to indicate a role in resistance. Higher Ki67 levels at resistance indicate more proliferative disease.
  
  
  CONCLUSIONS
  The phenotype of AI-recurrent lesions shows high between-tumour heterogeneity. There is evidence of an increase in Ki67, a reduction in IGF1R and a loss of ER expression in some individuals and some activation of growth factor signalling pathways that may explain resistance in individuals and merit treatment targeted to those pathways. Biopsy at recurrence will be necessary to identify the relevant target for individuals.
authors: Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors: M
authors: M
authors: Arnedos
authors: NE Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London.
authors: S
authors: S
authors: Drury
authors: Academic Department of Biochemistry, Royal Marsden Hospital, London.
authors: M
authors: M
authors: Afentakis
authors: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London.
authors: R
authors: R
authors: A'Hern
authors: Academic Department of Biochemistry, Royal Marsden Hospital, London.
authors: M
authors: M
authors: Hills
authors: Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors: J
authors: J
authors: Salter
authors: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London; Breast Unit.
authors: I E
authors: IE
authors: Smith
authors: Memorial Sloan-Kettering Cancer Centre, New York, USA.
authors: J S
authors: JS
authors: Reis-Filho
authors: Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; NE Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London. Electronic address: mitch.dowsett@icr.ac.uk.
authors: M
authors: M
authors: Dowsett
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D000730:Androstadienes / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D000077289:Letrozole; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009570:Nitriles / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D050777:Stathmin / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D000077384:Anastrozole; D000730:Androstadienes; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D055504:Insulin Receptor Substrate Proteins; D019394:Ki-67 Antigen; D000077289:Letrozole; D009570:Nitriles; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D050777:Stathmin; D013629:Tamoxifen; D014230:Triazoles; C526292:IRS1 protein, human; C493995:STMN1 protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human; C056516:exemestane
keywords: aromatase inhibitor; breast cancer; immunohistochemistry; relapse