title: Accurate Prediction and Validation of Response to Endocrine Therapy in Breast Cancer.
abstract: OBJECTIVE
  Aromatase inhibitors (AIs) have an established role in the treatment of breast cancer. Response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Accurate biomarkers are urgently needed to predict response in these settings and to determine which individuals will benefit from adjuvant AI therapy.
  
  
  METHODS
  Pretreatment and on-treatment (after 2 weeks and 3 months) biopsies were obtained from 89 postmenopausal women who had estrogen receptor-alpha positive breast cancer and were receiving neoadjuvant letrozole for transcript profiling. Dynamic clinical response was assessed with use of three-dimensional ultrasound measurements.
  
  
  RESULTS
  The molecular response to letrozole was characterized and a four-gene classifier of clinical response was established (accuracy of 96%) on the basis of the level of two genes before treatment (one gene [IL6ST] was associated with immune signaling, and the other [NGFRAP1] was associated with apoptosis) and the level of two proliferation genes (ASPM, MCM4) after 2 weeks of therapy. The four-gene signature was found to be 91% accurate in a blinded, completely independent validation data set of patients treated with anastrozole. Matched 2-week on-treatment biopsies were associated with improved predictive power as compared with pretreatment biopsies alone. This signature also significantly predicted recurrence-free survival (P = .029) and breast cancer -specific survival (P = .009). We demonstrate that the test can also be performed with use of quantitative polymerase chain reaction or immunohistochemistry.
  
  
  CONCLUSIONS
  A four-gene predictive model of clinical response to AIs by 2 weeks has been generated and validated. Deregulated immune and apoptotic responses before treatment and cell proliferation that is not reduced 2 weeks after initiation of treatment are functional characteristics of breast tumors that do not respond to AIs.
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Arran K
authors.initials: AK
authors.lastname: Turnbull
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Arthur
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Lorna
authors.initials: L
authors.lastname: Renshaw
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Larionov
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Charlene
authors.initials: C
authors.lastname: Kay
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Dunbier
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Thomas
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand. andrew.sims@ed.ac.uk.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: Arran K. Turnbull, Laura M. Arthur, Lorna Renshaw, Alexey A. Larionov, Charlene Kay, Jeremy S. Thomas, Andrew H. Sims, J. Michael Dixon, University of Edinburgh Cancer Research UK Centre, Edinburgh; Anita K. Dunbier, Mitch Dowsett, Institute of Cancer Research, London, United Kingdom; and Anita K. Dunbier, University of Otago, Dunedin, New Zealand.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D050822:Cytokine Receptor gp130 / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D000077289:Letrozole; D064148:Minichromosome Maintenance Complex Component 4 / Q000235:genetics; D020360:Neoadjuvant Therapy; D009419:Nerve Tissue Proteins / Q000235:genetics; D009570:Nitriles / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis; D057285:Precision Medicine; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*; D014463:Ultrasonography
chemical_list: C467202:ASPM protein, human; D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D047072:Aromatase Inhibitors; C410727:BEX3 protein, human; D014408:Biomarkers, Tumor; C494199:IL6ST protein, human; D009419:Nerve Tissue Proteins; D009570:Nitriles; D014230:Triazoles; D050822:Cytokine Receptor gp130; D000077289:Letrozole; C099243:MCM4 protein, human; D064148:Minichromosome Maintenance Complex Component 4