title: Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole.
abstract: OBJECTIVE
  To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) -positive (ER > or = 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials.
  
  
  METHODS
  FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67.
  
  
  RESULTS
  HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors.
  
  
  CONCLUSIONS
  Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.
authors.affiliation: Siteman Comprehensive Cancer Center,, Washington University School of Medicine, Campus Box 8056, 660 S Euclid Ave, St Louis, MO 63110, USA. mellis@wustl.edu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Yu
authors.initials: Y
authors.lastname: Tao
authors.forename: Oliver
authors.initials: O
authors.lastname: Young
authors.forename: Sharon
authors.initials: S
authors.lastname: White
authors.forename: Alan D
authors.initials: AD
authors.lastname: Proia
authors.forename: Julliette
authors.initials: J
authors.lastname: Murray
authors.forename: Lorna
authors.initials: L
authors.lastname: Renshaw
authors.forename: Dana
authors.initials: D
authors.lastname: Faratian
authors.forename: Jeremy
authors.initials: J
authors.lastname: Thomas
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: William R
authors.initials: WR
authors.lastname: Miller
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005784:Gene Amplification; D018773:Genes, erbB-1; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D000077289:Letrozole; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000032:analysis; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077289:Letrozole; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014230:Triazoles