title: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.
abstract: OBJECTIVE
  Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively.
  
  
  METHODS
  Postmenopausal patients with estrogen- and/or progesterone receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria.
  
  
  RESULTS
  For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer patients underwent breast conservation (36%, P =.036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004).
  
  
  CONCLUSIONS
  ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.
authors.affiliation: Duke University Breast Cancer Program, Duke University Comprehensive Cancer Center, Durham, NC 27710, USA. ellis053@mc.duke.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: A
authors.initials: A
authors.lastname: Coop
authors.forename: B
authors.initials: B
authors.lastname: Singh
authors.forename: L
authors.initials: L
authors.lastname: Mauriac
authors.forename: A
authors.initials: A
authors.lastname: Llombert-Cussac
authors.forename: F
authors.initials: F
authors.lastname: Jänicke
authors.forename: W R
authors.initials: WR
authors.lastname: Miller
authors.forename: D B
authors.initials: DB
authors.lastname: Evans
authors.forename: M
authors.initials: M
authors.lastname: Dugan
authors.forename: C
authors.initials: C
authors.lastname: Brady
authors.forename: E
authors.initials: E
authors.lastname: Quebe-Fehling
authors.forename: M
authors.initials: M
authors.lastname: Borgs
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000032:analysis; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000077289:Letrozole; D016015:Logistic Models; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use*; D016017:Odds Ratio; D017698:Postmenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011982:Receptors, Prostaglandin / Q000032:analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D004965:Estrogen Antagonists; D000077289:Letrozole; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011982:Receptors, Prostaglandin; D013629:Tamoxifen; D014230:Triazoles