title: HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study.
abstract: OBJECTIVE
  Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen.
  
  
  METHODS
  Three hundred and forty nine patients had estrogen receptor (ER)-positive breast cancer and received daily tamoxifen as initial therapy for advanced disease. HER-2 gene amplification, detected by fluorescence in situ hybridization, and HER-1 expression, evaluated by immunohistochemistry, was determined on 136 and 204 patients, respectively.
  
  
  RESULTS
  HER-2 amplification was correlated with lower ER (P = 0.02), HER-1 positivity (P = 0.004), and HER-2 protein overexpression (P < 0.00001). The response rate was 56% for HER-2 non-amplified versus 47% for HER-2 amplified tumors (P = 0.38), and 58% for HER-1-negative versus 36% for HER-1-positive (P = 0.05). Time to treatment failure (TTF) was 7 months for non-amplified HER-2 tumors and 5 months (P = 0.007) for amplified HER-2 tumors, and there was a trend toward a better overall survival (OS) in patients with non-amplified HER-2 tumors (median 31 versus 25 months, respectively, P = 0.07). For positive versus negative HER-1 tumors, TTF was 4 versus 8 months (P = 0.08) and median survival was 24 versus 31 months (P = 0.41). Combining HER-1 expression and HER-2 gene status, patients with both negative HER-1 expression and non-amplified HER-2 had longer TTF (P = 0.001) and OS (P = 0.03) than if either were positive. In multivariate analysis, HER-2 was not an independent factor for TTF and OS, although HER-1 was significant for TTF only (P </= 0.001).
  
  
  CONCLUSIONS
  Patients with HER-2 amplification and HER-1 expression had lower ER levels and were modestly less responsive to tamoxifen, suggesting that molecular events in addition to those involving the ErbB receptors are important in determining the endocrine-resistant phenotype.
authors.affiliation: Breast Center, Baylor College of Medicine, Methodist Hospital, Houston, Texas, USA.
authors.forename: Grazia
authors.initials: G
authors.lastname: Arpino
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Green
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Dannika
authors.initials: D
authors.lastname: Lew
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Richard M
authors.initials: RM
authors.lastname: Elledge
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism; D017697:Premenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen