title: ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer.
abstract: BACKGROUND
  Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas.
  
  
  METHODS
  ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors.
  
  
  RESULTS
  ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts.
  
  
  CONCLUSIONS
  ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease.
  
  
  BACKGROUND
  Clinical trial identifier: ISRCTN31514446.
authors.affiliation: Academic Department of Biochemistry, The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pinhel
authors.forename: Margaret
authors.initials: M
authors.lastname: Hills
authors.forename: Suzanne
authors.initials: S
authors.lastname: Drury
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Georges
authors.initials: G
authors.lastname: Sumo
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bliss
authors.forename: Ivana
authors.initials: I
authors.lastname: Sestak
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.forename: Peter
authors.initials: P
authors.lastname: Barrett-Lee
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; C508053:ERBB2 protein, human