title: Co-expression of estrogen receptor alpha and Apolipoprotein D in node positive operable breast cancer--possible relevance for survival and effects of adjuvant tamoxifen in postmenopausal patients.
abstract: BACKGROUND
  Estrogen receptor-alpha (ERalpha) is an important prognostic and predictive marker in breast cancer. ERalpha signaling normally down-regulates expression of Apolipoprotein D (ApoD), a lipocalin that binds, transports or chelates lipophilic ligands, including tamoxifen (TAM). Hence, the co-expression of ApoD may therefore identify clinical relevant subgroups of ERalpha positive breast cancer patients.
  
  
  METHODS
  ApoD, ERalpha, and progesterone receptor (PR) protein expressions were determined by immunohistochemistry (IHC) in primary tumors of 290 patients with operable breast cancer. The median follow-up was 12 years. Patients were stratified according to age, nodal stage and the expression of ERalpha and the combined cytoplasm and nuclear staining of ApoD (ApoD(CN)).
  
  
  RESULTS
  In elderly women (> or =70 years) (n = 76), ApoD(CN) expression identified different prognostic subgroups in ERalpha positive patients (Trend: p < 0.0001). Multivariate analysis in this age group (n = 72), showed that the ERalpha-positive /ApoD(CN)-negative subgroup had a better breast cancer specific survival (BCSS) compared with the ERalpha-positive/ApoD(CN)-positive group (hazard ratio (HR) = 4.3; 95% CI = 1.6-11.9; p = 0.005). This difference was predominantly seen in the node positive patients (n = 30) (HR = 10.5; 95% CI = 2.3-47.6; p = 0.002). In a subset of postmenopausal ERalpha-positive/node positive patients (n = 60) previously enrolled in a trial on 2 year adjuvant TAM 20 mg vs. placebo, a better BCSS was observed in ApoD(CN) negative patients compared to placebo (p = 0.02). In ApoD(CN) positive patients, adjuvant TAM did not provide any survival benefit.
  
  
  CONCLUSIONS
  ERalpha and ApoD(CN) co-expression seems to be of prognostic importance in node positive elderly patients with operable breast cancer. In addition, we hypothesize that ApoD(CN) expression may be a novel marker and/or mechanism of TAM resistance in postmenopausal node positive patients. Thus, when targeting the ERalpha pathway in these patients, the ApoD status of the tumor may be of clinical relevance.
authors.affiliation: Department of Surgery, Stavanger University Hospital, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Søiland
authors.forename: Ivar
authors.initials: I
authors.lastname: Skaland
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Varhaug
authors.forename: Hartwig
authors.initials: H
authors.lastname: Kørner
authors.forename: Emiel A M
authors.initials: EA
authors.lastname: Janssen
authors.forename: Einar
authors.initials: E
authors.lastname: Gudlaugsson
authors.forename: Jan P A
authors.initials: JP
authors.lastname: Baak
authors.forename: Jon Arne
authors.initials: JA
authors.lastname: Søreide
mesh_terms: D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D053399:Apolipoproteins D / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D016017:Odds Ratio; D017698:Postmenopause; D011379:Prognosis; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D053399:Apolipoproteins D; D047628:Estrogen Receptor alpha; D013629:Tamoxifen