title: An ER activity profile including ER, PR, Bcl-2 and IGF-IR may have potential as selection criterion for letrozole or tamoxifen treatment of patients with advanced breast cancer.
abstract: BACKGROUND
  The purpose of this study was to evaluate the association between response at recurrence to letrozole versus tamoxifen and the expression of estrogen regulated proteins individually and combined in an "ER activity profile" in primary tumor tissue. Our hypothesis is that letrozole may be more effective than tamoxifen for treatment of tumors with high intratumoral estrogen content, whereas tamoxifen may be more efficient for treatment of tumors with high levels of the estrogen receptor (ER) and low intratumoral estrogen content.
  
  
  METHODS
  For this study, we produced tissue microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER, the progesterone receptor (PR), the anti-apoptotic protein Bcl-2 and the Insulin like Growth Factor Receptor I (IGF-IR) were determined by semi-quantitative immunohistochemistry.
  
  
  RESULTS
  Response to letrozole and tamoxifen treatment, measured as time to progression (TTP), was independent of primary tumor expression level of ER, Bcl-2 and IGF-IR. However, high expression of PR as well as high expression of three different ER activity profiles; ER/PR/Bcl-2, ER/PR/IGF-IR and ER/PR/Bcl-2/IGF-IR identified letrozole treated patients with significantly longer TTP. The ER activity profile including ER, PR, Bcl-2 and IGF-IR showed a trend towards being a selection criterion for letrozole versus tamoxifen therapy.
  
  
  CONCLUSIONS
  This small sub-study supports our hypothesis that letrozole is superior to tamoxifen primarily in patients expressing high levels of estrogen regulated proteins in the primary tumor tissue. Furthermore, it seems that the "ER activity profile" with high PR, IGF-IR and Bcl-2 is a promising selection criterion, regarding prediction of response to letrozole versus tamoxifen.
authors.affiliation: Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Copenhagen Ø, Denmark.
authors.forename: Katrine L
authors.initials: KL
authors.lastname: Henriksen
authors.forename: Birgitte B
authors.initials: BB
authors.lastname: Rasmussen
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.forename: Susanne
authors.initials: S
authors.lastname: Møller
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.forename: Henning T
authors.initials: HT
authors.lastname: Mouridsen
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D046228:Microarray Analysis; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use*; D018579:Patient Selection; D010865:Pilot Projects; D011237:Predictive Value of Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole; D017526:Receptor, IGF Type 1