Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer

BMC Cancer. 2013 Sep 18;13:425. doi: 10.1186/1471-2407-13-425.

Abstract

Background: The role of estrogen receptor beta (ER-β) in breast cancer (BC) remains unclear. Some studies have suggested that ER-β may oppose the actions of estrogen receptor alpha (ER-α), and clinical evidence has indicated that the loss of ER-β expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-β and the ER-α/ER-β ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-β expression levels.

Methods: Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-β, ER-α and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred's method. Statistical analyses were performed using an ANOVA and Spearman's correlation coefficient tests, with significance at p ≤ 0.05.

Results: The frequency of ER-β expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-β-negative cases (p = 0.45), but in the ER-β-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-α and ER-β expression levels. Only patients with an ER-α/ER-β expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026).

Conclusions: Our results provide additional data that indicate that the measurement of ER-β in BC patients may help predict tamoxifen and anastrozole responsiveness in the neoadjuvant setting. These effects of hormonal treatment appear to be dependent on the ratio of ER-α/ER-β expression.

Trial registration: Current Controlled Trials ISRCTN89801719.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anastrozole
  • Antineoplastic Agents, Hormonal / administration & dosage
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / metabolism*
  • Female
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Staging
  • Nitriles / administration & dosage*
  • Nitriles / therapeutic use
  • Postmenopause
  • Prognosis
  • Tamoxifen / administration & dosage
  • Tamoxifen / therapeutic use*
  • Treatment Outcome
  • Triazoles / administration & dosage*
  • Triazoles / therapeutic use

Substances

  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Ki-67 Antigen
  • Nitriles
  • Triazoles
  • Tamoxifen
  • Anastrozole

Associated data

  • ISRCTN/ISRCTN89801719