A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer

Br J Cancer. 2011 Jun 7;104(12):1828-35. doi: 10.1038/bjc.2011.156. Epub 2011 May 10.


Background: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.

Methods: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated.

Results: In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.

Conclusion: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Drug Resistance, Neoplasm*
  • Estrogen Antagonists / administration & dosage*
  • Female
  • Histone Deacetylase 2 / analysis
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histone Deacetylase Inhibitors / adverse effects
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / adverse effects
  • Hydroxamic Acids / therapeutic use*
  • Middle Aged
  • Tamoxifen / administration & dosage
  • Tamoxifen / adverse effects
  • Tamoxifen / therapeutic use*
  • Vorinostat


  • Estrogen Antagonists
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Tamoxifen
  • Vorinostat
  • HDAC2 protein, human
  • Histone Deacetylase 2