title: A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology and Oncology, University of California, San Francisco, 1600 Divisadero, Rm A719 Box 1711, San Francisco, CA 94143, USA. pmunster@medicine.ucsf.edu
authors.forename: P N
authors.initials: PN
authors.lastname: Munster
authors.forename: K T
authors.initials: KT
authors.lastname: Thurn
authors.forename: S
authors.initials: S
authors.lastname: Thomas
authors.forename: P
authors.initials: P
authors.lastname: Raha
authors.forename: M
authors.initials: M
authors.lastname: Lacevic
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Melisko
authors.forename: R
authors.initials: R
authors.lastname: Ismail-Khan
authors.forename: H
authors.initials: H
authors.lastname: Rugo
authors.forename: M
authors.initials: M
authors.lastname: Moasser
authors.forename: S E
authors.initials: SE
authors.lastname: Minton
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D056464:Histone Deacetylase 2 / Q000032:analysis; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077337:Vorinostat
chemical_list: D004965:Estrogen Antagonists; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013629:Tamoxifen; D000077337:Vorinostat; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2