title: Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer.
abstract: OBJECTIVE
  Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not.
  
  
  METHODS
  Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples.
  
  
  RESULTS
  Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed.
  
  
  CONCLUSIONS
  Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. vstearn1@jhmi.edu
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Jacobs
authors.forename: Maryjo
authors.initials: M
authors.lastname: Fackler
authors.forename: Theodore N
authors.initials: TN
authors.lastname: Tsangaris
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Michaela
authors.initials: M
authors.lastname: Higgins
authors.forename: Julie
authors.initials: J
authors.lastname: Lange
authors.forename: Zandra
authors.initials: Z
authors.lastname: Cheng
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Slater
authors.forename: Stacie C
authors.initials: SC
authors.lastname: Jeter
authors.forename: Penny
authors.initials: P
authors.lastname: Powers
authors.forename: Susanne
authors.initials: S
authors.lastname: Briest
authors.forename: Calvin
authors.initials: C
authors.lastname: Chao
authors.forename: Carl
authors.initials: C
authors.lastname: Yoshizawa
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sugar
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D000077022:Survivin; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; C064352:MYBL2 protein, human; D000077022:Survivin; D015534:Trans-Activators; D000077337:Vorinostat; C576917:AURKA protein, human; D064096:Aurora Kinase A