title: A phase II breast cancer chemoprevention trial of oral alpha-difluoromethylornithine: breast tissue, imaging, and serum and urine biomarkers.
abstract: OBJECTIVE
  A double-blind randomized Phase II chemoprevention trial of alpha-difluoromethylornithine (DFMO) was conducted in a group of women at high risk for development of breast cancer. DFMO is an irreversible inhibitor of ornithine decarboxylase, the limiting enzyme of polyamine synthesis that is often up-regulated in breast cancer.
  
  
  METHODS
  Study entrants were required to have random periareolar fine-needle aspiration cytology prior to entry that exhibited hyperplasia or hyperplasia with atypia, as well as a mammogram and clinical breast exam judged as not suspicious for breast cancer and no clinical hearing loss. Subjects were randomized to 6 months of oral DFMO (0.5 g/m(2)/day) or placebo, followed by repeat fine-needle aspiration and biomarker assessment. The main study end point was an improvement in cytologic pattern.
  
  
  RESULTS
  Of 119 subjects entered, 96% completed the study and were evaluable for the main study end point. A modest reduction (28%) in average total urine polyamines was obtained in the DFMO group, but there was no reduction in the spermidine:spermine ratio. There was no difference in cytologic improvement between DFMO and placebo. Likewise, there was no difference between DFMO and placebo for the secondary end points of breast molecular marker changes (immunocytochemical expression of proliferating cell nuclear antigen, p53, and epidermal growth factor receptor), mammographic breast density, serum insulin-like growth factor I: insulin-like growth factor binding protein 3 ratio, adverse events, quality of life indices, or subsequent cancer development.
  
  
  CONCLUSIONS
  DFMO at a dose level of 0.5 g/m(2)/day administered for 6 months does not modulate breast risk biomarkers tested in this study.
authors.affiliation: University of Kansas Medical Center, Kansas City, Kansas 66160, USA. cfabian@kumc.edu
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Fabian
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Kimler
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Brady
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Mayo
authors.forename: C H Joseph
authors.initials: CH
authors.lastname: Chang
authors.forename: John A
authors.initials: JA
authors.lastname: Ferraro
authors.forename: Carola M
authors.initials: CM
authors.lastname: Zalles
authors.forename: Annette L
authors.initials: AL
authors.lastname: Stanton
authors.forename: Shahla
authors.initials: S
authors.lastname: Masood
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Norman F
authors.initials: NF
authors.lastname: Boyd
authors.forename: Dora W
authors.initials: DW
authors.lastname: Arneson
authors.forename: Karen A
authors.initials: KA
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001707:Biopsy, Needle; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000517:prevention & control*; D004311:Double-Blind Method; D000518:Eflornithine / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066246:ErbB Receptors; D005260:Female; D006728:Hormones / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008327:Mammography; D008875:Middle Aged; D009367:Neoplasm Staging; D011073:Polyamines / Q000652:urine*; D018809:Proliferating Cell Nuclear Antigen / Q000097:blood; D011788:Quality of Life; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D006728:Hormones; D018972:Insulin-Like Growth Factor Binding Protein 3; D011073:Polyamines; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D000518:Eflornithine