title: A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast.
abstract: OBJECTIVE
  Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in situ (DCIS).
  
  
  METHODS
  Twenty-seven pre- and postmenopausal women were randomized to 4-OHT (4 mg/day) or oral-T (20 mg/day) for 6 to 10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography/tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGFI), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined.
  
  
  RESULTS
  Posttherapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P ≤ 0.03 in both, between-group P = 0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (P = 0.0003), whereas mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P = 0.88). There were significant increases in plasma SHBG, factor VIII, and von Willebrand factor and a significant decrease in plasma IGFI with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups.
  
  
  CONCLUSIONS
  The antiproliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention.
authors.affiliation: Authors' Affiliations: Departments of Surgery.
authors.forename: Oukseub
authors.initials: O
authors.lastname: Lee
authors.affiliation: The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Katherine
authors.initials: K
authors.lastname: Page
authors.affiliation: Authors' Affiliations: Departments of Surgery.
authors.forename: David
authors.initials: D
authors.lastname: Ivancic
authors.affiliation: Preventive Medicine.
authors.forename: Irene
authors.initials: I
authors.lastname: Helenowski
authors.affiliation: Pathology.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Parini
authors.affiliation: Pathology.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Sullivan
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Margenthaler
authors.affiliation: Obstetrics and Gynecology.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Chatterton
authors.affiliation: Preventive Medicine.
authors.forename: Borko
authors.initials: B
authors.lastname: Jovanovic
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; and.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Dunn
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; and.
authors.forename: Brandy M
authors.initials: BM
authors.lastname: Heckman-Stoddard
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; and.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Foster
authors.affiliation: IIT Research Institute, Chicago, Illinois;
authors.forename: Miguel
authors.initials: M
authors.lastname: Muzzio
authors.affiliation: The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Julia
authors.initials: J
authors.lastname: Shklovskaya
authors.affiliation: The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Silvia
authors.initials: S
authors.lastname: Skripkauskas
authors.affiliation: Pathology.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kulesza
authors.affiliation: Medicine, Division of Hematology/Oncology;
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.affiliation: Authors' Affiliations: Departments of Surgery, The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hansen
authors.affiliation: Authors' Affiliations: Departments of Surgery, The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bethke
authors.affiliation: Authors' Affiliations: Departments of Surgery, The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Jeruss
authors.affiliation: Medicine, Division of Hematology/Oncology; The Robert H. Lurie Cancer Center of Northwestern University;
authors.forename: Raymond
authors.initials: R
authors.lastname: Bergan
authors.affiliation: Authors' Affiliations: Departments of Surgery, The Robert H. Lurie Cancer Center of Northwestern University; skhan@nmh.org.
authors.forename: Seema A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000188:drug therapy*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D013629:Tamoxifen; C016601:afimoxifene