title: A pilot surrogate end point biomarker trial of perillyl alcohol in breast neoplasia.
abstract: OBJECTIVE
  Efficient strategies to screen promising agents in early phase development are essential for rapid progress in breast cancer chemoprevention. We report our experience with the natural compound perillyl alcohol (POH) administered in a short-term surrogate end point biomarker (SEB) protocol, using the "window" between diagnostic and definitive surgery.
  
  
  METHODS
  Eligible patients included those with a diagnosis of atypical ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, or invasive carcinoma (<3 cm in size) that required further surgery. Thirty-seven of 267 women screened were enrolled in the study (14%). Five women received single-dose POH (1.5 g/m2) 2 days before surgery, 16 received escalating doses of POH (1.2 g/m2 to 4.8 g/m2/day) for 2 days before surgery, and 16 served as untreated controls. Exploratory SEB analysis [estrogen receptor, progesterone receptor, proliferation, apoptosis, M6P/insulin-like growth factor (IGF)-2R, IGF1, IGF2 and transforming growth factor beta] was conducted before and after POH.
  
  
  RESULTS
  Only a small portion of the population screened entered the study. Reasons for nonparticipation included protocol ineligibility, conflict of timing of surgery, miscellaneous logistical reasons, or patient's choice. POH administration was well tolerated and did not interfere with surgical management. The power to observe changes in candidate SEB was diminished by a 44% incidence of cases in which the index lesion was not present in the definitive surgical specimen.
  
  
  CONCLUSIONS
  Preoperative POH exposure was safe and suitable for a more definitive phase II SEB study. Further investigations must overcome logistical obstacles to accrual, and they must focus on approaches to maximize tissue collection and to incorporate genomic analysis of target lesions.
authors.affiliation: Breast Cancer Program, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., USA.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Ann
authors.initials: A
authors.lastname: Gallagher
authors.forename: Hideko
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Ronald
authors.initials: R
authors.lastname: Lieberman
authors.forename: Marie
authors.initials: M
authors.lastname: Pennanen
authors.forename: Bruce
authors.initials: B
authors.lastname: Trock
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015415:Biomarkers; D014408:Biomarkers, Tumor; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002278:Carcinoma in Situ; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D039821:Monoterpenes / Q000627:therapeutic use*; D010865:Pilot Projects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor; D039821:Monoterpenes; C032208:perillyl alcohol