title: Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence.
abstract: We hypothesized that (i) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (ii) flutamide treatment of women at high risk for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase II study, we studied the effect of preoperative flutamide treatment (125 mg/day × 6 weeks) in 12 women versus 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4 in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis. Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P ≤ 0.0006) and ovarian endosalpingiosis (P ≤ 0.01), ErbB4 in ovarian epithelium (P = 0.006), and CSF-1R in ovarian endosalpingiosis (P = 0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P ≤ 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC = 0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with high risk status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ovarian endosalpingiosis, previously associated with BRCA carrier status, suggests that ovarian endosalpingiosis may be a latent precursor to pelvic serous cancers.
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.
authors.forename: Christine
authors.initials: C
authors.lastname: Gruessner
authors.affiliation: Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.
authors.forename: Angelika
authors.initials: A
authors.lastname: Gruessner
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. Department of Obstetrics and Gynecology, University of Arizona, Tucson, Arizona.
authors.forename: Katherine
authors.initials: K
authors.lastname: Glaser
authors.affiliation: Department of Pathology, University of Jordan, Amman, Jordan.
authors.forename: Nisreen
authors.initials: N
authors.lastname: AbuShahin
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Laughren
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Heather
authors.initials: H
authors.lastname: Wright
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Samantha
authors.initials: S
authors.lastname: Pinkerton
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yi
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Jha'nae
authors.initials: J
authors.lastname: Stoffer
authors.affiliation: Department of Obstetrics and Gynecology, Yale University, New Haven, Connecticut.
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. University of Arizona Cancer Center, Tucson, Arizona. Department of Pathology, University of Arizona, Tucson, Arizona.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zheng
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. Department of Obstetrics and Gynecology, University of Arizona, Tucson, Arizona. University of Arizona Cancer Center, Tucson, Arizona. schambers@uacc.arizona.edu.
authors.forename: Setsuko K
authors.initials: SK
authors.lastname: Chambers
mesh_terms: D000328:Adult; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D004797:Enzyme-Linked Immunosorbent Assay; D005185:Fallopian Tube Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005187:Fallopian Tubes / Q000378:metabolism; D005260:Female; D005485:Flutamide / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D016173:Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism; D012372:ROC Curve; D066247:Receptor, ErbB-4 / Q000032:analysis / Q000096:biosynthesis; D012307:Risk Factors; D058994:Salpingectomy
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D005485:Flutamide; D016173:Macrophage Colony-Stimulating Factor; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4