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Cancer Prev Res (Phila). 2014 Sep;7(9):896-905. doi: 10.1158/1940-6207.CAPR-13-0408. Epub 2014 Jun 20.

Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence.

Author information

1
College of Medicine, University of Arizona, Tucson, Arizona. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.
2
Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.
3
College of Medicine, University of Arizona, Tucson, Arizona. Department of Obstetrics and Gynecology, University of Arizona, Tucson, Arizona.
4
Department of Pathology, University of Jordan, Amman, Jordan.
5
University of Arizona Cancer Center, Tucson, Arizona.
6
Department of Obstetrics and Gynecology, Yale University, New Haven, Connecticut.
7
College of Medicine, University of Arizona, Tucson, Arizona. University of Arizona Cancer Center, Tucson, Arizona. Department of Pathology, University of Arizona, Tucson, Arizona.
8
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.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00699907.

PMID:
24950779
PMCID:
PMC4154987
DOI:
10.1158/1940-6207.CAPR-13-0408
[Indexed for MEDLINE]
Free PMC Article

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