title: Clinical Trial of Acolbifene in Premenopausal Women at High Risk for Breast Cancer.
abstract: The purpose of this study was to assess the feasibility of using the selective estrogen receptor modulator (SERM) acolbifene as a breast cancer prevention agent in premenopausal women. To do so, we assessed change in proliferation in benign breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) as a primary endpoint, along with changes in other risk biomarkers and objective and subjective side effects as secondary endpoints. Twenty-five women with cytologic hyperplasia ± atypia and ≥2% of breast epithelial cells staining positive for Ki-67, received 20 mg acolbifene daily for 6-8 months, and then had benign breast tissue and blood risk biomarkers reassessed. Ki-67 decreased from a median of 4.6% [interquartile range (IQR), 3.1%-8.5%] at baseline to 1.4% (IQR, 0.6%-3.5%) after acolbifene (P < 0.001; Wilcoxon signed-rank test), despite increases in bioavailable estradiol. There were also significant decreases in expression (RT-qPCR) of estrogen-inducible genes that code for pS2, ERα, and progesterone receptor (P ≤ 0.026). There was no significant change in serum IGF1, IGFBP3, IGF1:IGFBP3 ratio, or mammographic breast density. Subjective side effects were minimal with no significant increase in hot flashes, muscle cramps, arthralgias, or fatigue. Objective measures showed a clinically insignificant decrease in lumbar spine bone density (DEXA) and an increase in ovarian cysts but no change in endometrial thickness (sonography). In summary, acolbifene was associated with favorable changes in benign breast epithelial cell proliferation and estrogen-inducible gene expression but minimal side effects, suggesting a phase IIB placebo-controlled trial evaluating it further for breast cancer prevention.
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Fabian
authors.affiliation: Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas. bkimler@kumc.edu.
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Kimler
authors.affiliation: Mercy Hospital, Miami, Florida.
authors.forename: Carola M
authors.initials: CM
authors.lastname: Zalles
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Phillips
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Trina
authors.initials: T
authors.lastname: Metheny
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Petroff
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Havighurst
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: KyungMann
authors.initials: K
authors.lastname: Kim
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
authors.forename: Brandy M
authors.initials: BM
authors.lastname: Heckman-Stoddard
mesh_terms: D000328:Adult; D044963:Biopsy, Fine-Needle; D015519:Bone Density / Q000187:drug effects; D001940:Breast / Q000187:drug effects*; D001943:Breast Neoplasms / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis / Q000096:biosynthesis; D008875:Middle Aged; D010048:Ovarian Cysts / Q000453:epidemiology; D010865:Pilot Projects; D010880:Piperidines / Q000627:therapeutic use*; D017697:Premenopause; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D019394:Ki-67 Antigen; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; C012121:ritetronium