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. In order 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 re-assessed. Ki-67 decreased from a median of 4.6% (interquartile range, 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, ER-α, and PgR (p≤0.026). There was no significant change in serum IGF-1, IGFBP3, IGF-1: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.

Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study

“…All slides were assessed by a single cytopathologist (CMZ) who assigned a categorical assessment of nonproliferative, hyperplasia, borderline hyperplasia with atypia, or hyperplasia with atypia as well as a Masood semiquantitative index score (cited in ref. 31).…”

“…Slides having 500 or more epithelial cells visible by Papanicolaou-staining were selected. Following destaining, antigen retrieval was performed with 10 mmol/L citrate buffer (pH 6) in a Biocare decloaking chamber for two minutes at 120 C. The MIB-1 monoclonal antibody was applied at a 1:20 dilution using a Dako autostainer (31). Women with less than 5 positive cells per 500 epithelial cells counted (<1%) were considered cohort A and those with 5 to 20 per 500 epithelial cells counted (1% or greater) as cohort B.…”

“…RNA was amplified using MessageAmpII aRNA amplification kit (Life Technologies) and reverse transcribed to cDNA using SMARTScribe Reverse Transcriptase (Clontech Laboratories, Inc.) and random nonamer primers. Real-time quantitative PCR (qPCR) was performed for selected estrogen and progesterone response genes and others of interest using hydrolysis probes as previously described (31,36). Baseline and postintervention specimens were assessed together.…”

“…Bioavailable estradiol and testosterone were calculated according to standard formulae (cited in ref. 31). Limit of detection for estradiol and testosterone were 10 and 22 pg/mL with 8% to 10% intra and interassay coefficient of variation.…”

Alteration of bone mineral density in breast cancer female survivors on chemotherapy treatment: an integrative review

“…The estrogen level required to maintain a relative regular bone remodeling in postmenopausal women is lower than that required to stimulate the classical target tissues, such as those of breast and uterus. Furthermore, the risk of fractures is inversely related to the levels of estrogen in the postmenopausal period, and one fourth of the estrogen dose, which would stimulate uterus and breast, would be sufficient to decrease bone reabsorption and increase bone mass in elderly women 21 .…”