Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.
ABSTRACT Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer.
In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers.
In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry.
Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.
SourceAvailable from: Hitoshi Endou[Show abstract] [Hide abstract]
ABSTRACT: We recently reported that prenatal rat exposure to di(n-butyl) phthalate (DBP) induced Leydig cell (LC) hyperplasia after nine weeks (wks) of age, yet the number of LCs was similar to that of the vehicle group until seven weeks. Nuclear pleomorphism of hyperplastic LCs is common and is considered to be continuous progressive degeneration. Thus, computer-assisted image cell nuclear analysis of LCs was performed on 5- and 7-wk-old Sprague-Dawley (SD) rats whose dams had been administered DBP (i.g.) at 100 mg/kg/day or vehicle (corn oil) on gestation day 12 to 21. The results of the 5-wk-old DBP group were similar to those of the vehicle group; LC nuclei of the 7-wk-old DBP group showed normal ploidy and similar amounts of DNA. However, the size, elongation and peripheral chromatin aggregation parameters were significantly higher, and the reticular chromatin distribution and isolated chromatin aggregation parameters were significantly lower compared with the vehicle group. The present study quantitatively demonstrated nuclear morphological alterations in rat LCs at 7 wks old (puberty) due to the prenatal DBP administration before apparent LC hyperplasia developed.Journal of Toxicologic Pathology 12/2013; 26(4):439-46. DOI:10.1293/tox.2013-0031 · 0.94 Impact Factor
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ABSTRACT: Breast cancer is the most common malignancy among women in the US, and prevention of this disease is therefore a major public health concern. Chemoprevention with anti-estrogens, including tamoxifen, raloxifene, and exemestane, has been shown to reduce the incidence of hormone receptor (HR)-positive breast cancer. However, breast cancer chemoprevention uptake has been poor and effective chemopreventive agents for HR-negative tumors are yet to be identified. A priority for breast cancer prevention research is improving the efficiency of chemoprevention trials by use of intermediate biomarkers correlated with breast cancer risk. This review provides an overview of the literature on breast-imaging-based, tissue-based, and circulating biomarkers which have been associated with breast cancer risk by observational studies and are being investigated as intermediate endpoints for early-phase chemoprevention trials.Current Breast Cancer Reports 09/2013; 5(3). DOI:10.1007/s12609-013-0116-x
Article: Metformin and Gynecologic Cancers.[Show abstract] [Hide abstract]
ABSTRACT: The obese population in the United States is reaching epic proportions, and obesity is linked to an increased risk for several cancers including gynecologic cancers. Obesity is not only a risk factor but also a marker of poor prognosis. It is crucial to develop novel treatment strategies to target this population. Metformin is a biguanide drug, typically used for diabetes treatment, currently being studied to evaluate its role in the treatment and prevention of gynecologic cancers.Obstetrical and Gynecological Survey 08/2014; 69(8):477-489. DOI:10.1097/OGX.0000000000000092 · 2.36 Impact Factor