Phase II breast cancer chemoprevention trial of the third generation selective estrogen receptor modulator arzoxifene

Abstract

1001 Background: Arzoxifene (ARZ) is a third generation SERM with efficacy in metastatic breast cancer but lacking uterine agonist activity. Methods: We conducted a randomized, double-blind, placebo-controlled Phase II prevention trial in 199 high risk women assessing the effects of ARZ 20 mg/day on several risk biomarkers. Biomarkers, including cytomorphology of breast epithelial cells obtained by random periareolar FNA (RPFNA) were assessed at baseline and following 6 months of placebo or ARZ. Subjects were stratified by presence or absence of atypia, ER expression, BRCA1/2 mutation, as well as menopause status. Results: At entry, mean age was 47, 52% were premenopausal and 47% of postmenopausal women were taking HRT. Mean 10 year Gail was 6.8% and mean Masood cytology index score was 14.3. The ARZ and placebo groups were well matched. The protocol defined primary endpoint was a decrease in RPFNA cytology Masood index score by ≥3 points at 6 months and required 160 evaluable subjects for 81% power to detect a change from 30% to 52% of subjects showing improvement. For the 181 evaluable subjects, there was no significant difference in the proportion of women achieving ≥3 point improvement (19% placebo vs. 24% ARZ, p=0.46); or in change in mean index score (0.6 placebo vs. 0.9 ARZ, p=0.53). There was also no difference in grade 3 or 4 side effects or dropout prior to 6 months. However, comparing ARZ to placebo, there was favorable modulation of the two risk biomarkers, mammographic breast density (p=0.001) and IGF-1:IGFBP-3 ratio (p=0.001), and reduction in bone turnover biomarker osteocalcin (p= 0.002), but without an increase in endometrial thickness. Conclusions: Although improvement in cytomorphology after 6 months of ARZ was not shown, the acceptable side effect profile and favorable modulation of other biomarkers (breast density, IGF-1:IGFBP-3, osteocalcin) provides support for continued evaluation of ARZ as a breast cancer prevention agent. No significant financial relationships to disclose.

Workshop on imaging science development for cancer prevention and preemption

“…More recently, newer selective estrogen receptor modulators (SERMSs) such as arzoxifene, and estrogen synthesis inhibitors such as aromatase inhibitors (letrozole, etc. ), are under evaluation as cancer preventive agents using breast density, cytomorphologic, and other molecular biomarker measurement methods (e.g., insulin-like growth factor (IGF)-1/IGF-BP3 ratio) to assess safety and efficacy [42,97]. However, standard CT methods to determine breast density are not optimal for risk assessment and treatment monitoring in every setting.…”

Selective estrogen receptor modulators: tissue specificity and clinical utility

“… 133 In addition, during other Phase I trials, it was found that arzoxifene caused decreases in proliferating cell nuclear antigen, IGF-1, and IGF binding protein 3. 142 Though no objective response was seen, the hormonal data and results on endometrium prompted Phase II trials. In these trials, results showed that lower doses (20 mg versus 50 mg) of arzoxifene showed better objective response rates, with hormone panels for FSH, LH, and SHBG confirming Phase I results.…”

Arzoxifene: the evidence for its development in the management of breast cancer

“…Arzoxifene as a chemopreventive agent was also studied in a phase II trial that randomized 199 women considered at high risk of breast cancer to arzoxifene 20 mg/day versus placebo ( Fabian et al 2006 ; Kimler et al 2006 ). Fifty-two percent of patients were premenopausal, whilst 47% of the postmenopausal women were on hormone replacement therapy (HRT).…”

“…Fifty-two percent of patients were premenopausal, whilst 47% of the postmenopausal women were on hormone replacement therapy (HRT). At 6 months, arzoxifene improved two risk biomarkers: Mammographic breast density was significantly reduced ( P <0.001), both in terms of the total dense area (+3.8 cm 2 versus −12.9 cm 2 ) and the percent of breast with increased density (+0.8% versus −4.6%) ( Kimler et al 2006 ) IGF-1: IGFBP-3 ratio was significantly reduced ( P =0.001) ( Fabian et al 2006 ). …”