The Promise study: A presurgical randomized clinical trial of CE/BZA vs placebo in postmenopausal women with ductal carcinoma in situ.

Abstract

512 Background: Conjugated estrogen/bazedoxifene (CE/BZA), the first tissue selective estrogen complex, was developed as an alternative to combination estrogen and progesterone therapy to treat hot flashes and osteoporosis. Preclinical studies found that CE/BZA reduced mammary ductal proliferation and increased expression of anti-tumorigenic markers in breast stroma. Our study aimed to determine if a pre-surgical window-of-opportunity intervention with CE/BZA in women with ductal carcinoma in situ (DCIS) had a protective effect on the duct epithelium and stroma of DCIS lesions without impacting quality of life. Differences between CE/BZA and placebo arms for the primary endpoint, change in Ki-67 protein expression, and quality-of-life endpoints are reported here. Methods: This multicenter, randomized, double-blind placebo-controlled Phase 2 trial was conducted between 9/19/17 and 8/21/24. Postmenopausal women with estrogen receptor positive (ER+) DCIS undergoing surgery were randomized to CE 0.45 mg /BZA 20 mg or placebo for 28 +/-7 days. Percentage of nuclei staining for Ki-67 was evaluated on slides from the baseline core biopsy and surgical specimen. Changes were compared between arms using the two-sample t-test, while changes within arms were analyzed using paired t-test. Analyses were done on log2 scale to satisfy the normality assumption. The Breast Cancer Prevention Trial Eight Symptom Scale (BESS) and Menopause-Specific Quality of Life (MENQOL) surveys were self-administered by patients before and after the intervention. Wilcoxon’s signed-rank and rank-sum tests were used to perform within- and between-arm comparisons, respectively. Results: Of the 171 patients consented,141 enrolled, and 117 completed the study. Ninety-four patients (46= CE/BZA, 48=placebo) took >80% of the medication and had Ki-67 evaluated at baseline and post-intervention. The BESS and MENQOL surveys were completed by 100 and 108 patients, and 125 patients were evaluated for toxicity. The mean absolute change in Ki-67 was -5.62 (SD=10.2; p=0.003) in the CE/BZA arm and -1.07 (SD=10.8; p=0.6) in the placebo arm, with a greater reduction in CE/BZA arm (p=0.016). There was no difference between arms in the BESS score across all 8 domains or in the MENQOL score. However, within each arm, vasomotor symptoms decreased in the CE/BZA arm (p=0.002) but not in the placebo arm (p=0.4). No grade > 3 treatment related adverse events were reported. Conclusions: In this prospective randomized clinical trial, CE/BZA significantly reduced epithelial proliferation in ER+ DCIS with no impact on quality of life compared to placebo. These results support consideration that CE/BZA is a safe option to manage menopausal symptoms for women concerned about their risk of developing breast cancer, and provide supportive evidence that CE/BZA may reduce the risk of developing invasive breast cancer. Clinical trial information: NCT02694809 .