Selective Progesterone Receptor Modulators in Early-Stage Breast Cancer: A Randomized, Placebo-Controlled Phase II Window-of-Opportunity Trial Using Telapristone Acetate

Abstract

Purpose: Selective progesterone receptor modulators (SPRMs) show preclinical activity against hormone-sensitive breast cancer, but have not been tested in patients with early, treatment-na€ ve tumors.Patients and Methods: In a double-blind presurgical window trial of oral telapristone acetate (TPA) 12 mg daily versus placebo, 70 patients with early-stage breast cancer were randomized 1:1 (stratified by menopause) and treated for 2 to 10 weeks. The primary endpoint was change in Ki67 between diagnostic biopsy and surgical specimens. Gene expression pre-and posttherapy was assessed using RNA-sequencing and gene set enrichment analysis was performed to determine pathways enriched in response to TPA and placebo treatments.Results: Among 61 evaluable women (29 placebo and 32 telapristone acetate), 91% of tumors were ER/PR positive. The mean Ki67 declined by 5.5% in all women treated with telapris-tone acetate (P ¼ 0.003), and by 4.2% in all women treated with placebo (P ¼ 0.04). After menopausal stratification, the Ki67 decline remained significant in 22 telapristone acetate-treated premenopausal women (P ¼ 0.03). Differential gene expression analysis showed no significant modulation overall. However, in a subset of tumors that demonstrated !30% relative reduction in Ki67 in the telapristone acetate group, genes related to cell-cycle progression, and those in the HER2 amplicon were significantly downregulated. In contrast, no significantly enriched pathways were identified in the placebo group.Conclusions: Patients treated with telapristone acetate whose Ki67 decreased by !30% demonstrated a selective antiproliferative signal, with a potentially important effect on HER2 amplicon genes. Evaluation of SPRMs in a neoadjuvant trial is merited, with attention to predictors of response to SPRM therapy, and inclusion of pre-and postmenopausal women.

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

“…We measured parameters designed to evaluate drug efficacy (reduction in Ki67, changes in gene expression); we did not observe significant changes in tumor Ki67 or gene expression in either the oral or the transdermal group (data not shown). We have recently reported a pre‐operative window study of oral TPA in patients with stages I–II breast cancer, where a one‐third reduction in Ki67 post‐therapy was accompanied by a significant decrease in cell‐cycle‐related genes 27 . In the present study, where the primary end point was drug permeation, we included women without cancer.…”

“…Images were transmitted to the University of North Carolina and scored for evaluation of proportional tissue area of adipose, epithelium, and stroma ( Figure 1c), as previously described. 26 Drug and serum hormone concentration assays Plasma and breast tissue concentration of TPA (CDB-4124) and its active monodemethylated metabolite (CDB-4453) were determined using liquid chromatography-tandem mass spectrometry, performed at the Illinois Institute of Technology Research Institute, as previously described 27 and detailed in Supplementary Methods. Serum concentrations of estradiol, progesterone, and follicle stimulating hormone (FSH) were measured using a validated protocol at Ligand Assay and Analysis Core Laboratory, University of Virginia.…”

“…Because TPA is known to suppress ovulation in premenopausal women, 27,29 we measured serum concentrations of estradiol, progesterone, and FSH prior to and following intervention. The median concentration of each hormone is summarized in Table 4.…”

“…We have recently reported a pre-operative window study of oral TPA in patients with stages I-II breast cancer, where a one-third reduction in Ki67 post-therapy was accompanied by a significant decrease in cell-cycle-related genes. 27 In the present study, where the primary end point was drug permeation, we included women without cancer. This inclusive design limits our ability to reach conclusions regarding biologic effects of TPA by either route of administration.…”

DeepSnap-Deep Learning Approach Predicts Progesterone Receptor Antagonist Activity With High Performance

“…It is also responsible for developing the central nervous system by the regulation of cell proliferation and differentiation via a wide range of physiological process modulated by progesterone-mediated classical ligand-binding or non-classical novel non-genomic pathways (Garg et al, 2017;Leehy et al, 2018;Wu et al, 2018;Cenciarini and Proietti, 2019;González-Orozco and Camacho-Arroyo, 2019;Hawley and Mosura, 2019;Rudzinskas et al, 2019). In the clinic, steroidal PR agonists have been used in oral contraception and postmenopasusal hormone therapy (Fensome et al, 2005;Afhüppe et al, 2009;Lee et al, 2020). In addition, PR antagonists are gaining attention as a potential anti-cancer treatment due to their inhibitory effects on cell growth in vitro, affecting ovarian, breast, prostate, and bone cancer cells (Tieszen et al, 2011;Zheng et al, 2017;Ponikwicka-Tyszko et al, 2019;Ritch et al, 2019;Trabert et al, 2019).…”