Antiprogestins for breast cancer treatment: We are almost ready.

The development of antiprogestins was initially a gynecological purpose. However, since mifepristone was developed, its application for breast cancer treatment was immediately proposed. Later, new compounds with lower antiglucocorticoid and antiandrogenic effects were developed to be applied to different pathologies, including breast cancer. We describe herein the studies performed in the breast cancer field with special focus on those reported in recent years, ranging from preclinical biological models to those carried out in patients. We highlight the potential use of antiprogestins in breast cancer prevention in women with BRCA1 mutations, and their use for breast cancer treatment, emphasizing the need to elucidate which patients will respond. In this sense, the PR isoform ratio has emerged as a possible tool to predict antiprogestin responsiveness. The effects of combined treatments of antiprogestins together with other drugs currently used in the clinic, such as tamoxifen, CDK4/CDK6 inhibitors or pembrolizumab in preclinical models is discussed since it is in this scenario that antiprogestins will be probably introduced. Finally, we explain how transcriptomic or proteomic studies, that were carried out in different luminal breast cancer models and in breast cancer samples that responded or were predicted to respond to the antiprogestin therapy, show a decrease in proliferative pathways. Deregulated pathways intrinsic of each model are discussed, as well as how these analyses may contribute to a better understanding of the mechanisms involved.

Steroid profile in patients with breast cancer and in mice treated with mifepristone.

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial.

PURPOSE: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844). PATIENTS AND METHODS: Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment. RESULTS: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling. CONCLUSIONS: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients. See related commentary by Ronchi and Brisken, p. 833.