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

Abstract

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 pre-surgical 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%, naive from previous treatment, were included for mifepristone treatment (200 mg/day p.o.; 14 days). Core needle biopsies (CNB) and surgical samples were formalin-fixed for immunohistochemical studies, while others were snap-frozen to perform 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 pre- and post-treatment. Results: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared to baseline (p=0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14/20 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 caspase3 expression. RNA-Seq and proteomics 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.

Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms

“…In 1982, mifepristone was reported as the first selective progesterone receptor modulator . Current studies for understanding the mechanism of action of mifepristone are changing our views on the drug beyond its abortifacient scope . Mifepristone has been found to have potential clinical applications in gynecological therapies, such as endometriosis and uterine fibroids .…”

“… 16 , 17 Current studies for understanding the mechanism of action of mifepristone are changing our views on the drug beyond its abortifacient scope. 18 , 19 , 20 Mifepristone has been found to have potential clinical applications in gynecological therapies, such as endometriosis and uterine fibroids. 21 , 22 A previous study indicated that mifepristone treatment inhibited the development of adenomyosis in mice.…”

Targeting nuclear hormone receptors for the prevention of breast cancer

“…Mifepristone, ulipristal acetate, and telapristone acetate have been shown to decrease cell proliferation, inhibit cell cycle progression, and increase apoptosis of breast cancer cell lines (115,116). Additionally, preclinical studies have also revealed that mifepristone and telapristone acetate can inhibit angiogenesis and migration of breast cancer cells in vivo (117,118). Recently, the phase I MIPRA trial exploring the effects of mifepristone in women with breast cancer pre-selected for high PR-A:PR-B ratios in the tumor demonstrated a significant decrease in Ki-67 proliferation marker with an increase in Cleaved caspase 3 compared to baseline expression after two weeks of treatment (119).…”

Tumor Lipid Signatures Are Descriptive of Acquisition of Therapy Resistance in an Endocrine-Related Breast Cancer Mouse Model

“…HR-positive breast tumors depend on activated ERα to support their growth, and thus, most endocrine therapies (ET) target the ER signaling pathway, usually blocking ERα transcriptional activity with drugs such as tamoxifen or fulvestrant and using aromatase inhibitors . Tumor growth can also be sustained by PR activation, and some ETs have been developed to target this receptor. − The most common progestins used for BC treatment, particularly at advanced stages, comprise megestrol acetate and medroxyprogesterone acetate (MPA), while antiprogestins (e.g., RU486 or mifepristone, and onapristone) have been used in clinical trials, but they are still not an option in the clinic. − Moreover, recent findings from the MIPRA window of opportunity clinical trial support the use of mifepristone in patients with luminal breast cancer with high PR isoform A/isoform B ratios . However, most BC patients initially respond to ET but eventually relapse (acquired resistance) and about 20–30% do not respond ( de novo resistance) .…”