Beneficial effects of mifepristone treatment in breast cancer patients selected by the progesterone receptor isoform ratio: Results from the MIPRA trial

Background: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas expressing 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 breast cancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844). Patients and Methods. Twenty patients bearing 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, and others were snap-frozen to perform RNA-Seq, proteomics, and/or Western blots studies. Plasma mifepristone levels were determined by mass spectrometry. The primary endpoint was the comparison of Ki-67 expression pre- and post-treatment. Results: A 49.62% decrease in Ki-67 staining was registered in all surgical specimens compared to baseline (p=0.0003). Using the pre-specified response parameter (30% relative reduction) we identified 14/20 responders. Mifepristone induced gland differentiation, an increase in tumor-infiltrating lymphocytes, a decrease in hormone receptors 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 upregulation of those related to immune bioprocesses and extracellular matrix re-modeling pathways. Conclusion: Our results support the use of mifepristone in luminal breast cancer patients with high PRA/PRB ratios. The combined effects of mifepristone with estrogen receptor modulators deserves clinic evaluation in these patients, to improve endocrine treatment responsiveness. Eight patients bearing luminal breast carcinomas and naive from previous treatment, were treated with mifepristone (200 mg/day p.o.; 14 days). Core needle biopsies (CNB) and surgical samples were obtained from pre- and post-treatment respectivelly, and were snap-frozen to perform RNA-Seq.