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. Overall design: 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.