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

ELÍA, ANDRÉS; HELGUERO, LUISA A.; PATACCINI, GABRIELA; CAILLET-BOIS, INES; LIGUORI, MARCOS; VANZULLI, SILVIA I.; ABASCAL, MARÍA F.; FABRIS, VICTORIA; MUÑOZ, JAVIER; BURRUCHAGA, JAVIER; ACOSTA HAAB, GABRIELA; GASS, HUGO; LOVISI, SILVIA; SÁNCHEZ, JANA; SALDAIN, LEO; ABBA, MARTÍN C.; LAMB, CAROLINE A.; LANARI, CLAUDIA; MARTÍNEZ-VAZQUEZ, PAULA; SPENGLER, EUNICE; CASTETS, ALEJANDRA; NOVARO, VIRGINIA; BELIZÁN, JOSÉ M.; ROJAS, PAOLA

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2022 vol. 29 p. 866 - 877

1078-0432

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.