journal contribution posted on 2023-04-01, 00:23 authored by Andrés Elía, Leo Saldain, Silvia I. Vanzulli, Luisa A. Helguero, Caroline A. Lamb, Victoria Fabris, Gabriela Pataccini, Paula Martínez-Vazquez, Javier Burruchaga, Ines Caillet-Bois, Eunice Spengler, Gabriela Acosta Haab, Marcos Liguori, Alejandra Castets, Silvia Lovisi, María F. Abascal, Virginia Novaro, Jana Sánchez, Javier Muñoz, José M. Belizán, Martín C. Abba, Hugo Gass, Paola Rojas, Claudia Lanari
Mifepristone plasma levels and mifepristone-related side effects. A, Plasma levels of mifepristone 7 or 14 days after mifepristone treatment. The data from 9-10 patients are shown. Data were analyzed with ANOVA for matched samples (Friedman test). B, Clinical adverse effects grade 1 recorded in mifepristone (MFP)-treated patients. C, Laboratory values. Patients M049, M095 and M140 were treated for diabetes. Patients M009, M019, M023, M042, M049, M062, M070, M077, M090, M095, M105 and M140 were treated for hypertension and patients M009, M019 and M124 were treated for hypothyroidism. Dotted areas represent normal levels. Patients under mifepristone treatment did not interrupt standard medicine care.
Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT)
Fundación Sales (Sales Foundation)
Horizon 2020 Framework Programme (H2020)
Fundação para a Ciência e a Tecnologia (FCT)
Comissão de Coordenação e Desenvolvimento Regional do Centro (CCDRC)
ARTICLE ABSTRACTPreclinical 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).
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.
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.
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