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 RNA-Seq and Proteomics analysis. A and B, Dot plot of relevant enriched pathways from GSEA results (Reactome and Hallmark databases) separating responsive (A) and unresponsive tumors (B). C, Immune cell deconvolution (xcell) in the different tumors analyzed by RNA-Seq. Plots with significant p values analyzed by Wilcoxon test and the T cell CD8+ plot are shown. D, Kegg diagram of the Cell cycle pathway, that may explain mifepristone therapeutics effects. A colored code was used: the first half of the box is colored according to the RNA-Seq data (8 tumors) and the last half of the box is colored according to the proteomic data (n=10 tumors; nuclear fraction).
Funding
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)
History
ARTICLE ABSTRACT
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 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
