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

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

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2022 p. 1 - 12

1078-0432

Purpose: Preclinicaldata suggest that antiprogestins inhibit the growth of luminal breastcarcinomas that express higher levels of progesterone receptorisoform A (PRA) than isoform B (PRB). Thus, we designed apresurgical window of opportunity trial to determine the therapeuticeffects of mifepristone in patients with breast cancer, based ontheir high PRA/PRB isoform ratio (MIPRA;NCT02651844).Patients andMethods: Twenty patients with luminal breast carcinomas with PRA/PRB> 1.5 (determined by Western blots), and PR ≥ 50%, naive fromprevious treatment, were included for mifepristone treatment(200 mg/day orally; 14 days). Core needle biopsies and surgicalsamples were formalin fixed for IHC studies, while others weresnap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/orWestern blot studies. Plasma mifepristone levels were determinedusing mass spectrometry. The primary endpoint was the comparison ofKi67 expression pretreatment and posttreatment.Results: A 49.62%decrease in Ki67 staining was observed in all surgical specimenscompared with baseline (P 1⁄4 0.0003). Using the prespecifiedresponse parameter (30% relative reduction), we identified 14 of 20responders. Mifepristone induced an increase in tumor-infiltratinglymphocytes; a decrease in hormone receptor and pSer118ER expression;and an increase in calregulin, p21, p15, and activated caspase 3expression. RNA-seq and proteomic studies identified downregulatedpathways related to cell proliferation and upregulated pathwaysrelated to immune bioprocesses and extracellular matrix remodeling.Conclusions: Ourresults support the use of mifepristone in patients with luminalbreast cancer with high PRA/PRB ratios. The combined effects ofmifepristone and estrogen receptor modulators warrant clinicalevaluation to improve endocrine treatment responsiveness in thesepatients.p { margin-bottom: 0.1in; line-height: 115% }