Regulation of PR, ER and plasma steroid hormones by mifepristone treatment in breast cancer patients from MIPRA trial

ANDRES ELIA; LEO SALDAIN; HUGO GASS; CAROLINE A. LAMB; VICTORIA T FABRIS; PAULA MARTÍNEZ VAZQUEZ; JAVIER BURRUCHAGA; EUNICE SPENGLER; INÉS CAILLET BOIS; ALEJANDRA CASTETS; SILVIA LOVISI; MARCOS LIGUORI; GABRIELA PATACCINI; MARÍA FLORENCIA ABASCAL; VIRGINIA NOVARO; ALFREDO MOLINOLO; SILVIA I. VANZULLI; PAOLA ROJAS ; CLAUDIA LANARI

Congreso; Reunión Anual de Sociedades de BioCiencias; 2021

Preclinical data suggests that antiprogestins inhibit the growth ofluminal breast carcinomas expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB). Thus, weconducted a pre-surgical window of opportunity trial to test the effect of mifepristone (MFP; 200 mg, PO, QD, 14 days) in 20 breastcancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844). The primary endpoint was to compare theKi67 levels of biopsies and the post-therapy surgical specimens. A49.62% decrease in the median was registered in all surgical specimens compared to baseline (p=0.0003). RNA-seq analysis showedthat MFP upregulated genes related to the immune system and matrix remodeling, and downregulated genes involved in cell-cycle andproliferative pathways. Now we report data regarding the PR and estrogen receptor alpha (ER) regulation by MFP and plasma levels ofMFP and 20 steroid hormones (LC-MS/MS). In western blot studiesan enrichment of the PR isoforms in the nuclear compartment withupshifted bands was observed in MFP-treated samples (p = 0.002,Wilcoxon). Immunohistochemical studies comparing pre- and posttreatment samples suggested a decrease in PR, ER, pSer294PRand pSer118ER after treatment. MFP plasma levels were 683.6 +/-28.6 nM at day 7, and 757.5 +/- 41.7 nM at day 14 after treatmentinitiation. An expected increase in cortisol levels (p < 0.001) andother steroids was observed in MFP-treated plasma from patients.Our results suggest that MFP is playing an active role regulatingtarget genes in MFP-treated patients. The decrease in pSer294 PRsuggest an inhibition in MAPK-mediated activation of PR. Since ina MFP-sensitive mouse model plasma levels of 20 nM are effectiveinducing tumor regression it may be suggested that lower MFP doses may exert similar therapeutic effects with less antiglucocorticoidside effects.