MIPRA, a window of opportunity study using mifepristone for postmenopausal breast cancer patients with higher levels of progesterone receptor A than B.

H GASS; P MARTÍNEZ-VAZQUEZ; I CAILLET BOIS; M LIGUORI; V NOVARO; P A ROJAS; S I VANZULLI; V T FABRIS; E SPENGLER; S LOVISI; M F ABASCAL; A MOLINOLO; A ELÍA; C A LAMB; J BURRUCHAGA; A CASTETS; G PATACCINI; G ACOSTA HAAB; C LANARI

Simposio; San Antonio Breast Cancer Symposium; 2020

Background:Different antiprogestins have been clinically evaluated in gynecological and breast cancers. Mifepristone (MFP), onapristone, and telapristone acetate showed partial responses in breast cancer clinica ltrials. Preclinical data indicates that antiprogestins inhibit cell proliferation of luminal breast carcinomas expressing levels of progesterone receptor isoformA (PRA) higher than those of isoform B (PRB), as evaluated by western blots (WB). Thus, we designed a pre-surgical window trial of oral MFP to evaluate its therapeutic effects on the suppression of cell proliferation and on the differential gene expression in 20 breast cancer patients selected by their high PRA/PRB isoform ratio.Methods. MIPRA is an open label, one arm, prospective interventional study (NCT02651844). We interviewed 140 untreated breast cancer patients and 133 consented to participate. Four core ultrasound guided biopsies were performed, two were formalin-fixed for diagnosis, ER, PR, HER2 and Ki-67 evaluation, and two were snap frozen for WB and molecular studies. Only patients that met the inclusion criteria and had PRA/PRB>1.5 determined by WB and PR≥50% determined by immunohistochemistry (IHC) were included for MFP treatment. Plasma was obtained before and after treatment for future studies. Patients were treated for 14 days before surgery which was performed on day 15. MFP (200mg/day/os) was administered by trained hospital volunteers. Clinical exam was performed at days 7 and 14 to register possible adverse effects and to measure tumor size. During surgery, samples were formalin- fixed for IHC studies, and others were snap frozen for further molecular studies. One patient had a bilateral breast cancer, and both tumors matched with the inclusion criteria, and were included. The primary end point was Ki-67 labelling, comparing diagnostic core needle biopsy to post-therapy surgical specimens. Ki-67 changes were quantitated by an expert pathologist counting at least ten 40x fields per slide. This is currently being validated by a second pathologist. One patient was excluded since less than 500 total cells could be counted in the biopsy. Considering previous studies performed with Tamoxifen, we pre-specified that 30% of relative reduction in Ki-67 would be considered as a positive response. Secondary and other end points include the comparison of apoptotic, proliferative and hormone receptor markers (IHC), the measurement of MFP plasma levels and RNAseq analysis pre- and post-treatment (ongoing). Ki-67 changes from baseline were tested with paired Wilcoxon matched-pairs signe drank test.Results:The median (range) Ki-67 value of biopsies was 11.87 (2.7-34.56) and for surgical specimens 6.45 (0.48-23.77). A 45.67% of decrease in the median % Ki-67 (41.63% comparing the arithmetic mean values and 50.83 comparing the geometric mean values) was registered in all surgical specimens compared to baseline (p=0.003). Using the pre-specified response parameter (30% relative reduction in Ki-67), we identified 15/20 (75%) responders. If we consider only responsive tumors, a 49.87% decrease in the median % Ki-67 (50.83%, arithmetic mean; 62.34% geometric mean) was observed (p