Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher lev... more Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to study the benefits of mifepristone (MFP) in luminal breast carcinomas from postmenopausal patients selected by their PR+ expression (>50%) and their PR isoform ratio (PRA/PRB>1.5; PRA-H). A decrease in the cell proliferation marker Ki67 was registered after treatment in 14 out of the 20 tumors evaluated. This inhibition was associated with a decrease in PR, estrogen receptor (ER) and pSer118ER evaluated by immunohistochemistry while no changes in pSer167ER expression were observed (PMID: 36269797). In selected tissues from these samples we observed that the staining intensity in trapped glands within the MFP-treated tumors did not follow a similar trend as that of tumor cells. Thus, the aim of this study was to evaluate the expression of hormone ...
Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal t... more Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal tissue (A), thin and scarce collagen fibers, and increased stromal matrix (arrow; B), an area of tissue remodeling (C), and an area of increased differentiation (D) observed in the surgical samples (S) compared to the respective core needle biopsies (CNB). E, Image illustrates an area of necrosis (dotted arrow) together with a differentiated structure (black arrow) in a surgical sample. F, Cells with Alcian blue+ (left), PAS+ (middle) and MUC-1+ (immunohistochemistry; right) vacuoles observed in a mifepristone-treated tumor. Inset: High power field of a differentiated gland/duct.
Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcino... more Purpose: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).Patients and Methods: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.Results:A 49.62%...
Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using... more Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using the Oviz-Bio tool (https://academic.oup.com/nar/article/48/W1/W415/5835823). Only driver breast cancer genes (99) were selected from the Intogene data base (https://www.intogen.org/download) and we found mutations in 19 driver genes after read depth filtering (DP >50). Of note is the missense mutation found in ESR1 in the M070 patient. Left, Percentage of samples with mutations. Color defines the type of mutations.
A, Library size before and after low count filtering. B, P-value histogram distribution observed ... more A, Library size before and after low count filtering. B, P-value histogram distribution observed in the differential expression analysis. C, Pairwise scatter plots of the first five principal components from the principal component analysis of RNA-Seq data.
Mifepristone plasma levels and mifepristone-related side effects. A, Plasma levels of mifepriston... more 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.
A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (N... more A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (Nuc) or cytosolic (Cyt) localization in western blot studies. *: Prevailing PR isoforms in Western blot studies; #: Distribution of PR in the Nuc or Cyt compartments; CNB: Core needle biopsy, S: Surgical sample. In grey font: Mifepristone unresponsive tumors by Ki67 criteria. B, Representative western blots of CNB and surgical samples from all patients. The upper band is PRB and the lower band PRA, as labeled in the first set.
Evaluation of Ki67 expression in paired samples before and after mifepristone treatment by two in... more Evaluation of Ki67 expression in paired samples before and after mifepristone treatment by two independent pathologists, and time elapsed between core needle biopsy and surgery.
Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcino... more Purpose: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).Patients and Methods: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.Results:A 49.62%...
Background: Preclinical data suggests that antiprogestins inhibit the growth of luminal breast ca... more Background: Preclinical data suggests that antiprogestins inhibit the growth of luminal breast carcinomas expressing higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a pre-surgical window of opportunity trial to determine the therapeutic effects of oral mifepristone (MFP) in 20 breast cancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Methods. MIPRA is an open-label, one-arm, prospective interventional study. After the selection process, 20 patients that met the inclusion criteria, with ER+, PRA/PRB>1.5 determined by Western blots, and total PR ≥50% determined by immunohistochemistry (IHC), were included for daily MFP treatment (200 mg/day p.o., 14 days). Core needle biopsies and surgical samples were formalin-fixed for IHC studies, and others were snap-frozen for further molecular studies. Besides, plasma samples were obtained for MFP dosing by LC-MS/MS. RNA was extracted from frozen tissue with a colum...
Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher lev... more Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to study the benefits of mifepristone (MFP) in luminal breast carcinomas from postmenopausal patients selected by their PR+ expression (>50%) and their PR isoform ratio (PRA/PRB>1.5; PRA-H). A decrease in the cell proliferation marker Ki67 was registered after treatment in 14 out of the 20 tumors evaluated. This inhibition was associated with a decrease in PR, estrogen receptor (ER) and pSer118ER evaluated by immunohistochemistry while no changes in pSer167ER expression were observed (PMID: 36269797). In selected tissues from these samples we observed that the staining intensity in trapped glands within the MFP-treated tumors did not follow a similar trend as that of tumor cells. Thus, the aim of this study was to evaluate the expression of hormone ...
Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal t... more Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal tissue (A), thin and scarce collagen fibers, and increased stromal matrix (arrow; B), an area of tissue remodeling (C), and an area of increased differentiation (D) observed in the surgical samples (S) compared to the respective core needle biopsies (CNB). E, Image illustrates an area of necrosis (dotted arrow) together with a differentiated structure (black arrow) in a surgical sample. F, Cells with Alcian blue+ (left), PAS+ (middle) and MUC-1+ (immunohistochemistry; right) vacuoles observed in a mifepristone-treated tumor. Inset: High power field of a differentiated gland/duct.
Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcino... more Purpose: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).Patients and Methods: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.Results:A 49.62%...
Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using... more Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using the Oviz-Bio tool (https://academic.oup.com/nar/article/48/W1/W415/5835823). Only driver breast cancer genes (99) were selected from the Intogene data base (https://www.intogen.org/download) and we found mutations in 19 driver genes after read depth filtering (DP >50). Of note is the missense mutation found in ESR1 in the M070 patient. Left, Percentage of samples with mutations. Color defines the type of mutations.
A, Library size before and after low count filtering. B, P-value histogram distribution observed ... more A, Library size before and after low count filtering. B, P-value histogram distribution observed in the differential expression analysis. C, Pairwise scatter plots of the first five principal components from the principal component analysis of RNA-Seq data.
Mifepristone plasma levels and mifepristone-related side effects. A, Plasma levels of mifepriston... more 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.
A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (N... more A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (Nuc) or cytosolic (Cyt) localization in western blot studies. *: Prevailing PR isoforms in Western blot studies; #: Distribution of PR in the Nuc or Cyt compartments; CNB: Core needle biopsy, S: Surgical sample. In grey font: Mifepristone unresponsive tumors by Ki67 criteria. B, Representative western blots of CNB and surgical samples from all patients. The upper band is PRB and the lower band PRA, as labeled in the first set.
Evaluation of Ki67 expression in paired samples before and after mifepristone treatment by two in... more Evaluation of Ki67 expression in paired samples before and after mifepristone treatment by two independent pathologists, and time elapsed between core needle biopsy and surgery.
Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcino... more Purpose: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).Patients and Methods: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.Results:A 49.62%...
Background: Preclinical data suggests that antiprogestins inhibit the growth of luminal breast ca... more Background: Preclinical data suggests that antiprogestins inhibit the growth of luminal breast carcinomas expressing higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a pre-surgical window of opportunity trial to determine the therapeutic effects of oral mifepristone (MFP) in 20 breast cancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Methods. MIPRA is an open-label, one-arm, prospective interventional study. After the selection process, 20 patients that met the inclusion criteria, with ER+, PRA/PRB>1.5 determined by Western blots, and total PR ≥50% determined by immunohistochemistry (IHC), were included for daily MFP treatment (200 mg/day p.o., 14 days). Core needle biopsies and surgical samples were formalin-fixed for IHC studies, and others were snap-frozen for further molecular studies. Besides, plasma samples were obtained for MFP dosing by LC-MS/MS. RNA was extracted from frozen tissue with a colum...
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