Mifepristone for Breast Cancer Patients With Higher Levels of Progesterone Receptor Isoform A Than Isoform B. (MIPRA)
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|ClinicalTrials.gov Identifier: NCT02651844|
Recruitment Status : Completed
First Posted : January 11, 2016
Last Update Posted : May 6, 2022
- Seventy per cent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to endocrine treatment.
- Actual therapy targets ER.
- There is enough evidence that progestins participate regulating breast cancer growth.
- Antiprogestins block cell proliferation and increase apoptosis in breast cancer models which express high levels of PRA.
- Antiprogestins have been used to treat breast cancer patients that failed to other treatments; benefits were seen in selected patients.
- Mifepristone (MFP) is currently used for medical abortion and for the treatment of Cushing disease.
- MFP might exert agonistic effects when PRB isoform is activated by cAMP. This makes mandatory the evaluation of the PR isoform ratio in breast cancer patients in which MFP is a therapeutic possibility.
Main Goal To evaluate if therapeutic doses of MFP exert beneficial effects on breast cancers expressing levels of PRA higher than those of PRB, evaluated as an inhibition in proliferation markers and/or an increase in apoptotic markers.
- Postmenopausal women (one year after menses stop).
- Women with tumors showing ratios of PRA/PRB higher than 1.5 and PR higher than 50%.
- Women without previous treatment.
- All clinical stages with tumors larger than 1.5 cm.
- Patients without autoimmune diseases and/or asthma.
- Open Interventional.
- Twenty women will take MFP (200 mg) p.o. once /day during 14 days. As for preliminary studies, to reach this number the investigators will have to evaluate 80-100 patients.
- Surgery is performed 14 days after treatment initiation, 24 hs after last dose.
- PR isoform ratio will be evaluated by western blots (WB) in one core biopsy. Additional cores will be used for diagnosis, immunohistochemistry (IHC) of PR, Ki-67 and other markers.
- At surgery samples will be frozen for molecular studies and fixed and processed for pathological evaluation.
- Wilcoxon signed rank test will be used to evaluate differences in biomarker expression between core biopsy and surgical samples of each patient.
- Blood will be collected before treatment initiation and prior to final surgery.
- Mammographic and echographic studies will be carried out before and after treatment.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: Mifepristone||Not Applicable|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Mifepristone Treatment for Breast Cancer Patients Expressing Levels of Progesterone Receptor Isoform A (PRA) Higher Than Those of Isoform B (PRB): Neoadjuvant Therapy.|
|Actual Study Start Date :||April 2016|
|Actual Primary Completion Date :||October 31, 2019|
|Actual Study Completion Date :||October 31, 2019|
Tablets of Mifepristone 200 mg p.o. once a day during 14 days between biopsy and surgery after confirming inclusion criteria
At the time a patient enters the protocol, 14 pills will be given to the personnel responsible of giving the patient the medicine at her home (This was a special requirement from the Argentine Authorities).
Patients and personnel will sign the form each then she gets the medication and after that the signed form will be kept at the CRF file.
Other Name: RU-486
- Measurable decrease in tumor cell proliferation from baseline to time of surgery [ Time Frame: Baseline to time of surgery (14 days of treatment between biopsy core and surgery) ]Treatment efficacy will be assessed by comparing tissue samples from the baseline biopsy and tissue samples collected from the day of surgery, evaluating if there is a decrease in the proliferating index (Ki-67 expression by immunohistochemistry). Positive response: differences higher than 30%.
- Measurable increases in apoptotic markers from baseline to time of surgery [ Time Frame: Baseline to time of surgery (14 days of treatment between biopsy core and surgery) ]Treatment efficacy will be assessed by comparing tissue samples from the baseline biopsy and tissue samples collected from the day of surgery, evaluating if there is an increase in apoptotic cells measuring TUNNEL and caspase 3 expression. Positive response: difference higher than 30%.
- Measurable changes in signaling pathways downstream PR [ Time Frame: Baseline to time of surgery (14 days of treatment between biopsy core and surgery) ]MFP action will be measured evaluating the expression of downstream markers related to PR activation such as CCND1, MYC, pSTAT5 and other proteins by immunohistochemistry. Positive response: differences higher than 30%
- Changes in tumor size [ Time Frame: Baseline to time of surgery (14 days of treatment between biopsy core and surgery) ]Measured by ecographic imaging. Twenty per cent of decrease in overall tumor size will be considered as a significant change.
- RNAseq analysis of gene expression and Proteomics to evaluate possible deregulated pathways [ Time Frame: Baseline to time of surgery (14 days of treatment between biopsy core and surgery) ]Differences in gene and protein expression between biopsy core and surgery sample higher than 20 % will be considered as an effective drug response.
- Measure serum Mifepristone levels after 7/14 days Mifepristone treatment and other steroid hormone precursors [ Time Frame: Baseline to time of surgery (14 days of treatment between biopsy core and surgery), and an intermediate timepoint ]Levels of Mifepristone and other steroids will be measured by HPLC or LC-MS/MS in the blood sample after treatment and correlate these levels with response to treatment (outcome 1).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02651844
|General Pacheco, Buenos Aires, Argentina, 1617|
|Study Director:||Claudia Lanari, PhD||IBYME-CONICET|