SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02651844

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Mifepristone Treatment for Breast Cancer Patients Expressing Levels of Progesterone Receptor Isoform A (PRA) Higher Than Those of Isoform B (PRB): Neoadjuvant Therapy.

- 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. - Eligibility - 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. - Study design - 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.

NCT02651844 Breast Cancer
MeSH: Breast Neoplasms
HPO: Breast carcinoma Neoplasm of the breast

1 Interventions

Name: Mifepristone

Description: 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.

Type: Drug

Mifepristone


Primary Outcomes

Description: 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%.

Measure: Measurable decrease in tumor cell proliferation from baseline to time of surgery

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Secondary Outcomes

Description: 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%.

Measure: Measurable increases in apoptotic markers from baseline to time of surgery

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Description: 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%

Measure: Measurable changes in signaling pathways downstream PR

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Other Outcomes

Description: Measured by ecographic imaging. Twenty per cent of decrease in overall tumor size will be considered as a significant change.

Measure: Changes in tumor size

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Description: Differences in gene expression between biopsy core and surgery sample higher than 20 % will be considered as an effective drug response.

Measure: RNAseq analysis of gene expression

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Description: Levels of Mifepristone will be measured by HPLC in the blood sample after treatment and correlate these levels with response to treatment (outcome 1).

Measure: Measure serum Mifepristone levels after 14 days Mifepristone treatment

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 T47D

T47D cells will be used as a positive control. --- T47D ---



HPO Nodes


HPO:
Breast carcinoma
Genes 51
RAD51 RAD51C RAD51D CDKN2A KRAS MRE11 SLC22A18 STK11 MSH6 KLLN BRIP1 BRCA1 ATR BRCA2 PIK3CA PPM1D POLD1 NTHL1 POLE ESR1 WRN CHEK2 APC BARD1 MLH1 NBN COL14A1 AKT1 PRKN MSH2 FGFR2 IDH1 IDH2 CTNNB1 RB1CC1 PTEN MDM2 AAGAB CDH1 RNF43 PALLD PALB2 OPCML SEC23B TP53 SDHB SDHC SDHD SMAD4 TWIST1 RAD50
Neoplasm of the breast
Genes 73
RAD51 RAD51C RAD51D CDKN2A KRAS CDKN2B CDKN2D MRE11 SLC22A18 STK11 MSH6 RASGRP1 KLLN BRIP1 MGMT BRCA1 LMNA ATR ACD BRCA2 PIK3CA PPM1D POLD1 NTHL1 POLE ESR1 POT1 MC1R MITF WRN CHEK2 APC BARD1 MLH1 PRKAR1A CASP10 NBN PRKCD COL14A1 AKT1 C11ORF95 PRKN RELA MSH2 FGFR2 IDH1 GNAS IDH2 CTNNB1 RB1CC1 PTEN MDM2 FAS FASLG AAGAB CDH1 TERT RNF43 PALLD PALB2 OPCML TERF2IP PRLR SEC23B TP53 SDHB SDHC SDHD SMAD4 BAP1 CDK4 TWIST1 RAD50