There are 2 clinical trials
- 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.
T47D cells will be used as a positive control. --- T47D ---
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)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)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)The Investigators hypothesize that single agent lenvatinib has biological activity in estrogen receptor positive breast cancer, and that the effects are more pronounced in patients with positive RET expression in the tumor.
The investigators tested 9 ER+ breast cancer cell lines for RET expression using Western blot, and identified 4 with high expression (BT474, MB361, HCC1419, UACC812), 2 with normal expression (MCF7, CAMA1), and 3 with low expression (T47D, ZR-75-1, BT483). --- T47D ---
To evaluate the effects of combining lenvatinib with endocrine therapy in ER+ breast cancer cell lines with different RET expression, the investigators performed experiments using 6 cell lines, including 2 with high RET expression (BT474, MB361), 2 with normal RET expression (MCF7, CAMA1), and 2 with low RET expression (T47D, ZR-75-1). --- T47D ---
Lenvatinib was at least additive with tamoxifen in all 6 ER positive breast cancer cell lines tested, with the combination resulting in ≥50% cell kill compared to single agent tamoxifen in BT474, CAMA1, and T47D cell lines. --- T47D ---
Description: To evaluate Ki67 changes. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. Ki67 has been shown to be a surrogate marker of biological activity and treatment response in estrogen receptor positive breast cancer treated with endocrine therapy.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate histological response such as the improvement in the appearance of microscopic tissue specimens after treatment with lenvatinib. The improved appearance of biopsy specimens after treatment often suggests the patient's prognosis will improve as well.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate apoptosis. Apoptosis is the death of cells which occurs as a normal and controlled part of an organism's growth or development. The presence of apoptosis indicates anti-cancer effects.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate RET. RET is an estrogen response gene. RET is associated with resistance to tamoxifen and aromatase inhibitors, and increased RET expression has been demonstrated in hormone resistant cell lines and primary tumors.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate downstream targets such as AKT. AKT /protein kinase B (PKB) is a cardinal node in diverse signaling cascades important in both normal cellular physiology and various disease states. AKT signaling regulates cell proliferation and survival, cell growth (size), glucose metabolism, cell motility and angiogenesis. Aberrant regulation of these processes results in cellular perturbations considered hallmarks of cancer, and numerous studies testify to the frequent hyperactivation of AKT signaling in many human cancer.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate downstream targets such as ERK. ERK is Extracellular signal-regulated kinase. Deregulation of ERK signalling pathway is linked to many other aspects of the tumour phenotype.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: to obtain the percentage change in primary breast tumor dimension measured by ultrasound
Measure: Changes in the primary tumor dimensions Time: after 10-28 days of single agent lenvatinibDescription: to obtain the proportion of subjects with tumor reduction of at least 10%
Measure: The proportion of subjects with tumor reduction Time: after 10-28 days of single agent lenvatinibDescription: To compare clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers
Measure: Comparison of the clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers Time: after 10-28 days of single agent lenvatinibDescription: : Comparison of the number of patients with Ki67 changes, histological response, apoptosis, RET and downstream targets such as AKT and ERK, between RET negative versus RET positive, ER positive breast cancers.
Measure: Comparison in the overall average changes in biological effects of lenvatinib between RET negative and RET positive, ER positive breast cancers. Time: after 10-28 days of single agent lenvatinib