Aging Mammary Stem Cells and Breast Cancer Prevention

Study Overview
=================
Brief Summary
-----------------
To examine whether rapamycin can reduce malignant markers and aberrant mammary stem/progenitor cells (MaSCs) number in surgical specimens

Detailed Description
-----------------
A non-randomized, open-label, phase II, window of opportunity trial will be carried out to see if a 5-7 day rapamycin treatment can reduce malignant markers and aberrant MaSC number

Official Title
-----------------
Aging Mammary Stem Cells and Breast Cancer Prevention

Conditions
-----------------
Cancer of Breast

Intervention / Treatment
-----------------
* Drug: Rapamycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women with confirmed menopausal status. All patients who have NOT had a prior bilateral oophorectomy and/or are younger than age 60, will require menopausal status verified by FSH and estradiol local labs. Women diagnosed with DCIS/LCIS, Atypical lobular hyperplasia (ALH) or ADH lesions detected by pathology Women scheduled for mastectomy or lumpectomy after DCIS/LCIS, ALH or ADH diagnosis Women consented to the UT Health Cancer Center MD Anderson Cancer Center tissue biorepository (HSC20070684H) Women of child-bearing potential willing to practice 2 forms of contraception, one of which must be a barrier method until at least 30 days after the last dose of rapamycin. Women of child-bearing potential must have a negative serum pregnancy test at time of enrollment. Patients must be able to swallow and retain oral medication. All patients must have given signed informed consent prior to registration on study. Patients must have normal organ and marrow function as defined below: Leukocytes ≥ 3,000/uL Absolute neutrophil count ≥ 1,500/uL Platelets ≥ 100,000/uL AST ≤ 2.5 X ULN ALT ≤ 2.5 X ULN Total bili ≤ 1.5 X ULN or Direct bili ≤ 1 X ULN Exclusion Criteria: Women who are pregnant. Women who are receiving any other concomitant treatment for their DCIS/LCIS, ALH or ADH Women who are taking rapamycin for another diagnosis. Women with an allergy to rapamycin or its derivatives. Active infection requiring systemic therapy. Patients who are taking any pills containing herbal (alternative) medicines are NOT eligible for participation. Patients must be off any such medications by the time of registration. Immunocompromised subjects, including patients with human immunodeficiency virus Women currently taking strong CYP3A4 inducers or inhibitors. Drugs that cannot be coadministered with rapamycin include but are not limited to: Calcium channel blockers: nicardipine, Antifungal agents: clotrimazole, fluconazole, Antibiotics: troleandomycin, Gastrointestinal prokinetic agents: cisapride, metoclopramide, Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir), Anticonvulsants: carbamazepine, phenobarbital, phenytoin, Antibiotics: rifapentine. The research team can provide a full list of these medications. Patients with any of the following conditions or complications are NOT eligible for participation: GI tract disease resulting in an inability to take oral medication Malabsorption syndrome Require IV alimentation History of prior surgical procedures affecting absorption Uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The effect of short-term rapamycin treatment<br>Subjects will be given a low dose of rapamycin at 2 mg/day for 5-7 days of treatment. A surgical specimen will be taken 3-7 days after the last dose of rapamycin. The specimens will be evaluated for lesion size, nuclear grade, presence of necrosis in each patient's core biopsy and surgical specimens, as well as IHC (ImmunoHistoChemistry) for biomarkers including p16, COX2 (cyclooxygenase-2), and Ki-67. Specimens will also be tested for rapamycin treatment on the properties of mammary stem/progenitor cells as another biomarker for gauging the efficacy of rapamycin treatment. | Drug: Rapamycin<br>* Low dose of rapamycin at 2 mg/day for -5-7 days of treatment<br>* Other names: Sirolimus;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Short-term Rapamycin Treatment on Biomarker Ki67 Associated With Progression to Invasive Breast Cancer | Comparing biopsy tissues before the treatment with surgical samples after rapamycin treatment in the same individuals to determine percentage nuclei with positive staining for Ki67 in the CCIS lesions. | Baseline to 5-7 day rapamycin plus 3-7 day washout | 
| The Effect of Short-term Rapamycin Treatment on the Frequency of Luminal Progenitor Epithelial Cells | Assessment will be used to measure changes in luminal progenitor cell population between controls and treated patients. | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | 
| The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Mammary Stem Cells | Measurement of difference in sphere formation efficiency (SFE) by mammary stem cells (MaSCs) in the basal myoepithelial cell population between the control and treatment groups. SFE is an in vitro method by quantifying the number of spheres formed divided by the number of cells seeded. Higher SFE indicates higher frequency of MaSCs. | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | 
| The Effect of Short-term Rapamycin Treatment on the Frequency of Mature Luminal Epithelial Cells | Measurement of Mature luminal cell populations in the treatment group compared to the control group. | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | 
| The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Luminal Progenitor Cells | The measurement of sphere formation efficiency (SFE) between luminal progenitor (LP) cells from the control group and those from the treatment group. SFE is an in vitro method by quantifying the number of spheres formed divided by the number of cells seeded. Higher SFE indicates higher frequency of LP cells. | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. |