Cancer of Breast
Conditions
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
Interventions
DRUGRapamycin
Low dose of rapamycin at 2 mg/day for -5-7 days of treatment
Sponsors
National Cancer Institute (NCI)
LuZhe Sun
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
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: 1. Leukocytes ≥ 3,000/uL 2. Absolute neutrophil count ≥ 1,500/uL 3. Platelets ≥ 100,000/uL 4. AST ≤ 2.5 X ULN 5. ALT ≤ 2.5 X ULN 6. 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: 1. GI tract disease resulting in an inability to take oral medication 2. Malabsorption syndrome 3. Require IV alimentation 4. History of prior surgical procedures affecting absorption 5. Uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Effect of Short-term Rapamycin Treatment on Biomarker Ki67 Associated With Progression to Invasive Breast Cancer | Baseline to 5-7 day rapamycin plus 3-7 day washout | 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. |
| The Effect of Short-term Rapamycin Treatment on the Frequency of Luminal Progenitor Epithelial Cells | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | Assessment will be used to measure changes in luminal progenitor cell population between controls and treated patients. |
| The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Mammary Stem Cells | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | 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. |
| The Effect of Short-term Rapamycin Treatment on the Frequency of Mature Luminal Epithelial Cells | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | Measurement of Mature luminal cell populations in the treatment group compared to the control group. |
| The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Luminal Progenitor Cells | 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group. | 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. |
Countries
United States
Participant flow
Recruitment details
We acquired primary tissue samples from patients diagnosed with non-invasive lesions as detected by clinical pathology at the University of Texas Health Science Center at San Antonio (UTHSCSA) (San Antonio, TX). Inclusion criteria and exclusion criteria were descried in the study.
Participants by arm
| Arm | Count |
|---|---|
| Rapamycin Treatment Group A total of 40 patients were consented to undergo treatment and 38 successfully completed the regiment. | 40 |
| Un-treated Control Group The control group included 12 patients with DCIS or ADH, who declined to participate in the sirolimus study but agreed to donate their tissues, and 6 patients with invasive ductal carcinoma for a total of 18 controls | 18 |
| Total | 58 |
Baseline characteristics
| Characteristic | Rapamycin Treatment Group | Un-treated Control Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 15 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 3 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 9 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 8 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 33 Participants | 15 Participants | 48 Participants |
| Region of Enrollment United States | 40 participants | 18 participants | 58 participants |
| Sex: Female, Male Female | 40 Participants | 18 Participants | 58 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 40 |
| other Total, other adverse events | 24 / 40 |
| serious Total, serious adverse events | 0 / 40 |
Outcome results
Primary
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.
Time frame: Baseline to 5-7 day rapamycin plus 3-7 day washout
Population: Tissue samples were randomly selected from 12 patients with DCIS who participated in the treatment study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Effect of Short-term Rapamycin Treatment on Biomarker Ki67 | The Effect of Short-term Rapamycin Treatment on Biomarker Ki67 Associated With Progression to Invasive Breast Cancer | Pre-treatment | 8.235 percentage of Ki67+ cells | Standard Deviation 5.848 |
| Effect of Short-term Rapamycin Treatment on Biomarker Ki67 | The Effect of Short-term Rapamycin Treatment on Biomarker Ki67 Associated With Progression to Invasive Breast Cancer | Post-treatment | 3.666 percentage of Ki67+ cells | Standard Deviation 3.176 |
p-value: 0.002t-test, 2 sided
Primary
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.
Time frame: 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.
Population: We were only able to obtain fresh surgical tissues and mammary epithelial cell profiles by flowcytometry from 27 patients in the treatment group. Out of the 27, only 22 samples yielded enough basal myoepithelial cells for the quantification of the SFE. Comparison between control group and treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Effect of Short-term Rapamycin Treatment on Biomarker Ki67 | The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Luminal Progenitor Cells | 20.82 Spheres formed from 1,000 cells | Standard Deviation 20.97 |
| Treatment Group | The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Luminal Progenitor Cells | 30.32 Spheres formed from 1,000 cells | Standard Deviation 34.15 |
p-value: 0.3093t-test, 2 sided
Primary
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.
Time frame: 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.
Population: We were only able to obtain fresh surgical tissues and mammary epithelial cell profiles by flowcytometry from 27 patients in the treatment group. Out of the 27, only 22 samples yielded enough basal myoepithelial cells for the quantification of the SFE. Comparison between control group and treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Effect of Short-term Rapamycin Treatment on Biomarker Ki67 | The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Mammary Stem Cells | 3.681 spheres formed per 1,000 cells | Standard Deviation 2.303 |
| Treatment Group | The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Mammary Stem Cells | 0.717 spheres formed per 1,000 cells | Standard Deviation 1.414 |
p-value: <0.0001t-test, 2 sided
Primary
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.
Time frame: 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.
Population: We were only able to obtain fresh surgical tissues and mammary epithelial cell profiles by flowcytometry from 27 patients in the treatment group. The mean data of luminal progenitor cells were compared between the control and treatment groups with unpaired t test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Effect of Short-term Rapamycin Treatment on Biomarker Ki67 | The Effect of Short-term Rapamycin Treatment on the Frequency of Luminal Progenitor Epithelial Cells | 11.82 percentage of total lineage neg. cells | Standard Deviation 9.221 |
| Treatment Group | The Effect of Short-term Rapamycin Treatment on the Frequency of Luminal Progenitor Epithelial Cells | 6.178 percentage of total lineage neg. cells | Standard Deviation 5.525 |
p-value: 0.0137t-test, 2 sided
Primary
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.
Time frame: 5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.
Population: We were only able to obtain fresh surgical tissues and mammary epithelial cell profiles by flowcytometry from 27 patients in the treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Effect of Short-term Rapamycin Treatment on Biomarker Ki67 | The Effect of Short-term Rapamycin Treatment on the Frequency of Mature Luminal Epithelial Cells | 11.82 percentage of total lineage neg. cells | Standard Deviation 9.221 |
| Treatment Group | The Effect of Short-term Rapamycin Treatment on the Frequency of Mature Luminal Epithelial Cells | 6.178 percentage of total lineage neg. cells | Standard Deviation 5.525 |
p-value: 0.0072t-test, 2 sided