Estrogen Receptor Positive, HER2/Neu Negative, Male Breast Carcinoma, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer
Conditions
Brief summary
This clinical trial studies fluorine F 18 fluorothymidine (FLT) positron emission tomography (PET) in measuring treatment response in patients with newly diagnosed estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage I-III breast cancer. Comparing results of diagnostic procedures done before and during hormone therapy may help doctors predict a patient's response to treatment and help plan the best treatment.
Detailed description
PRIMARY OBJECTIVES: I. Measure the effect of a short course of endocrine therapy on primary breast cancer metabolism and proliferation by measuring changes in serial FLT PET measures pre and post a short course of endocrine therapy. SECONDARY OBJECTIVES: I. Compare changes in imaging measures to tissue measures of response, in particular antigen identified by proliferation-related Ki-67 antigen (Ki-67), in the pre-therapy biopsy versus the post-therapy surgical specimen. II. Correlate imaging measures to measures of gene expression from pre and post therapy assays to determine if there are molecular changes associated with early response to therapy. OUTLINE: Patients undergo FLT PET at baseline and 1-6 weeks after the start of treatment.
Interventions
Undergo FLT PET
PROCEDUREPositron Emission Tomography
Undergo FLT PET
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGRun-in (short pre-surgery course) of endocrine-targeted therapy
Patients undergo run-in (short pre-surgery course) of endocrine-targeted therapy with aromatase inhibitor between the two (baseline and repeat) FLT PET scans. This is not an experimental therapy. This is a standard of care therapy that patients will continue after surgery, when the study is completed.
Sponsors
National Cancer Institute (NCI)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A new diagnosis of invasive breast cancer \> 1.0 cm in size, ER+ clinical stage I-III * Patient must have surgical resection followed by systemic adjuvant therapy with an aromatase inhibitor (AIs) as part of planned treatment; any approved AI at standard clinical dosing may be used; in pre-menopausal patients, ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist will be started prior to initiation of the AI on a separate clinical trial in parallel with the imaging study * Have tissue block available from core biopsy for correlative biomarkers and genomic assay * Have menopausal status determined prior to study enrollment; for study purposes, postmenopausal is defined as * A prior documented bilateral oophorectomy, or * A history of at least 12 months without spontaneous menstrual bleeding, or * Age 60 or older with a prior hysterectomy without oophorectomy, or * Age less than 60 with a prior hysterectomy without oophorectomy (or in whom the status of the ovaries is unknown) with a documented follicle-stimulating hormone (FSH) level demonstrating confirmatory elevation in the postmenopausal range for the lab * Negative pregnancy test within 7 days of baseline positron emission tomography (PET) scan for pre-menopausal patients * Tumor HER2/neu expression must be determined (as part of standard clinical care) prior to study enrollment; HER2 may be tested by any Food and Drug Administration (FDA) approved HER2 testing method; if determination is intermediate by immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) or another alternate HER2 test must be performed * Be a candidate for \[18F\]FLT PET imaging * Be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study-specific screening procedures * Be willing and able to comply with scheduled visits and other trial procedures
Exclusion criteria
* Current use of aromatase inhibitor as prevention or treatment for breast cancer * Life expectancy of less than two months * HER2/neu positive by IHC and/or another FDA approved HER2 testing method * Inability to tolerate scanning (e.g. - claustrophobia, severe pain) * Weight exceeding capacity of imaging table
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Ki-67 Positive Cells Between Pre-therapy and Post-therapy Tumor Specimens | Baseline to up to 6 weeks | Tumor tissue samples from pre-treatment (baseline) biopsy and post-treatment surgery are stained using immuno-histochemistry techniques to visualize dividing cells expressing the Ki-67 protein, which is a cellular marker for proliferation. The % values of positive cells from the baseline and post-treatment samples are then compared for each individual patient. Association between Ki-67 and KFLT decline will be analyzed to evaluate the potential clinical utility of change in FLT as a biomarker for early response, using Ki-67 as the standard for early response. |
| Percentage of Ki-67 Positive Tumor Cells in Surgical (Post-therapy) Sample | 1 to 6 weeks post-therapy start | Surgically removed breast tumor tissue is stained using immuno-histochemistry techniques to visualize dividing cells expressing the Ki-67 protein, which is a cellular marker for proliferation. |
| Percent Change in Net Influx Constant (Ki) by FLT PET | Baseline to up to 6 weeks | Percent change between pre-treatment (baseline) and post-therapy PET measurements in breast tumors will be computed. Association between Ki-67 and Ki by FLT (KFLT) decline will be analyzed using the mid-P adjustment to Fisher's exact test to evaluate the potential clinical utility of change in FLT as a biomarker for early response, using Ki-67 as the standard for early response. |
| Percent Change in SUV by FLT PET | Baseline to up to 6 weeks | Percent change between pre-treatment (baseline) and post-therapy measurements of FLT standardized uptake value (SUV) in breast tumors will be computed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Standardized Uptake Values (SUV) by FLT PET | Baseline | FLT SUV in breast tumor tissue as determined by the pre-therapy (baseline) FLT PET |
| Post-treatment FLT Transport (K1) Values by FLT PET | 1 to 6 weeks post-therapy start | K1 (blood flow measure) in breast tumor tissue as determined by the post-therapy FLT PET |
| Post-treatment Standardized Uptake Values (SUV) by FLT PET | 1 to 6 weeks post-therapy start | FLT SUV in breast tumor tissue as determined by the post-treatment FLT PET |
| Post-therapy Ki (Flux Constant) Values by FLT PET | 1 to 6 weeks post-therapy start | Ki (flux constant) in breast tumor tissue as determined by the post-therapy FLT PET |
| Percentage Change in K1 (Blood Flow Parameter) by FLT PET | Baseline to up to 6 weeks | Percent change between pre-treatment (baseline) and post-therapy PET measurements in breast tumors will be computed. |
| Baseline Ki (Flux Constant) Values by FLT PET | Baseline | Ki (flux constant) in breast tumor tissue as determined by the pre-therapy (baseline) FLT PET scan |
| Baseline FLT Transport (K1) Values by FLT PET | Baseline | K1 (blood flow measure) in breast tumor tissue as determined by the pre-therapy (baseline) FLT PET |
Other
| Measure | Time frame | Description |
|---|---|---|
| Post-treatment Gene Expression Levels | 1 to 6 weeks post-therapy start | Analyzed using BeadStudio software. Four clustering metrics for calculating dissimilarities (correlation, absolute correlation, Euclidean, and Manhattan) are available in BeadStudio and will be applied using standard analysis methods and diagnostics in BioConductor. To focus the analysis, proposed gene sets will be examined based on biological pathways and molecular signatures. |
| Pre-treatment Gene Expression Levels | Baseline | Analyzed using BeadStudio software. Four clustering metrics for calculating dissimilarities (correlation, absolute correlation, Euclidean, and Manhattan) are available in BeadStudio and will be applied using standard analysis methods and diagnostics in BioConductor. To focus the analysis, proposed gene sets will be examined based on biological pathways and molecular signatures. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Diagnostic (FLT PET) Patients with early stage, ER positive primary breast cancer undergo FLT PET scan at baseline and 1-6 weeks after the start of standard endocrine treatment. The surgery follows 1-7 days after the second FLT PET scan.
Tracer used in the FLT PET (positron emission tomography) scanning procedure: \[F18\] fluorothymidine.
Positron Emission Tomography: Undergo FLT PET
Laboratory Biomarker Analysis: Correlative studies - Ki67 staining of the tumor tissue in the biopsy and surgical specimen. | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | Diagnostic (FLT PET) |
|---|---|
| Age, Continuous | 60.4 years |
| Clinical stage Stage I | 10 Participants |
| Clinical stage Stage IIA | 14 Participants |
| Clinical stage Stage IIB | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 28 |
| serious Total, serious adverse events | 0 / 28 |
Outcome results
Primary
Percentage Change in Ki-67 Positive Cells Between Pre-therapy and Post-therapy Tumor Specimens
Tumor tissue samples from pre-treatment (baseline) biopsy and post-treatment surgery are stained using immuno-histochemistry techniques to visualize dividing cells expressing the Ki-67 protein, which is a cellular marker for proliferation. The % values of positive cells from the baseline and post-treatment samples are then compared for each individual patient. Association between Ki-67 and KFLT decline will be analyzed to evaluate the potential clinical utility of change in FLT as a biomarker for early response, using Ki-67 as the standard for early response.
Time frame: Baseline to up to 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Percentage Change in Ki-67 Positive Cells Between Pre-therapy and Post-therapy Tumor Specimens | -80.0 % change |
Primary
Percentage of Ki-67 Positive Tumor Cells in Surgical (Post-therapy) Sample
Surgically removed breast tumor tissue is stained using immuno-histochemistry techniques to visualize dividing cells expressing the Ki-67 protein, which is a cellular marker for proliferation.
Time frame: 1 to 6 weeks post-therapy start
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Percentage of Ki-67 Positive Tumor Cells in Surgical (Post-therapy) Sample | 3 % stained cells |
Primary
Percent Change in Net Influx Constant (Ki) by FLT PET
Percent change between pre-treatment (baseline) and post-therapy PET measurements in breast tumors will be computed. Association between Ki-67 and Ki by FLT (KFLT) decline will be analyzed using the mid-P adjustment to Fisher's exact test to evaluate the potential clinical utility of change in FLT as a biomarker for early response, using Ki-67 as the standard for early response.
Time frame: Baseline to up to 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Percent Change in Net Influx Constant (Ki) by FLT PET | -32.0 % change |
Comparison: Association between response assessed by Ki-67 protein staining (i.e. \< 10% positive cells in the surgical sample) and by the influx constant Ki decline (i.e. 30 % or larger decline between the baseline and post-therapy FLT PET) was analyzed using the mid-P adjustment to Fisher's exact test.p-value: 0.51Fisher Exact
Primary
Percent Change in SUV by FLT PET
Percent change between pre-treatment (baseline) and post-therapy measurements of FLT standardized uptake value (SUV) in breast tumors will be computed.
Time frame: Baseline to up to 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Percent Change in SUV by FLT PET | -26.6 % change |
Secondary
Baseline FLT Transport (K1) Values by FLT PET
K1 (blood flow measure) in breast tumor tissue as determined by the pre-therapy (baseline) FLT PET
Time frame: Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Baseline FLT Transport (K1) Values by FLT PET | 0.0501 mL/min/mL |
Secondary
Baseline Ki (Flux Constant) Values by FLT PET
Ki (flux constant) in breast tumor tissue as determined by the pre-therapy (baseline) FLT PET scan
Time frame: Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Baseline Ki (Flux Constant) Values by FLT PET | 0.015 mL/min/mL |
Secondary
Baseline Standardized Uptake Values (SUV) by FLT PET
FLT SUV in breast tumor tissue as determined by the pre-therapy (baseline) FLT PET
Time frame: Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Baseline Standardized Uptake Values (SUV) by FLT PET | 2.5 g/mL |
Secondary
Percentage Change in K1 (Blood Flow Parameter) by FLT PET
Percent change between pre-treatment (baseline) and post-therapy PET measurements in breast tumors will be computed.
Time frame: Baseline to up to 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Percentage Change in K1 (Blood Flow Parameter) by FLT PET | -6.2 % change |
Secondary
Post-therapy Ki (Flux Constant) Values by FLT PET
Ki (flux constant) in breast tumor tissue as determined by the post-therapy FLT PET
Time frame: 1 to 6 weeks post-therapy start
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Post-therapy Ki (Flux Constant) Values by FLT PET | 0.0142 mL/min/mL |
Secondary
Post-treatment FLT Transport (K1) Values by FLT PET
K1 (blood flow measure) in breast tumor tissue as determined by the post-therapy FLT PET
Time frame: 1 to 6 weeks post-therapy start
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Post-treatment FLT Transport (K1) Values by FLT PET | 0.0675 mL/min/mL |
Secondary
Post-treatment Standardized Uptake Values (SUV) by FLT PET
FLT SUV in breast tumor tissue as determined by the post-treatment FLT PET
Time frame: 1 to 6 weeks post-therapy start
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (FLT PET) | Post-treatment Standardized Uptake Values (SUV) by FLT PET | 1.76 g/mL |
Other Pre-specified
Post-treatment Gene Expression Levels
Analyzed using BeadStudio software. Four clustering metrics for calculating dissimilarities (correlation, absolute correlation, Euclidean, and Manhattan) are available in BeadStudio and will be applied using standard analysis methods and diagnostics in BioConductor. To focus the analysis, proposed gene sets will be examined based on biological pathways and molecular signatures.
Time frame: 1 to 6 weeks post-therapy start
Other Pre-specified
Pre-treatment Gene Expression Levels
Analyzed using BeadStudio software. Four clustering metrics for calculating dissimilarities (correlation, absolute correlation, Euclidean, and Manhattan) are available in BeadStudio and will be applied using standard analysis methods and diagnostics in BioConductor. To focus the analysis, proposed gene sets will be examined based on biological pathways and molecular signatures.
Time frame: Baseline