Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer
Conditions
Brief summary
This pilot clinical trial studies chemotherapy before surgery and tissue sample collection in patients with stage IIA-IIIC breast cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride, cyclophosphamide, paclitaxel and trastuzumab may kill more tumor cells. Collecting and storing samples of tissue from patients with breast cancer to study in the laboratory may help doctors learn more about how well patients will respond to treatment.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the effects of preoperative neoadjuvant paclitaxel and doxorubicin (doxorubicin hydrochloride)/cyclophosphamide (AC) on: senescence; invasion/motility (tumor microenvironment of metastasis \[TMEM\] and 67 kDa laminin receptor \[67LR\]). II. To create a biospecimen repository for future studies derived from patients with breast cancer receiving standard neoadjuvant chemotherapy. OUTLINE: Patients with human epidermal growth factor receptor 2 (HER2)-positive disease are assigned to Stratum A, and patients with HER2-negative disease are randomized to Stratum B or C. STRATUM A: Patients receive paclitaxel intravenously (IV) over 1 hour and trastuzumab IV over 30-90 minutes weekly for 12 weeks. Beginning 2-3 weeks later, patients receive doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks STRATUM B: Patients receive paclitaxel, doxorubicin hydrochloride, and cyclophosphamide as in Stratum A. STRATUM C: Patients receive doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks. Patients then receive paclitaxel IV over 1 hour weekly for 12 weeks. Patients undergo surgery 2-6 weeks after the last chemotherapy dose. In all arms, treatment continues in the absence of unacceptable toxicity.
Interventions
DRUGCyclophosphamide
Given IV
OTHERCytology Specimen Collection Procedure
Correlative studies
DRUGDoxorubicin Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPaclitaxel
Given IV
BIOLOGICALTrastuzumab
Given IV
DRUGEndocrine therapy
Patients with ER-positive, HER2-negative disease may receive neoadjuvant endocrine therapy (NET) with an aromatase inhibitor: (either Anastrozole 1 mg po daily; Letrozole 2.5 mg po daily, Exemestane 25 mg po daily or Tamoxifen 20 mg po daily) for 4-6 months prior to surgery (or longer if clinically indicated). Anastrozole for 6 months is the preferred regimen for NET.
Sponsors
National Cancer Institute (NCI)
Albert Einstein College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed adenocarcinoma of the breast associated with the following clinical stage: IIA, IIB, IIIA, IIIB, or IIIC; patients with stage IV disease are also eligible if there is an intention to perform breast surgery after neoadjuvant therapy is completed, or in patients participating in clinical trials where surgery after neoadjuvant therapy may be an option (eg. E2108) * Estrogen receptor (ER), progesterone receptor (PR), and HER2/neu status documented by core needle biopsy of the primary tumor and/or regional lymph node must be known prior to beginning systemic therapy * Patients must have had a bilateral diagnostic mammogram within 6 months of registration, and may also have a targeted sonography of the breast and/or ipsilateral axilla and magnetic resonance imaging (MRI) if clinically indicated * Patients with clinically suspicious axillary lymph node involvement must have either aspiration cytology or biopsy prior to beginning therapy * It is strongly encouraged that all patients have metallic clips placed in the tumor prior to neoadjuvant therapy in order to facilitate evaluation for microscopic disease at the time of surgery; placement of clips is particularly encouraged for patients being considered for breast conserving surgery * No prior chemotherapy, irradiation, or definitive therapeutic surgery (eg, mastectomy or lumpectomy or axillary dissection) for this malignancy; patients who have had a prior sentinel lymph node biopsy for this malignancy are eligible * Patients who received tamoxifen or another selective estrogen receptor modulator (SERM) for prevention or for other indications (e.g., osteoporosis, prior ductal carcinoma in situ \[DCIS\]) are eligible; tamoxifen therapy or other SERMs should be discontinued at least 1 week before the patient is enrolled on this study * The patient is medically suitable candidate for preoperative chemotherapy and surgery in the judgment of the treating physicians * Ability to understand and the willingness to sign a written informed consent document, and willing to provide blood samples before and during preoperative therapy; patients are also asked but not required to have research biopsies performed before and after therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Senescence and Secondary Biomarkers, Including TMEM, Mena, and 67LR | Baseline to 6 months | Descriptive statistics by treatment group will be presented. The two-sampled t-test will be performed. Appropriate transformation may be used to improve normality of the outcome variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Quantitative Biomarker Levels in Patients With Chemotherapy-responsive and -Resistant Tumors, Including Senescence, Cell Death, TMEM, Mena, and 67LR | Baseline to 8 weeks (2 courses) | Paired T-test or Wilcoxon signed-rank test will be performed. Two-sample t-test will be performed to compare biomarker between the two groups. If the data are not normally distributed, a suitable data transformation such as the log or rank transformation will be applied. Logistic regression models will also be fit to the data with treatment sensitive/resistance category as the outcome and baseline as well as pre-post change in biomarker level as the main predictor variable to obtain estimates of odds ratios unadjusted and adjusted for potential confounders including patients characteristics. |
Countries
United States
Participant flow
Pre-assignment details
31 patients were enrolled into the study however one patient screen failed prior to being randomized into one of the study strata.
Participants by arm
| Arm | Count |
|---|---|
| Stratum A: HER2-positive Patients receive Paclitaxel 80 mg/m\^2 IV infusion over 1 hour for 12 weeks and Trastuzumab 8 mg/kg IV loading dose over 90 minutes, then 6 mg/kg IV every three weeks (after Paclitaxel when given concurrently) for a total of 17 doses over 51 weeks. Beginning 2-3 weeks after the last dose of Paclitaxel, patients receive Doxorubicin hydrochloride 60 mg/m\^2 IV over 5-10 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes every 2 weeks for 8 weeks.
Cytology Specimen Collection Procedure:
Correlative studies
Laboratory Biomarker Analysis:
Correlative studies | 1 |
| Stratum B: HER2-negative Patients receive sequential Paclitaxel followed by Doxorubicin hydrochloride and Cyclophosphamide (AC) as described in Stratum A.
Cytology Specimen Collection Procedure:
Correlative studies
Laboratory Biomarker Analysis:
Correlative studies | 8 |
| Stratum C: HER2-negative Patients receive sequential Doxorubicin hydrochloride and Cyclophosphamide (AC) followed by Paclitaxel. Patients receive Doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks. Patients then receive paclitaxel IV over 1 hour weekly for 12 weeks.
Cytology Specimen Collection Procedure:
Correlative studies
Laboratory Biomarker Analysis:
Correlative studies | 9 |
| Stratum I: HER2-negative Patients receive Paclitaxel 80 mg/m\^2 IV infusion over 1 hour for 12 weeks followed by Doxorubicin hydrochloride and Cyclophosphamide (AC). Patients receive Doxorubicin hydrochloride 60 mg/m\^2 IV over 5-10 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes every 2 weeks for 8 weeks.
Cytology Specimen Collection Procedure:
Correlative studies
Laboratory Biomarker Analysis:
Correlative studies | 5 |
| Stratum II: HER2-positive Patients receive Paclitaxel 80 mg/m\^2 IV infusion over 1 hour for 12 weeks and Trastuzumab 8 mg/kg IV loading dose over 90 minutes, then 6 mg/kg IV every three weeks (after Paclitaxel when given concurrently) for a total of 17 doses over 51 weeks. Beginning 2-3 weeks after the last dose of Paclitaxel, patients receive Doxorubicin hydrochloride 60 mg/m\^2 IV over 5-10 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes every 2 weeks for 8 weeks.
Cytology Specimen Collection Procedure:
Correlative studies
Laboratory Biomarker Analysis:
Correlative studies | 6 |
| Stratum III: ER-positive, HER2-negative Patients with ER-positive, HER2-negative disease may receive neoadjuvant endocrine therapy (NET) with an aromatase inhibitor: (either Anastrozole 1 mg po daily; Letrozole 2.5 mg po daily, Exemestane 25 mg po daily or Tamoxifen 20 mg po daily) for 4-6 months prior to surgery (or longer if clinically indicated). Anastrozole for 6 months is the preferred regimen for NET.
Cytology Specimen Collection Procedure:
Correlative studies
Laboratory Biomarker Analysis:
Correlative studies | 1 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawn by Provider | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Stratum B: HER2-negative | Stratum C: HER2-negative | Stratum I: HER2-negative | Stratum II: HER2-positive | Stratum III: ER-positive, HER2-negative | Stratum A: HER2-positive | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 9 Participants | 5 Participants | 6 Participants | 1 Participants | 1 Participants | 27 Participants |
| Age, Continuous | 52 years | 45 years | 56 years | 38 years | 56 years | 33 years | 47 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 14 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 8 participants | 9 participants | 5 participants | 6 participants | 1 participants | 1 participants | 30 participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 4 Participants | 6 Participants | 1 Participants | 1 Participants | 29 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 8 | 0 / 9 | 0 / 5 | 0 / 6 | 0 / 1 |
| other Total, other adverse events | 0 / 1 | 0 / 8 | 0 / 9 | 0 / 5 | 0 / 6 | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 8 | 0 / 9 | 0 / 5 | 0 / 6 | 0 / 1 |
Outcome results
Primary
Changes in Senescence and Secondary Biomarkers, Including TMEM, Mena, and 67LR
Descriptive statistics by treatment group will be presented. The two-sampled t-test will be performed. Appropriate transformation may be used to improve normality of the outcome variable.
Time frame: Baseline to 6 months
Population: Change in baseline to 6 month specimens for senescence, TMEM, mena, and 67LR biomarkers were not collected and analyzed.
Secondary
Changes in Quantitative Biomarker Levels in Patients With Chemotherapy-responsive and -Resistant Tumors, Including Senescence, Cell Death, TMEM, Mena, and 67LR
Paired T-test or Wilcoxon signed-rank test will be performed. Two-sample t-test will be performed to compare biomarker between the two groups. If the data are not normally distributed, a suitable data transformation such as the log or rank transformation will be applied. Logistic regression models will also be fit to the data with treatment sensitive/resistance category as the outcome and baseline as well as pre-post change in biomarker level as the main predictor variable to obtain estimates of odds ratios unadjusted and adjusted for potential confounders including patients characteristics.
Time frame: Baseline to 8 weeks (2 courses)
Population: Change in baseline to 8 week specimens for cell death, TMEM, mena, and 67LR biomarkers were not collected and analyzed.