Chemotherapy Before Surgery and Tissue Sample Collection in Patients With Stage IIA-IIIC Breast Cancer

Study Overview
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Brief Summary
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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 o 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
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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.

Official Title
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Prospective Tissue Collection in Breast Cancer Patients Receiving Preoperative Systemic Therapy

Conditions
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Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: Cyclophosphamide
* Other: Cytology Specimen Collection Procedure
* Drug: Doxorubicin Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Biological: Trastuzumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum A (HER2-positive disease)<br>Patients receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes weekly for 12 weeks. Beginning 2-3 weeks after the last dose of paclitaxel, patients receive doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Cytology Specimen Collection Procedure<br>* Correlative studies<br>* Other names: Cytologic Sampling;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Trastuzumab<br>* Given IV<br>* Other names: Trastuzumab Biosimilar PF-05280014;|
| Experimental: Stratum B (paclitaxel followed by AC)<br>Patients receive paclitaxel, doxorubicin hydrochloride, and cyclophosphamide as in Stratum A. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Cytology Specimen Collection Procedure<br>* Correlative studies<br>* Other names: Cytologic Sampling;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Stratum C (AC followed by paclitaxel)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Cytology Specimen Collection Procedure<br>* Correlative studies<br>* Other names: Cytologic Sampling;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 improved normality of the outcome variable. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 8 weeks (2 courses) |