Neoadjuvant Chemotherapy Using Doxorubicin and Paclitaxel in Treating Women With Large Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as doxorubicin and paclitaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy before and after surgery may shrink the tumor so it can be removed and may kill any tumor cells remaining after surgery. PURPOSE: This randomized phase II trial is comparing two different regimens of doxorubicin and paclitaxel to see how well they work in treating women who are undergoing surgery for breast cancer.

Detailed Description
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OBJECTIVES: Primary Determine whether tumors in women with palpable invasive breast cancer with wild type p53 are more sensitive to doxorubicin than to paclitaxel when given as sequential single-agent neoadjuvant chemotherapy. Determine whether tumors with inactivated p53 are more sensitive to paclitaxel than to doxorubicin when given as sequential single-agent neoadjuvant chemotherapy in these patients. Secondary Correlate other biological markers (physiological and molecular) with tumor response in patients treated with these regimens. Determine changes in these biological markers during and after neoadjuvant chemotherapy in these patients. Compare breast MRI, in terms of assessing tumor response, with physical exam, mammogram, and ultrasound in patients treated with these regimens. Determine whether there are MRI indicators (e.g., tumor morphology or lesion enhancement) that are predictive of response in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor size (> 5 cm vs ≤ 3-5 cm) and presence of palpable regional lymph nodes (yes vs no). Patients are randomized to 1 of 2 treatment arms. All patients undergo biopsy, bilateral mammogram, MRI, ultrasound, blood marker, molecular (gene microarrays and functional p53 status), and physiologic studies before initiation of neoadjuvant chemotherapy. Some of these studies are repeated after completion of treatment with the first chemotherapeutic agent and after completion of treatment with the second chemotherapeutic agent as outlined below. Arm I: Patients receive doxorubicin IV on days 1, 15, 29, and 43. Patients with no residual tumor (indicated by clinical evaluation and radiologic studies) after completion of doxorubicin undergo definitive surgery. After surgery, patients receive paclitaxel IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, and 57. Patients with residual tumor > 2 cm after completion of doxorubicin undergo 8-12 core needle biopsies. Patients with residual tumor < 2 cm after completion of doxorubicin undergo 4-6 core needle biopsies. After core needle biopsies, patients receive paclitaxel as above. Arm II: Patients receive paclitaxel IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, and 57. Patients with no residual tumor (indicated by clinical evaluation and radiologic studies) after completion of paclitaxel undergo definitive surgery. After surgery, patients receive doxorubicin IV on days 1, 15, 29, and 43. Patients with residual tumor > 2 cm after completion of paclitaxel undergo 8-12 core needle biopsies. Patients with residual tumor < 2 cm after completion of paclitaxel undergo 4-6 core needle biopsies. After core needle biopsies, patients receive doxorubicin as above. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Samples from core needle biopsies are analyzed by microarray analysis for gene expression profiles. Patients are followed every 6 months for 5 years. PROJECTED ACCRUAL: A total of 100 patients (50 per treatment arm) will be accrued for this study within 4-5 years.

Official Title
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Neoadjuvant Chemotherapy in Palpable Breast Cancer: Evaluation of Physiologic, Radiologic, and Molecular Markers in Predicting Response

Conditions
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Breast Cancer

Intervention / Treatment
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* Other: Doxorubicin followed by Paclitaxel
* Other: Paclitaxel followed by Doxorubicin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of invasive breast cancer Tumor ≥ 3 cm and palpable Multiple masses are allowed provided at least 1 mass is ≥ 3 cm Clinically positive axillary or supraclavicular lymph nodes allowed Fine needle aspiration or core needle biopsy positive for invasive breast cancer AND/OR fine needle aspiration of lymph nodes positive HER2/neu-positive OR negative No inflammatory breast cancer No distant metastases Hormone receptor status: Estrogen receptor (ER)-positive OR ER-negative PATIENT CHARACTERISTICS: Age 18 and over Sex Female Menopausal status Premenopausal or postmenopausal Performance status Karnofsky 60-100% Life expectancy Not specified Hematopoietic Granulocyte count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Bilirubin ≤ 2 times upper limit of normal (ULN) SGOT ≤ 2 times ULN Renal Not specified Cardiovascular LVEF ≥ 50% No congestive heart failure No serious conduction system abnormality No other significant cardiovascular disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Patients with other prior or concurrent malignancies allowed provided they have received no prior chemotherapy AND they are likely to have been cured from a prior malignancy No severe medical or psychiatric condition that would preclude study compliance No known HIV positivity PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy Endocrine therapy No prior hormonal therapy for breast cancer Radiotherapy No prior radiotherapy for this malignancy Surgery Not specified

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sequence Doxorubicin followed by Paclitaxel<br>Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin | Other: Doxorubicin followed by Paclitaxel<br>* Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel Paclitaxel followed by Doxorubicin<br>Other: Paclitaxel followed by Doxorubicin<br>* Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin<br>|
| Other: Sequence of neoadjuvant CT: Paclitaxel followed by Doxorubicin<br>Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin | Other: Paclitaxel followed by Doxorubicin<br>* Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| •Determine whether tumors in women with palpable invasive breast cancer with wild type p53 are more sensitive to doxorubicin than to paclitaxel when given as sequential single-agent neoadjuvant chemotherapy |  | asses pathological response to neoadjuvant chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer