RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving chemotherapy and bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known which chemotherapy regimen is more effective with or without bevacizumab in treating breast cancer. PURPOSE: This randomized phase III trial is studying six different chemotherapy regimens to compare how well they work with or without bevacizumab in treating women with stage I, stage II, or stage IIIA breast cancer that can be removed by surgery.
OBJECTIVES: Primary * Compare the efficacy of docetaxel followed by doxorubicin hydrocloride and cyclophosphamide (AC) vs docetaxel and capecitabine followed by AC vs docetaxel and gemcitabine hydrochloride followed by AC, with or without bevacizumab, in terms of an increase in the rate of pathologic complete response (pCR) in the breast, in women with palpable or operable breast cancer. Secondary * Compare docetaxel/capecitabine with AC vs docetaxel/gemcitabine hydrochloride with AC vs docetaxel with AC, with or without bevacizumab, in terms of the rate of pCR in the breast and all post-therapy lymph nodes evaluated histologically (pCR breast and nodes). * Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens (docetaxel with AC, docetaxel and capecitabine with AC, and docetaxel and gemcitabine hydrochloride with AC) will increase the rate of pCR of the breast and nodes compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients. * Determine whether the addition of capecitabine or gemcitabine hydrochloride to docetaxel, with or without bevacizumab, will increase the rate of clinical overall response (cOR) compared to docetaxel alone with or without bevacizumab in these patients. * Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens will increase the rate of cOR compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients. * Determine whether the addition of capecitabine or gemcitabine hydrochloride to docetaxel, with or without bevacizumab, will increase the rate of clinical complete response (cCR) compared to docetaxel alone with or without bevacizumab in these patients. * Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens (docetaxel with AC, docetaxel/capecitabine with AC, and docetaxel/gemcitabine hydrochloride with AC) will increase the rate of cCR compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients. * Identify gene expression profiles that can predict pCR in patients treated with the different sequential docetaxel/anthracycline-based regimens with or without bevacizumab. * Identify gene expression profiles that can predict cOR in patients treated with docetaxel alone, docetaxel/capecitabine, or docetaxel/gemcitabine hydrochloride with or without bevacizumab. * Determine the accuracy of an in vitro chemoresponse assay (ChemoFx®) as a predictor of pCR in patients treated with the different sequential docetaxel/anthracycline-based regimens without bevacizumab. * Determine the accuracy of ChemoFx® as a predictor of cOR in patients treated with docetaxel alone, docetaxel/capecitabine, or docetaxel/gemcitabine hydrochloride without bevacizumab in these patients. * Determine the impact of preoperative bevacizumab and sequential chemotherapy regimens and postoperative bevacizumab therapy on cardiac function in these patients. * Determine the impact of bevacizumab on surgical complications in these patients. * Determine the toxicity of the preoperative regimens and the toxicity of postoperative bevacizumab in these patients. * Compare the docetaxel/anthracycline-based regimens with vs without bevacizumab, in terms of an increase in disease-free survival, of these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor size (2-4 cm vs \> 4 cm), nodal status (negative vs positive), hormone receptor status (estrogen receptor \[ER\]-positive and/or progesterone-receptor \[PgR\]-positive vs ER- and PgR-negative), and age (\< 50 years vs ≥ 50 years). Patients are randomized to 1 of 6 treatment arms. Core needle biopsies are performed at baseline. Tumor tissue samples are also collected during definitive surgery. Samples are examined for gene expression and polymorphism by reverse transcriptase-polymerase chain reaction analysis and chemoresponse assay (ChemoFx®). After completion of study therapy, patients are followed periodically for 10 years. PROJECTED ACCRUAL: A total of 1,200 patients will be accrued for this study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,206
15 mg/kg IV
825 mg/m2 orally
600 mg/m2 IV
100 mg/m2 IV
60 mg/m2 IV
1000 mg/m2 IV
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
East Bay Radiation Oncology Center
Castro Valley, California, United States
Eden Medical Center
Castro Valley, California, United States
Valley Medical Oncology Consultants - Castro Valley
Castro Valley, California, United States
Kaiser Permanente - Fremont
Fremont, California, United States
Pathologic Complete Response (pCR) of the Primary Tumor in the Breast
Percentage of patients absent of histologic evidence of invasive tumor cells in the surgical breast specimen.
Time frame: Time of surgery, on average 6 or 13 months
pCR in the Breast and Nodes
Percentage of patients absent of histologic evidence of invasive tumor cells in the surgical breast specimen and axillary lymph nodes.
Time frame: Time of surgery, on average 6 or 13 months
Clinical Overall Response (cOR) Following Docetaxel Alone, Docetaxel/Capecitabine, and Docetaxel/Gemcitabine Hydrochloride, With or Without Bevacizumab, as Assessed by Physical Exam at the Completion of the Docetaxel-based Portion of Chemotherapy
Percentages of patients assessed as Clinical Complete Response or Clinical Partial Response according to RECIST.
Time frame: Assessed at cycle 5 of chemotherapy, on average at 15 weeks
Clinical Overall Response: cOR as Assessed by Physical Exam at the Completion of the Sequential Chemotherapy Regimens
The percentage of patients assessed by physical exam as Clinical Complete Response or Clinical Partial Response according to RECIST.
Time frame: Three to four weeks after the last chemotherapy dose on average 6 or 13 months
Clinical Complete Response (cCR) Following Docetaxel Alone, Docetaxel/Capecitabine, and Docetaxel/Gemcitabine Hydrochloride, With or Without Bevacizumab, as Assessed by Physical Exam at Completion of Therapy
Percentages of patients assessed as Clinical Complete Response or Clinical Partial Response according to RECIST.
Time frame: Assessed at cycle 5 of chemotherapy, on average at 15 weeks
Clinical Complete Resonse: cCR as Assessed by Physical Exam at the Completion of the Sequential Chemotherapy Regimens
The percentage of patients assessed by physical exam as Clinical Complete Response according to RECIST.
Time frame: Three to four weeks after the last chemotherapy dose, on average at 6 or 13 months
Percentage of Cardiac Events
Time frame: After each cycle, 3-5 weeks postoperative, 9 and 12 months from study entry, every 6 month years 2-5, and annually years 6-10, for postoperative bevacizumab patients, every 6 weeks during postoperative therapy and at 18 months following study entry.
Surgical Complication
Number of patients with Grade 4 or above surgery-related toxicities
Time frame: 24 months after study entry
Toxicities Including Events Other Than Congestive Heart Failure, of Chemotherapy Alone, Bevacizumab With Chemotherapy, and Bevacizumab Alone
The number of patients who experienced Grade 1 or above Adverse Events. Referring to the Adverse Events tables for specifics.
Time frame: 24 months after study entry
Disease-free Survival (DFS)
Percentage of patients free from local recurrence following mastectomy, local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral breast cancer, second primary cancer after 5 years.
Time frame: Measured through 5 years after study enrollment
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Valley Medical Oncology
Fremont, California, United States
Cancer Care Associates
Fresno, California, United States
Kaiser Permanente Medical Center - Hayward
Hayward, California, United States
Scripps Cancer Center - San Diego
La Jolla, California, United States
Loma Linda University Cancer Institute at Loma Linda University Medical Center
Loma Linda, California, United States
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