Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Trial of Neoadjuvant Therapy in Patients With Palpable and Operable Breast Cancer Evaluating the Effect on Pathologic Complete Response (pCR) of Adding Capecitabine or Gemcitabine to Docetaxel When Administered Before AC With or Without Bevacizumab and Correlative Science Studies Attempting to Identify Predictors of High Likelihood for pCR With Each of the Regimens
Brief Summary: 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.


Options:
A: Inclusion Criteria:

* adult patients, \>=18 years of age;
* HER2-negative metastatic breast cancer
* candidates for taxane-based chemotherapy;
* ECOG performance status of 0 or 1.

Exclusion Criteria:

* previous chemotherapy for metastatic breast cancer;
* prior adjuvant/neo-adjuvant chemotherapy within 6 months prior to study;
* prior radiotherapy for treatment of metastatic disease;
* chronic daily treatment with aspirin (325 mg/day) or clopidogrel(\>75mg/day).
B: Inclusion Criteria:

* The patient must have consented to participate and must have signed and dated an appropriate Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines for the study treatment and submission of pre-entry core biopsy material for correlative studies.
* Patients must be female.
* Patients must be 18 years of age or older.
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy.
* The primary breast tumor must be palpable and measure greater than or equal to 2.0 cm on physical exam.
* All patients must have their left ventricular ejection fraction (LVEF) assessed by multigated acquisition (MUGA) scan or echocardiogram within 3 months prior to study entry. The LVEF must be greater than or equal to the lower limit of normal (LLN) for the cardiac imaging facility performing the study. Note: If the cardiac imaging facility cannot provide a LLN, use 50% as the LLN value.

  - Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments to determine if bevacizumab therapy can be continued, it is critical that this baseline study be an accurate assessment of the patient's LVEF. If the baseline LVEF is greater than 75%, the investigator should have the study reviewed for accuracy prior to study entry. Following study entry, the LVEF determination may be reviewed up until the time of the post-chemotherapy (preoperative) evaluation. Please note that if a more accurate value is obtained from the review of the baseline MUGA or echocardiogram, the correct value must be submitted to the NSABP before the post-chemotherapy (preoperative) MUGA or echocardiogram is performed or it cannot be used for managing postoperative bevacizumab.
* All patients must have an EKG within 3 months prior to study entry.
* At the time of randomization:

  * Absolute neutrophil count (ANC) must be greater than or equal to 1200/mm3.
  * Platelet count must be greater than or equal to 100,000/mm3.
  * Hemoglobin must be greater than or equal to 10 g/dL.
  * There must be evidence of adequate hepatic function by these criteria:
  * Total bilirubin must be less than or equal to the ULN for the lab unless the patient has a grade 1 bilirubin elevation (greater than ULN to 1.5 x ULN) resulting from Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and
  * Alkaline phosphatase must be less than or equal 2.5 x ULN for the lab; and
  * Aspartate Aminotransferase (AST) must be less than or equal to 1.5 x ULN for the lab.
  * Alkaline phosphatase and AST may not both be greater than the ULN. For example, if the alkaline phosphatase is greater than the ULN but less than or equal 2.5 x ULN, then the AST must be less than or equal the ULN. If the AST is greater than the ULN but less than or equal 1.5 x ULN, then the alkaline phosphatase must be less than or equal ULN.
* Patients with either skeletal pain or alkaline phosphatase that is greater than ULN but less than or equal 2.5 x ULN are eligible for inclusion in the study if bone scans do not demonstrate metastatic disease. Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy.
* Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion in the study if liver imaging does not demonstrate metastatic disease and adequate bone marrow and liver function results as described above are met.
* The following criteria for evidence of adequate renal function must be met:
* Serum creatinine less than or equal ULN for the lab.
* Calculated creatinine clearance must be greater than 50 mL/min.
* Urine protein/urine creatinine (UPC) ratio must be less than 1.0.
* Patient must be able to swallow oral medications.

Exclusion criteria:

* Tumor determined to be strongly human epidermal growth factor receptor 2 (HER2)-positive by immunohistochemistry (3+) or by fluorescent in situ hybridization (positive for gene amplification).
* Excisional or incisional biopsy for this primary breast tumor.
* Surgical axillary staging procedure prior to study entry. Exceptions: 1) Fine Needle Aspiration (FNA) or core biopsy of an axillary node is permitted for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel lymph node biopsy for patients with clinically negative axillary nodes is permitted.
* Tumors clinically staged as T4.
* Ipsilateral cN2b or cN3 disease. (Patients with cN1 or cN2a disease are eligible.)
* Definitive clinical or radiologic evidence of metastatic disease.
* Synchronous bilateral breast cancer (invasive or DCIS).
* Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry.
* Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible if this therapy is discontinued prior to randomization.)
* Therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention. (Patients are eligible only if these medications are discontinued prior to randomization.)
* Prior history of breast cancer, including DCIS. (Patients with a history of lobular carcinoma in situ \[LCIS\] are eligible.)
* Prior therapy with anthracyclines, taxanes, capecitabine, 5-FU (fluorouracil), gemcitabine, or bevacizumab for any malignancy.
* Other malignancies unless the patient is considered to be disease-free for 5 or more years prior to randomization and is deemed by her physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
* Cardiac disease that would preclude the use of anthracyclines. This includes:

  * angina pectoris that requires the use of anti-anginal medication;
  * history of documented congestive heart failure;
  * serious cardiac arrhythmia requiring medication;
  * severe conduction abnormality;
  * valvular disease with documented cardiac function compromise; and
  * uncontrolled hypertension defined as BP greater than 150/90 on antihypertensive therapy. (Patients with hypertension that is well controlled on medication are eligible.)
* History of myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function.
* History of transient ischemic attack (TIA) or cerebrovascular accident (CVA).
* History of other arterial thrombotic event within 12 months before study entry.
* Symptomatic peripheral vascular disease.
* Any significant non-traumatic bleeding within 6 months before study entry.
* Serious or non-healing wound, skin ulcers, or incompletely healed bone fracture.
* Gastroduodenal ulcer(s) determined by endoscopy to be active.
* Invasive procedures defined as follows:

  * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy. (Note: Placement of a vascular access device is not considered a major surgical procedure.)
  * Anticipation of need for major surgical procedures (other than the required breast surgery) during the course of the study.
* Known bleeding diathesis or coagulopathy. (Patients on warfarin with an in-range international normalized ratio \[INR\] \[usually between 2 and 3\] are eligible.)
* Sensory/motor neuropathy greater than or equal grade 2, as defined by the NCI's Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0).
* Other non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude treatment with any of the treatment regimens or would prevent required follow-up.
* Conditions that would prohibit administration of corticosteroids.
* History of severe hypersensitivity reaction to drugs formulated with polysorbate 80.
* Administration of any investigational agents within 30 days before study entry.
* Pregnancy or lactation at the time of proposed randomization.
C: Inclusion Criteria:

1. Female patients with histologically or cytologically confirmed carcinoma of the breast. Every effort should be made to ensure that paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen are available for confirmation of diagnosis.
2. Patients with locally advanced or metastatic disease who have received up to three prior chemotherapy regimens, and no more than two prior regimens for advanced and/or metastatic disease.

   * Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a taxane (e.g., paclitaxel, docetaxel), either in combination or in separate regimens.
   * Patients with known human epidermal growth factor 2 (HER2/neu) over-expressing tumors may additionally have been treated with trastuzumab in centers where this treatment is available.
   * Patients with known estrogen and/or progesterone receptor-expressing tumors may have additionally been treated with hormonal therapy.
3. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy \<= Grade 2 and alopecia.
4. Age \>= 18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
6. Life expectancy of \>= 3 months.
7. Adequate renal function as evidenced by serum creatinine \<1.5 mg/dL or calculated creatinine clearance \> 50 mL/minute (min) per the Cockcroft and Gault formula.
8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L, hemoglobin \>= 10.0 g/dL (a hemoglobin \< 10.0 g/dL acceptable if it is corrected by growth factor or transfusion), and platelet count \>= 100 x 10\^9/L.
9. Adequate liver function as evidenced by bilirubin \<= 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine transaminase (ALT), and aspartate transaminase (AST) \<= 3 x ULN (in the case of liver metastases \<= 5 x ULN), or in case of bone metastases, liver specific alkaline phosphatase \<= 3 x ULN.
10. Patients willing and able to complete the EORTC (European Organization for Research on the Treatment of Cancer) quality of life questionnaire (QLQ-C30 with breast cancer module QLQ-BR23) and to record their pain level on the Visual Analog Scale (VAS).
11. Patients willing and able to comply with the study protocol for the duration of the study.
12. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.

Exclusion Criteria:

1. Patients who have received more than three prior chemotherapy regimens for their disease, including adjuvant therapies, or patients who have received more than two prior chemotherapy regimens for advanced disease (other therapies are allowed e.g., anti-estrogens, trastuzumab and radiotherapy).
2. Patients who have received capecitabine as a prior therapy for their disease.
3. Patients who have received chemotherapy, radiation, or biological therapy within two weeks, or hormonal therapy, within one week before study treatment start, or any investigational drug within four weeks before study treatment start.
4. Radiation therapy encompassing \> 30% of marrow.
5. Prior treatment with mitomycin C or nitrosourea.
6. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
7. Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment with study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment; radiographic stability should be determined by comparing a contrast-enhanced Computed Tomography Scan (CT) or Magnetic Resonance Imaging (MRI) brain scan performed during screening to a prior scan performed at least 4 weeks earlier.
8. Patients with meningeal carcinomatosis.
9. Patients who are receiving anti-coagulant therapy with warfarin or related compounds, other than for line patency, and cannot be changed to heparin-based therapy, are not eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT)/international normalized ratio (INR) must be closely monitored.
10. Women who are pregnant or breast-feeding; women of childbearing potential with either a positive pregnancy test at screening or no pregnancy test; women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception (considered to be two methods of contraception, one of which must be a barrier method, e.g. condom, diaphragm or cervical cap). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
11. Severe/uncontrolled intercurrent illness/infection.
12. Significant cardiovascular impairment (history of congestive heart failure \> New York Heart Association \[NYHA\] Grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia).
13. Patients with organ allografts requiring immunosuppression.
14. Patients with known positive human immunodeficiency virus (HIV) status.
15. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated \>= 5 years previously with no subsequent evidence of recurrence.
16. Patients with pre-existing neuropathy \> Grade 2.
17. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative.
18. Patients who participated in a prior E7389 clinical trial.
19. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.
D: Inclusion Criteria:

1. Female patients with histologically or cytologically confirmed carcinoma of the breast.

   Every effort should be made to make paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis.
2. Patients with locally recurrent or metastatic disease who have received at least two (and not more than five) prior chemotherapeutic regimens for breast cancer, at least two of which were administered for treatment of locally recurrent and/or metastatic disease.

   Prior therapy must be documented by the following criteria prior to entry onto study:
   * Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a taxane (e.g., paclitaxel, docetaxel) in any combination or order. Treatment with any of these agents is not required if they are contraindicated for a certain patient.
   * One or two of these regimens may have been administered as adjuvant and/or neoadjuvant therapy, but at least 2 must have been given for relapsed or metastatic disease.
   * Patients must have proved refractory to the most recent chemotherapy, documented by progression on or within six (6) months of therapy.
   * Patients with Human Epidermal Growth Factor 2 (HER2/neu) positive tumors may additionally have been treated with trastuzumab.
   * Patients may have additionally been treated with anti-hormonal therapy.
3. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy \<= Grade 2 and alopecia.
4. Age \>= 18 years.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
6. Life expectancy of \>= 3 months.
7. Adequate renal function as evidenced by serum creatinine \<= 2.0 mg/dL or calculated creatinine clearance \>= 40 mL/min per the Cockcroft and Gault formula.
8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L, hemoglobin \>= 10.0 g/dL (a hemoglobin \<10.0 g/dL is acceptable if it is corrected by growth factor or transfusion), and platelet count \>= 100 x 10\^9/L.
9. Adequate liver function as evidenced by bilirubin \<= 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \<= 3 x ULN (in the case of liver metastases \<= 5 x ULN), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. In case alkaline phosphatase is \>3 x ULN (in absence of liver metastases) or \> 5 x ULN (in presence of liver metastases) AND patient is known to have bone metastases, the liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
10. Patients willing and able to comply with the study protocol for the duration of the study.
11. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.

EXCLUSION CRITERIA

1. Patients who have received any of the following treatments within the specified period before E7389 or TPC treatment start:

   * chemotherapy, radiation, trastuzumab or hormonal therapy within three weeks.
   * any investigational drug within four weeks.
2. Radiation therapy encompassing \> 30% of marrow.
3. Prior treatment with mitomycin C or nitrosourea.
4. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
5. Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (e.g., radiologic) and/or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment; radiographic stability should be determined by comparing a contrast-enhanced computed tomography or magnetic resonance imaging brain scan performed during screening to a prior scan performed at least 4 weeks earlier.
6. Patients with meningeal carcinomatosis.
7. Patients who are receiving anti-coagulant therapy with warfarin or related compounds, other than for line patency, and cannot be changed to heparin-based therapy if randomized to E7389 are not eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT) or international normalized ratio (INR) must be closely monitored.
8. Women who are pregnant or breast-feeding; women of childbearing potential with either a positive pregnancy test at screening or no pregnancy test; women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the Investigator. Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
9. Severe/uncontrolled intercurrent illness/infection.
10. Significant cardiovascular impairment (history of congestive heart failure \> New York Heart Association grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia).
11. Patients with organ allografts requiring immunosuppression.
12. Patients with known positive HIV status.
13. Patients who have had a prior malignancy, other than previous breast cancer, carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated \>= 5 years previously with no subsequent evidence of recurrence.
14. Patients with pre-existing neuropathy \> Grade 2.
15. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative.
16. Patients who participated in a prior E7389 clinical trial whether or not E7389 was received.
17. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.

Answer: B