Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel With or Without Bevacizumab in Treating Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the disease-free survival of patients (defined as invasive disease-free
survival [IFDS]) with lymph node positive and high risk lymph node negative breast cancer
randomized to treatment with either doxorubicin (doxorubicin hydrochloride)/cyclophosphamide
plus placebo followed by paclitaxel (AC + placebo > T + placebo) or the same chemotherapy
regimen plus bevacizumab.

SECONDARY OBJECTIVES:

I. To compare short-term (20-24 weeks) versus long-term (50-54 weeks) bevacizumab therapy.

II. To compare the overall survival. III. To evaluate toxicity. IV. To evaluate the
association between outcomes in E5103 (disease-free survival, overall survival and
toxicities) and genotype (derived from candidate single nucleotide polymorphisms and genome
wide evaluations).

V. To compare the quality of life of breast cancer patients treated with AC/paclitaxel and
bevacizumab or placebo, in terms of physical symptoms, physical functioning, psychological
state and social functioning over an 18 month period.

VI. To determine the impact of theoretical biomarker information on patients' willingness to
accept the toxicities of bevacizumab for the estimated potential benefit.

VII. To create a biospecimen repository including plasma, serum and CellSearch cassettes
containing circulating tumor cells (CTC) for evaluating determinants of late relapse,
including candidate biomarkers reflecting occult tumor burden (e.g., CTCs and plasma tumor
deoxyribonucleic acid [DNA]) and host factors (e.g., estrogen, insulin-insulin-like growth
factor [IGF] axis, inflammation, etc).

VIII. To create a biorepository of metastatic tumor samples in patients who have had a late
relapse.

IX. To determine body mass index (BMI) and comorbidity burden in patients with operable
breast cancer five or more years after diagnosis.

X. To determine whether there is a relationship between late relapse and BMI at diagnosis and
at 5 years after diagnosis, and whether BMI-associated inflammatory and/or metabolic
biomarkers are associated with early and late recurrence.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive doxorubicin hydrochloride intravenously (IV), cyclophosphamide IV
over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or
3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1
hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with
paclitaxel and placebo repeats every 3 weeks for 4 courses.

ARM II: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and
bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4
courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and
bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats
every 3 weeks for 4 courses.

ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and
bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3
weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II.
Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2
months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment
with bevacizumab alone repeats every 3 weeks for 10 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 15 years.

Inclusion Criteria:

- Patients must have histologically confirmed adenocarcinoma of the breast at
significant risk of distant recurrence based on at least one of the following
criteria:

- For axillary lymph node positive disease:

- Involvement of at least one sentinel or axillary lymph node on routine
histologic examination; patients with negative sentinel nodes and negative
axillary nodes or involvement only demonstrated by immunohistochemistry are
not eligible unless they meet one of the other eligibility criteria below

- NOTE: consider intramammary nodes as equivalent to axillary nodes for the
purposes of eligibility and stratification

- For axillary lymph node negative disease:

- Estrogen receptor (ER) negative tumor >= 1 cm

- ER+ tumor >= 5 cm regardless of recurrence score

- ER+ tumor >= 1 cm but < 5 cm with a recurrence score >= 11 (patients
enrolled in the TAILORx trial are eligible)

- NOTE: axillary dissection is strongly encouraged in patients with lymph node
involvement identified on sentinel node biopsy

- Patients must have completed definitive breast surgery including total mastectomy and
axillary dissection (modified radical mastectomy), total mastectomy and sentinel node
biopsy, breast conservation surgery and axillary dissection or breast conservation
surgery and sentinel node biopsy

- NOTE: breast conservation surgery includes lumpectomy, partial mastectomy, and
excisional biopsy

- Margins of breast conservation surgery or mastectomy must be histologically free of
invasive breast cancer and ductal carcinoma in situ (DCIS); patients with resection
margins positive for lobular carcinoma in situ (LCIS) are eligible

- Time from last surgery for breast cancer (breast conservation surgery, mastectomy,
sentinel node biopsy, axillary dissection or re-excision of breast conservation
surgery margins) to planned treatment start date must be > 28 days and =< 84 days

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Absolute neutrophil count >= 1,000/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 mg/dL

- Aspartate aminotransferase (AST) =< 2 times upper limit of normal(ULN)

- Serum creatinine =< 1.5 mg/dL

- Urine protein:creatinine ratio < 1.0 or 24-hour protein

- Partial thromboplastin time (PTT) =< 1.5 times ULN

- Left ventricle ejection fraction (LVEF) >= institutional limits of normal by
echocardiogram (ECHO) or multigated acquisition scan (MUGA)

- Patients who have undergone breast conservation surgery must receive radiation; prior
to randomization, the investigator must specify the planned radiation technique:

- Whole breast radiation (WBRT) after chemotherapy

- Accelerated partial breast radiation (APBI) after chemotherapy

- Accelerated partial breast radiation (APBI) prior to chemotherapy

- NOTE: if APBI was completed prior to study entry, day 1 of protocol therapy must
be at least 4 weeks after the completion of APBI

- Post-mastectomy radiation therapy (RT) is required for all patients with a primary
tumor of >= 5 cm or involvement of 4 or more lymph nodes; post-mastectomy RT may be
administered at the investigator's discretion for all other mastectomy patients

- Patients with human epidermal growth factor receptor (HER)2 + (3+ by
immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH] ratio >= 2)
breast cancer are not eligible

- Patients with synchronous bilateral breast cancer (diagnosed within one month) are
eligible if the higher tumor, node, metastasis (TNM) stage tumor meets the eligibility
criteria for this trial

- Patients must not have clinical evidence of inflammatory disease or fixed axillary
nodes at diagnosis

- Patients must not have received prior cytotoxic chemotherapy or hormonal therapy for
this breast cancer; prior treatment with an anthracycline, anthracenedione or taxane
for any condition is not allowed

- NOTE: prior use of tamoxifen for chemoprevention is allowed but must be
discontinued at study entry; similarly, prior raloxifene use is allowed but must
be discontinued at study entry

- Patients must not have had any major surgical procedure within 28 days of planned
treatment start date

- NOTE: non-operative biopsy or placement of a vascular access device is not
considered a major surgery

- Patients may not have had placement of a vascular access device within 24 hours of
planned day 1 of treatment

- Patients must not have clinically significant cardiovascular or cerebrovascular
disease, including:

- Any history of

- Cerebrovascular disease including transient ischemic attack (TIA), stroke or
subarachnoid hemorrhage

- Ischemic bowel

- Within the last 12 months

- Myocardial infarction

- Unstable angina

- New York Heart Association (NYHA) class II or greater congestive heart
failure

- Grade II or greater peripheral vascular disease

- Uncontrolled hypertension defined as systolic blood pressure (SBP) > 160 or
diastolic blood pressure (DBP) > 90

- Uncontrolled or clinically significant arrhythmia

- NOTE: blood pressure must be obtained within =< 8 weeks prior to
randomization

- NOTE: patients with controlled atrial fibrillation are eligible

- Patients who require full-dose anticoagulation may enroll provided they meet the
following criteria:

- The patient must have an in-range international normalized ratio (INR) (usually
between 2 and 3) on a stable dose of warfarin or be on stable dose of low
molecular weight (LMW) heparin

- The patient must not have active bleeding or pathological conditions that carry
high risk of bleeding (e.g. varices)

- NOTE: prophylactic use of anticoagulants to maintain patency of a vascular access
device is permitted

- Patients must not have a bleeding diathesis, hereditary or acquired bleeding disorder
or coagulopathy

- Patients must not have a non-healing wound or fracture; patients with an abdominal
fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months
prior to randomization are not eligible

- Patients must not have hypersensitivity to paclitaxel or drugs using the vehicle
Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood or urine test within 7 days prior to randomization to rule out
pregnancy

- Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception