Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast Cancer
Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast Cancer
If residual breast cancer is found in the breast or lymph node tissue removed after
 preoperative chemotherapy, one may be at increased risk of breast cancer recurrence in the
 future. The purpose of this research study is to determine if having additional treatment
 after preoperative chemotherapy and surgery with bevacizumab and metronomic chemotherapy
 would make a difference in reducing the participants chance of breast cancer recurrence
 compared to the standard of care, which is observation alone. This study will evaluate the
 potential additional benefits from participating in an exercise and dietary intervention
 compared to the dietary intervention alone. Bevacizumab is an antibody that is made in the
 laboratory. Bevacizumab works differently from the way chemotherapy drugs work. Bevacizumab
 works to slow or stop the growth of cells in cancer tumors by decreasing the blood supply to
 tumors. Bevacizumab has been approved by the U.S Food and Drug Administration to treat
 advanced colorectal, lung and kidney cancers. Metronomic chemotherapy also attacks tumor
 blood supply. Standard chemotherapy drugs are used, cyclophosphamide and methotrexate (CM),
 but in very small daily doses by mouth, well below the threshold where they can cause people
 to feel sick. Previous research studies have shown that women with breast cancer who take
 metronomic CM and bevacizumab feel very well, and the combination therapy is active in
 reducing their cancer. Participants in this study will also be provided with diet or diet and
 exercise counseling over the telephone. Studies have shown that many women who are treated
 for breast cancer will gain weight during and after their treatment, and may also experience
 fatigue and weakness. Many studies have shown that making changes in diet and increasing
 exercise can help prevent weight gain and also may increase energy and decrease other side
 effects of chemotherapy and other breast cancer treatments.
-  Because no one knows which of the study options are best, participants will be
 "randomized" to one of the study groups: 1. Diet Intervention arm, 2. Diet and Exercise
 Intervention Arm, 3. Bevacizumab, cyclophosphamide, methotrexate and diet intervention,
 4. Bevacizumab, cyclophosphamide, methotrexate, diet and exercise intervention arm.

 -  Participants assigned to groups 1 or 2 will receive a diet intervention or diet and
 exercise intervention. They will be seen by the doctor for physical examination every 12
 weeks for the first two years during the intervention, and then on an every 6 month
 basis. Routine laboratory testing will be done at the time of the visits as well. Other
 blood tests will be done to measure the effect of the diet and exercise interventions at
 the beginning of the treatment, at 6 months, and at 1 year from the start of the
 treatment. Additionally, one blood test will be done at the beginning of the treatment
 to look for hereditary differences in genes related to metabolism.

 -  Participants assigned to groups 3 or 4 will undergo the following: Medication:
 Participants that are placed in the bevacizumab and cyclophosphamide and methotrexate
 (CM) arm will receive bevacizumab intravenously once every 3 weeks for approximately 6
 months, followed by every 6 week treatments for additional 1.5 years; cyclophosphamide
 orally once a day and methotrexate orally twice a day for the first two days of each
 week. The treatments with CM therapy and bevacizumab will continue for approximately 6
 months. Physical Exams: once 6 weeks of drug therapy (2 cycles)is completed, physical
 examination frequency is reduced to every 6 weeks (every other cycle) for the additional
 6 cycles. Once 24 weeks of drug therapy (8 cycles or about 6 months since the start of
 therapy) are completed, physical examination will be done every 12 weeks for the
 duration of protocol therapy. Blood Tests: chemistry and hematology testing will be done
 prior to start of Cycles 1, 2 and 3 and then every 6 weeks (every other cycle) for the
 duration of cyclophosphamide and methotrexate chemotherapy. After 24 weeks (8 cycles) of
 drug treatment, hematology/chemistry testing frequency can be reduced to every 12 weeks
 (every other cycle) for the rest of bevacizumab treatment. Urine Tests will be done
 every other cycle for the duration of treatment. Heart function testing by
 echocardiogram will be done at 6 months, 1, 2, and 3 years after participants start the
 study. Ultrasound of the blood vessels will be done on those randomized to receive
 bevacizumab with CM chemotherapy. This test will be done at baseline and after
 completion of the first and second cycles of therapy.

 -  Activities for all Groups: Lifestyle Intervention: All women in this study will complete
 a number of tests at baseline, 6 and 12 months. Diet Only Group: Participants assigned
 to this group will be asked to participate in a series of 13 telephone calls over the
 course of 1 year with. Those assigned to the Diet and Exercize Group (in addition to the
 information listed above) will receive counseling targeted toward increasing physical
 activity.
Inclusion Criteria:

 -  Histologically or cytologically confirmed invasive breast cancer. HER2 positive
 disease is not allowed. Metastatic breast cancer (Stage IV) is not allowed.

 -  For patients entering the trial after neoadjuvant chemotherapy, there must be the
 presence of residual invasive disease on pathologic review following neoadjuvant
 chemotherapy. Residual disease is defined as a Miller-Payne response in the breast of
 0-4 and/or residual carcinoma in one or more regional lymph nodes that would meet AJCC
 7th edition criteria for N1 - N3 disease. The presence of DCIS without invasion does
 not qualify as residual disease. Alternatively, if Miller-Payne grading is not
 available, the patient will be eligible if the pathology report indicates any residual
 invasive carcinoma following neoadjuvant therapy.

 -  If tumor is triple negative (ER-/PR-/HER2-) and the patient received neoadjuvant
 chemotherapy, disease may be clinical stage I-III pre-operatively, per AJCC 7th
 edition, based on baseline evaluation by clinical examination and/or breast imaging.
 Patients must have the presence of residual invasive disease on pathologic review
 following their neoadjuvant chemotherapy.

 -  If tumor is triple negative and the patient did not receive neoadjuvant chemotherapy,
 there must be pathologic lymph node positivity and Stage IIB or greater disease after
 surgery. For the purposes of eligibility, lymph node positivity can refer to either
 axillary or intramammary lymph nodes.

 -  If tumor is hormone receptor positive, disease must be clinical Stage III
 neoadjuvantly, per AJCC 7th edition, based on baseline evaluation by clinical
 examination and/or breast imaging, or pathologic Stage IIB or greater at time of
 definitive surgery. Patients with hormone receptor positive breast cancer who do not
 receive neoadjuvant chemotherapy are not eligible for this protocol.

 -  For patients who completed neoadjuvant chemotherapy, the regimen must contain an
 anthracycline, a taxane, or both. Patients who have received neoadjuvant therapy as
 part of a clinical trial are acceptable. Protocol therapy must be initiated < 180 days
 after last surgery for breast cancer. For triple negative patients who receive
 adjuvant chemotherapy only, the regimen must contain both an anthracycline and a
 taxane. For these patients, protocol therapy must be initiated < 28 weeks after
 initiation of adjuvant chemotherapy.

 -  Patients with ER+ and/or PR+ breast cancer should receive adjuvant hormonal therapy

 -  No prior exposure to bevacizumab or other inhibitors of angiogenesis is allowed.

 -  Patients must have completed definitive resection of primary tumor. Negative margins
 for both invasive and ductal carcinoma in situ (DCIS) are desirable, however positive
 margins are acceptable if the treatment team believes no further surgery is possible
 and patient has received radiotherapy. Patients with margins positive for lobular
 carcinoma in situ are eligible.

 -  Post-mastectomy radiotherapy is suggested for all patients with a primary tumor 5cm or
 greater or involvement of 4 or more lymph nodes. Whole breast radiotherapy is required
 for patients who underwent breast conserving therapy, including lumpectomy, partial
 mastectomy, and excisional biopsy.

 -  Patients must have the presence of residual invasive disease on pathologic review
 following their preoperative chemotherapy. The presence of DCIS without invasion does
 not qualify as residual disease. Alternatively, if Miller-Payne grading is not
 available, the patient will be eligible if the pathology report indicates any residual
 invasive carcinoma following preoperative therapy.

 -  LVEF equal to or greater than institutional limits of normal after preoperative
 chemotherapy, as assessed by echocardiogram, within 30 days prior to registration

 -  ECOG Performance Status 0-1 within 2 weeks of registration

 -  18 years of age or greater

 Exclusion Criteria:

 -  Laboratory assessments as outlined in the protocol

 -  Stage IV breast cancer. Patients with metastatic disease are ineligible. However,
 specific staging studies are not required in the absence of symptoms

 -  Prior history of hypertensive crisis or hypertensive encephalopathy

 -  History if myocardial infarction or unstable angina within 12 months prior to
 registration

 -  History of stroke or transient ischemic attack at any time

 -  Significant vascular disease within 6 months prior to registration

 -  History of hemoptysis within 1 month prior to registration

 -  Ongoing or active infection

 -  NYHA Grade II or greater congestive heart failure

 -  Unstable angina pectoralis

 -  Psychiatric illness/social situations that would limit compliance with study
 requirements

 -  Evidence of bleeding diathesis or significant coagulopathy

 -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
 prior to registration or anticipation of need for major surgical procedure during the
 course of the study

 -  Core biopsy or other minor surgical procedure, excluding placement of a vascular
 access device, within 7 days prior to registration

 -  History of abdominal fistula or gastrointestinal perforation within 6 months prior to
 registration

 -  Serious, non-healing wound, active ulcer, or unhealed bone fracture

 -  Known hypersensitivity to any component of bevacizumab or compounds of similar
 chemical or biologic composition to cyclophosphamide or methotrexate

 -  Known HIV infection, as immunosuppression could be worsened by use of cyclophosphamide
 and methotrexate, and the impact of chemotherapy and/or bevacizumab therapy on the
 pharmacology of standard anti-HIV therapy is not known

 -  Patient may not be pregnant, expect to become pregnant, plan to conceive a child while
 on study or breastfeeding.

 -  Prior history of any malignancy treated without curative intent, or treated with
 curative intent within the past 5 years. Prior history of DCIS > 5 years before
 current breast cancer diagnosis is acceptable if ipsilateral (and no radiotherapy
 given) or contralateral (with or without radiotherapy) or contralateral (with or
 without radiotherapy). Prior history of contralateral stage 1 breast cancer > 5 years
 prior to the current breast cancer diagnosis is acceptable, however prior ER/PR+
 breast cancer > stage 1 at any time is not allowed.

 -  Patients with a pleural effusion or abdominal ascites are excluded because of the
 theoretical risk for methotrexate accumulation and related toxicity

 -  Current use of anticoagulants is allowed as long as patients have been on a stable
 dose for more than two weeks with stable INR

 -  Chronic therapy with full dose aspirin or standard non-steroidal anti-inflammatory
 agents is allowed

 -  While on study, patients may not receive other investigational agents as part of other
 clinical trials

 -  Adjuvant bisphosphonate use, on or off of clinical trial, is allowed. Patients may be
 started on adjuvant bisphosphonate therapy either before or after ABCDE trial
 enrollment