Patient case: 45-year-old female with colon cancer; genetic feature: ERBB2 amplification

Clinical trial: Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast Cancer

Summary: 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.

Detailed description: -  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.

Eligibility: 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

Relevance to patient case: not relevant