Randomized Phase III Trial Evaluating the Role of Weight Loss in Adjuvant Treatment of Overweight and Obese Women With Early Breast Cancer

1. Documentation of Disease:

   1.1 Subjects must have histologically confirmed invasive breast cancer and registration must occur within 12 months after the first histologic diagnosis of invasive breast cancer.

   • A core biopsy interpreted as invasive cancer meets this criterion; if no core biopsy is performed, the date of first histologic diagnosis will be the date of first surgical procedure that identifies invasive cancer (biopsy, lumpectomy or mastectomy).
   • Neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy and surgery; eligibility for neoadjuvant patients can be defined by either clinical stage prior to therapy or pathologic stage at surgery; if patient is eligible based on either, they are eligible for the study.
   • Bilateral breast carcinoma is allowed provided diagnoses are synchronous - that is, within 3 months of one another - and at least one of the two breast carcinomas meet the eligibility criteria and neither Her-2 positive or inflammatory.
   • No evidence of metastatic disease

   1.2 Her-2 negative, defined as:

   • In-situ hybridization (ISH) ratio of < 2.0 (if performed)
   • Immunohistochemistry (IHC) staining of 0-2+ (if performed)
   • Deemed to not be a candidate for Her-2 directed therapy.

   1.3 Eligible tumor-node-metastasis (TNM) Stages include:

   • Estrogen receptor (ER) and Progesterone receptor (PR) negative (defined as <1% staining for ER and PR by IHC): T2 or T3 N0, T0-3N1-3. Note: Patients with T1, N1mi disease are NOT eligible.
   • ER and/or PR positive (defined as ≥ 1% staining for ER and/or PR on IHC): T0-3N1-3 or T3N0. Note: Patients with T1-2, N1mi disease are NOT eligible
   • The eligibility of neo-adjuvant subjects can be assessed on the basis of clinical (c)TNM or pathologic (yp)TNM. The same eligible TNM combinations apply; patients may be eligible if they meet eligibility requirements at either time point, as long as they do not have T4 disease prior to therapy.

   1.4 No history of invasive breast cancer in 5 years prior to study registration other than the current diagnosis (prior ductal breast carcinoma in situ [DCIS] at any time is acceptable).

   1.5 Patients must have had a bilateral mammogram within 12 months prior to registration, unless the initial surgery was a total mastectomy, in which case only a mammogram of the remaining breast is required. (Subjects with bilateral total mastectomies do not require imaging).

   1.6 Investigations, including chest X-ray or computed tomography (CT) chest, bone scan (with radiographs of suspicious areas) and abdominal ultrasound or liver scan or CT abdomen have been performed between the first histologic diagnosis and the time of registration as detailed below.

   • Chest X-Ray, 2 view (or Chest CT, or positron emission tomography [PET]/CT) is mandatory
   • Bone scans (with x-rays of abnormal areas) are required only if alanine aminotransferase (ALT), aspartate aminotransferase (AST) or Alkaline Phosphatase is elevated or if there are signs or symptoms of metastatic disease
   • Abdominal imaging is required only if ALT, AST or Alkaline Phosphatase is elevated or if there are signs or symptoms of metastatic disease

2. Prior Treatment

   2.1 All adjuvant or neoadjuvant chemotherapy, radiation, and surgery completed at least 21 days prior to registration.

   2.2 All triple negative patients must receive chemotherapy of the treating physician's choice.

   2.3 ER/PR+ patients must receive chemotherapy (of the treating physician's choice) unless Oncotype Dx or another genomic predictor score indicates that they are at low or intermediate risk of disease recurrence with endocrine therapy alone.

   2.4 Patients may have breast reconstruction during protocol participation, but definitive breast cancer surgery must be completed at least 21 days prior to registration.

   Concomitant biologic therapy, hormonal therapy, and bisphosphonates are acceptable.

   2.5 Surgical margins must be clear of invasive carcinoma. If there is microscopic residual ductal in situ disease present at lumpectomy or total mastectomy margins, further excision is highly recommended. If further excision is not undertaken, the subject may still be entered on study, provided that in addition to breast or chest wall irradiation, a boost to the tumor bed is delivered. In situ lobular disease at the margin is acceptable.

   2.6 All subjects (both adjuvant and neoadjuvant) must have sentinel lymph node biopsy and/or axillary lymph node dissection. Sentinel lymph node biopsy alone is allowed in the following instances:

   • Sentinel lymph node biopsy is negative: pN0
   • Sentinel lymph node biopsy is positive for isolated tumor cells only:

   pN0 (i+)

   • Clinically node negative, T1-2 tumors with sentinel lymph node biopsy positive in < 2 lymph nodes without matted nodes and undergoing breast conserving surgery and tangential whole breast irradiation, or undergoing mastectomy and chest wall irradiation.

   • For patients who had a positive node prior to neoadjuvant chemotherapy, sentinel node alone is allowed after neoadjuvant therapy if:

     • Sentinel node biopsy is negative after chemotherapy and either at least 2 sentinel nodes were removed or a clip was placed in the involved node prior to treatment.
     • =< 2 lymph nodes are positive for cancer and the patient is participating in A011202
   • All women who undergo breast conserving therapy must receive concomitant radiotherapy. Radiation after mastectomy is to be administered according to prespecified institutional guidelines. Radiation must be completed at least 21 days prior to registration.
   • Patients with hormone receptor positive breast cancer as defined above must receive at least 5 years of adjuvant hormonal therapy in the form of tamoxifen or an aromatase inhibitor, alone or in combination with ovarian suppression. (NOTE: for patients with ER and PR staining in less than 5% of cells, hormonal therapy for at least 5 years is strongly recommended but not required). Hormonal therapy can be initiated prior to or during protocol therapy.
3. Participants must be women
4. Age ≥ 18 years
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

6. Comorbid Conditions

   6.1 No history of other malignancy within the past 4 years, except for malignancies with a >95% likelihood of cure (e.g. non-melanoma skin cancer, papillary thyroid cancer, in situ cervical cancer). Patients cannot have metastatic breast or other cancer.

   6.2 No diabetes mellitus currently treated with insulin or sulfonylureas.

   6.3 No history of serious digestive and/or absorptive problems, including inflammatory bowel disease and chronic diarrhea that preclude adherence to the study diet.

   6.4 No history of severe cardiovascular, respiratory or musculoskeletal disease or joint problems that preclude moderate physical activity. Examples would include unstable angina, recent myocardial infarction, oxygen-dependent pulmonary disease, and osteoarthritis requiring imminent joint replacement. Moderate arthritis that does not preclude physical activity is not a reason for ineligibility.

   6.5 No prior bariatric surgery or planning to undergo this procedure within the next 2 years after study registration.

   6.6 No comorbid conditions that would cause life expectancy of less than 5 years.

   6.7 No history of psychiatric disorders that would preclude participation in the study intervention (e.g. untreated major depression or psychosis, substance abuse, severe personality disorder) or prevent the patient from giving informed consent.

7. Other

7.1 BMI ≥27 kg/m2 documented within 56 days prior to study registration. The most recent BMI obtained must be used for eligibility. If most recent BMI is <27 then the patient is not eligible to enroll.

7.2 Self-reported ability to walk at least 2 blocks (at any pace).

7.3 Not participating in another weight loss, physical activity or dietary intervention clinical trial. Co-enrollment in some trials involving pharmacologic therapy is allowed. Participants in both arms are also allowed to pursue weight loss and physical activity programs on their own, as long as these programs are not provided as part of a clinical trial.

7.4 Able to read and comprehend English. Eligibility is restricted to individuals who can comprehend and read English given that participation in the study will require the ability to read lifestyle intervention materials and communicate with a coach through 42 phone calls over 2 years. The study team plans to make the intervention available in Spanish in the future.