Breast Cancer WEight Loss Study (BWEL Study)

This randomized controlled trial of weight loss interventions in overweight and obese women
with early stage breast cancer consists of two arms, please see the arms section for more
information. Patients will be randomized 1:1 within stratification factors: menopausal status
(premenopausal vs. postmenopausal), hormone receptor status of the tumor (ER and/or PR
positive vs. ER and PR negative), and race/ethnicity (African American vs. Hispanic vs.
Other). The primary objective of this trial is to compare the effect of the telephone-based
intervention versus a health educational control on invasive disease-free survival (IDFS).
The total sample size is 3136 patients. Patient follow up for primary and secondary endpoints
will continue to a maximum of 10 years, as per the standard protocol for cooperative group
adjuvant trials.

The primary and secondary objectives of the study:

Primary objective To compare the effect of a supervised weight loss intervention plus health
education materials versus health education materials alone upon invasive disease free
survival (IDFS) in overweight (BMI 27-29.9 kg/m2) and obese (BMI ≥30kg/m2) women diagnosed
with HER-2 negative, stage II and III breast cancer.

Secondary objectives

1. To determine the relationship between changes in weight and IDFS, and to explore
interaction between the level of clinical benefit from weight loss and the intervention.

2. To evaluate the effect of a supervised weight loss intervention upon:

1. Overall survival

2. Distant disease free survival

3. Weight

4. Body composition (as measured by waist and hip circumference)

5. Insulin Resistance Syndrome associated conditions - diabetes, hospitalization for
CV disease

3. To determine the impact of a supervised weight loss intervention on IDFS within
subgroups of women with 1) hormone receptor positive breast cancer and 2) hormone
receptor negative breast cancer.

4. To determine the impact of a supervised weight loss intervention on IDFS within
subgroups of 1) premenopausal women and 2) post-menopausal women.

Patients are to be followed every 6 months for the first 3 years after study enrollment and
then annually until 10 years from registration. The intervention will last 2 years or until
disease recurrence/progression, new invasive primary cancer as defined in the protocol or
patient withdrawal.

1. Documentation of Disease:

1.1 Subjects must have histologically confirmed invasive breast cancer and
registration must occur within 14 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 T0N0, T1N0, T2N0 or T1N1mi and T2N1mi
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.