Summary

This randomized phase III compares weight loss interventions in treating overweight and obese women with a higher risk for breast cancer that comes back (recurrence). Many studies have shown that women who are overweight or obese when diagnosed with breast cancer appear to have a higher risk of cancer recurrence. This study aims to test whether overweight or obese women who take part in a weight loss program after being diagnosed with breast cancer have a lower rate of cancer recurrence as compared to women who do not take part in the program.

Objectives

PRIMARY OBJECTIVE:
I. 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 (body mass index [BMI] 27-29.9 kg/m^2) and obese (BMI >= 30 kg/m^2) women diagnosed with HER-2 negative, stage II and III breast cancer.

SECONDARY OBJECTIVES:
I. 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.
II. To evaluate the effect of a supervised weight loss intervention upon:
IIa. Overall survival.
IIb. Death from breast cancer.
IIc. Distant disease free survival.
IId. Breast cancer free survival.
IIe. Weight.
IIf. Body composition (as measured by waist and hip circumference).
IIg. Insulin resistance syndrome associated conditions – diabetes, hospitalization for cardiovascular (CV) disease.
IIh. Employment and work productivity.
III. 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.
IV. To determine the impact of a supervised weight loss intervention on IDFS within subgroups of 1) premenopausal women and 2) post-menopausal women.

OTHER OBJECTIVES:
I. Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

CORRELATIVE SCIENCE OBJECTIVES:
I. To determine the impact of a supervised weight loss intervention upon:
Ia. Fasting insulin, glucose and homeostasis model assessment (HOMA).
Ib. Metabolic biomarkers, including adiponectin, leptin, IGF-1, IGFBP-3 and related factors.
Ic. Inflammatory mediators, including IL-6, TNF-alpha (a), hsCRP, and related factors.
II. To evaluate whether the benefits of the weight loss intervention are predicted by the following:
IIa. Baseline and change in levels of fasting insulin and glucose.
IIb. Baseline and change in other metabolic and inflammatory biomarkers (including adiponectin, leptin, IGF-1, IGFBP-3, IL-6, TNF-a, hsCRP).
III. To explore whether the benefits of the weight loss intervention are predicted by the following (A011401-ST1):
IIIa. Insulin and IGF-1 receptors (and related markers of signaling pathway activation) in breast tumor tissue.
IIIb. Crown-like structure breast in non-malignant breast tissue.
IV. To explore the relationship between gene expression in tumor tissue and the benefits of the supervised weight loss intervention (A011401-ST1).
V. To evaluate the prevalence and predictors of Clonal Hematopoiesis of Indeterminate Potential (CHIP) in BWEL participants and to explore the relationship between CHIP and outcomes including iDFS, breast cancer-free survival, OS, second cancers and CVD (A011401-ST1).
VI. To evaluate the presence and predictors of minimal residual disease (MRD) in BWEL participants who remain free of breast cancer recurrence at least 5 years after enrollment in BWEL (A011401-ST2).
VII. To explore the relationship between presence of MRD in BWEL participants who remain free of breast cancer recurrence at least 5 years after enrollment in BWEL and subsequent disease outcomes (A011401-ST2).

HEALTH BEHAVIORS AND PATIENT REPORTED OUTCOMES OBJECTIVES:
I. To determine the impact of a supervised weight loss intervention upon the following measures at months 6 (primary) as well as at 24 and 36 (secondary):
Ia. Weekly minutes of moderate and vigorous physical activity (primary).
Ib. Patient reported physical function (primary).
Ic. Daily caloric intake (secondary).
Id. Daily intake of servings of fruits and vegetables (secondary).
Ie. Proportion of patients meeting recommended levels of aerobic physical activity (secondary).
If. Minutes of self-reported physical activity (secondary).
Ig. General physical and mental health (secondary).
Ih. Anxiety, depression, fatigue, sleep, social roles, and pain (secondary).
Ii. Body image and clothing (secondary).
Ij. Cancer-treatment related and menopausal symptoms (i.e. cognition, endocrine symptoms, neuropathy, joint pain/stiffness) (secondary).
Ik. Circadian rhythm as measured by actigraphy for 1) amplitude and 2) shift in phase of circadian rhythm in relation to Earth’s day-night cycle (secondary).
II. To evaluate the relationship between changes in weight and changes in 1) physical activity patterns, 2) dietary intakes (secondary), and 3) circadian rhythm (secondary).
III. To use longitudinal data to explore the relationships amongst changes in weight, dietary intakes and minutes of physical activity and changes in patient reported outcomes including patterns of symptoms over time (exploratory).
IV. To evaluate whether baseline levels of patient reported outcomes are associated with adherence to physical activity, adherence to diet recommendations, or weight loss at 6 months; and whether 6-month and 24-month levels of patient reported outcomes are associated with adherence to physical activity, adherence to diet recommendations, or weight loss at 36 months. (exploratory).

BODY COMPOSITION SUBSTUDY OBJECTIVES (A011401-IM1):
I. To evaluate baseline body composition (total fat mass, visceral fat, subcutaneous fat and lean mass) and assess the incidence of sarcopenic obesity (high fat mass combined with low lean mass).
II. To evaluate the relationship between baseline body composition and changes in weight, metabolic biomarkers and inflammatory mediators in patients randomized to the weight loss intervention.
III. To explore the relationship between baseline body composition and invasive disease-free survival and overall survival in patients randomized to the health education only arm.
IV. To explore disparities in baseline body composition and assess the incidence of sarcopenic obesity between black and Hispanic BWEL participants versus non-Hispanic white (NHW) BWEL participants.
V. To explore the relationship between baseline body composition and invasive disease-free survival and overall survival by race/ethnicity.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive health education program brochures describing diabetes prevention, healthy dental habits, vision care, and skin care at study entry and at 1 year. Patients also receive a 2-year health magazine subscription. In addition, all patients are invited to join twice-yearly webinars/teleconferences focused on breast cancer and other health topics such as treatment updates in breast cancer, management of menopausal side effects, general cancer screening, etc. Patients also receive a twice-yearly study newsletter with study updates and other general breast cancer news.

ARM II: Patients receive health education program brochures describing diabetes prevention, healthy dental habits, vision care, and skin care at study entry and at 1 year, and a 2-year health magazine subscription. Patients also receive a telephone-based weight loss intervention over 30 minutes for 2 years consisting of: weekly calls for 12 weeks, calls every 2 weeks for 4-12 months and calls once per month for 13-24 months that focus on: weight loss, caloric restriction, and physical activity goals.

After completion of study treatment, patients are followed up every 6 months for 3 years and then annually until 10 years.

Eligibility

1. Subjects must have histologically confirmed invasive breast cancer and registration must occur within 16 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 either: ** 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 is Her-2 positive or inflammatory; OR ** The contralateral breast cancer was at least 5 years prior to the current diagnosis * No evidence of metastatic or locally recurrent disease
2. Her-2 negative, defined as: * In-situ hybridization (ISH) ratio of < 2.0 (if performed) * Immunohistochemistry (IHC) staining of 0-2 positive (+) (if performed) * Deemed to not be a candidate for Her-2 directed therapy
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 T0N0, T1N0 and T1N1mi disease, and patients with T4 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, T1N1mi and T2N1mi disease, and patients with T4 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
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 does not make a patient ineligible)
5. Patients must have had a bilateral mammogram within 16 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)
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 required only if clinically indicated or recommended by National Comprehensive Cancer Network (NCCN) guidelines * Bone scans (with x-rays of abnormal areas) are required only if indicated or recommended by NCCN guidelines * Abdominal imaging is required only if clinically indicated or recommended by NCCN guidelines
7. PRIOR TREATMENT
8. All adjuvant or neoadjuvant chemotherapy, radiation, and surgery completed at least 21 days prior to registration * All triple negative patients must receive chemotherapy of the treating physician’s choice * 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 * 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
9. 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
10. All subjects (both adjuvant and neoadjuvant) must have sentinel lymph node biopsy and/or axillary lymph node dissection, as per pre-specified institutional guidelines
11. All women who undergo breast conserving therapy must receive concomitant radiotherapy; radiation after mastectomy is to be administered according to pre-specified institutional guidelines; radiation must be completed at least 21 days prior to registration
12. Patients with hormone receptor positive breast cancer as defined above must plan to 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
13. Age >= 18 years
14. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
15. COMORBID CONDITIONS
16. 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
17. No diabetes mellitus currently treated with insulin or sulfonylureas
18. No history of serious digestive and/or absorptive problems, including inflammatory bowel disease and chronic diarrhea that preclude adherence to the study diet
19. 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
20. No prior bariatric surgery or planning to undergo this procedure within the next 2 years after study registration
21. No use of weight loss medications (with the exception of metformin) at the time of study enrollment or plans to take these agents within the next 2 years after study enrollment
22. No comorbid conditions that would cause life expectancy of less than 5 years
23. 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
24. No chronic (>= 1 month) use of oral steroids at the time of study enrollment; inhaled or topical steroids are acceptable; patients previously taking oral steroids are required to undergo a 30-day washout prior to registration
25. BMI >= 27 kg/m^2 documented within 56 days prior to study registration; the most recent BMI obtained within that window must be used for eligibility; if most recent BMI is < 27 then the patient is not eligible to enroll
26. Self-reported ability to walk at least 2 blocks (at any pace)
27. 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
28. Able to read and comprehend spoken English or Spanish * Eligibility is restricted to individuals who can comprehend and read English or Spanish 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 trial is unable to accommodate the needs of deaf participants as the study relies on spoken language to provide coaching

Treatment Sites in Georgia