Patient must be >= 18 years of age on the day of signing informed consent

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance (performance status [PS]) =< 2

Patient must have radiographically confirmed metastatic breast cancer with histologic confirmation of either metastatic or primary tumor biopsy by local assessment that is hormone receptor positive by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines and with known HER2 status.
* NOTE: Confirmation can be documented via a report from a metastatic biopsy; a separate biopsy does not need to be completed. If there is no report from a metastatic biopsy, the pathology report from primary breast cancer diagnosis documenting breast cancer along with estrogen receptor (ER), progesterone receptor (PR) and HER2 status can be utilized

Patient must have radiologically confirmed bone-dominant (BD) or bone-only (BO) disease confirmed by scans obtained within 60 days prior to registration
* BD is defined as disease involving bone with or without limited measurable metastases by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with >= 1 non-irradiated bone metastasis on imaging
** NOTE: Limited measurable metastases include lymph nodes and the soft tissue components of lytic or mixed lytic/blastic bone metastases. Any number of lymph nodes =< 3 cm and up to 2 lymph nodes > 3 cm will be allowed. Up to 5 measurable soft tissue components of lytic or mixed lytic/blastic bone metastases will be allowed. Sites of radiation to bone lesions prior to enrollment must be recorded
* BO is defined as detectable disease confined within the bone (any site, any number of lesions). Diagnosis requires abnormalities identified by imaging (bone scan or CT or PET/CT or magnetic resonance imaging [MRI]) with no other sites of metastases identified and with >= 1 non-irradiated bone metastasis on imaging

Patients with RECIST 1.1 measurable lesions in viscera, active central nervous system (CNS), leptomeningeal carcinomatous or pleural or peritoneal disease will not be eligible. Patients with prior CNS metastases treated with radiation or resection and without evidence of clinical or radiographic progression within 28 days of registration are eligible

Patient must have no contraindication to FDG-PET imaging which includes glucose values > 200 mg/dL and severe claustrophobia

Patient must be newly starting one of the following systemic therapies:
* Plan to receive either 1st, 2nd or 3rd line endocrine therapy for metastatic breast cancer. Endocrine therapy may include selective estrogen receptor modulators (SERMs), aromatase inhibitors, and/or fulvestrant that may be combined with Food and Drug Administration (FDA)-approved biologic agents(examples include CDK 4/6 inhibitors mTOR inhibitors and PARP inhibitors for gBRCA mutation)
* Plan to receive chemotherapy or antibody drug conjugates per National Comprehensive Cancer Network (NCCN) or institutional standard
* Plan to receive HER2-targeted therapy per ASCO, NCCN, and/or institutional guidelines as indicated for patients with HER2 positive disease
* NOTE: The use of bone-stabilizing agents (bisphosphonates or denosumab) is permitted
* NOTE: Dose modification of an existing treatment does not qualify as a new therapy

Patient must not have received colony stimulating growth factor within 14 days prior to completing the T0 FDG-PET/CT scan

Patient must meet institutional guidelines for renal function for MRI and CT scanning

Patient must have life expectancy estimated at >= 24 weeks

Patients who have received greater than 3 lines of cytotoxic chemotherapy for metastatic breast cancer are not eligible

Patients using an investigational agent or using an investigational device within 3 weeks of T0 FDG PET/CT are not eligible

Patients with known additional malignancy that is progressing or requires active treatment are not eligible. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy

Patient must be participating in the trial at an institution which has agreed to perform the imaging research studies, completed the ECOG-American College of Radiology Imaging Network (ACRIN) defined PET/CT scanner qualification procedures and received ECOG-ACRIN PET/CT scanner approval

Patient must complete the baseline (T0) FDG-PET within 28 days after registration. A FDG-PET/CT completed prior to registration may be used if all imaging parameters have been met and patient is able to start treatment within 21 days after completion of FDG/PET CT
* For patients completing the baseline (T0) FDG-PET AFTER registration all parameters must be met
* For patients who completed the baseline (T0) FDG-PET PRIOR to registration all parameters must be met with the following exemption:
** Pregnancy testing documentation prior to FDG-PET (T0 time point) for patients of childbearing potential will not be required

Patient must not be pregnant because FDG is a radiopharmaceutical with the potential for teratogenic effects and PET/CT involves additional radiation exposure. In addition, because of radiation exposure to a nursing infant from FDG, patients who are breastfeeding are also excluded from this study. All patients of childbearing potential must have a blood test or urine study must be done within 7 days prior to FDG-PET/CT to rule out pregnancy

PRIMARY OBJECTIVE:
I. Evaluate the performance of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) response criteria (modified PET Response Criteria in Solid Tumors [PERCIST] complete, partial and stable metabolic disease versus progressive metabolic disease) as a binary predictor of progression-free survival (PFS) in patients with bone-dominant (BD) metastatic breast cancer (MBC) treated with systemic therapy.

SECONDARY OBJECTIVES:
I. Evaluate the ability of FDG-PET/CT modified PERCIST criteria (complete versus [vs] partial vs stable vs metabolic progression) to independently predict PFS in patients with BD MBC.
II. Evaluate the ability of FDG-PET/CT modified PERCIST criteria (complete, partial, and stable versus progressive metabolic disease) to predict time to skeletal related events (SRE) and overall survival (OS) in patients with BD MBC.
III. Evaluate the ability of FDG-PET/CT metrics (percent change in peak standardized uptake value corrected for lean body mass (SULpeak), maximum standardized uptake value corrected for body weight (SUVmax) as continuous variables in index or up to 5 lesions) to predict PFS, time to SRE and OS in patients with BD MBC.
IV. Assess the utility of FDG-PET/CT to identify disease progression by identification of new lesions not identified by standard CT and bone scan.
V. Assess the ability of qualitative and quantitative changes in serial circulating tumor deoxyribonucleic acid (ctDNA) measures to predict PFS, time to skeletal related events (tSRE), and overall survival in patients.

EXPLORATORY OBJECTIVES:
I. Define criteria for selection of FDG-avid bone lesions for analysis based on thresholds for SULpeak or SUVmax.
II. In collaboration with National Cancer Institute (NCI) Quantitative Imaging Network (QIN), explore alternative methods for measuring metabolic response with FDG-PET/CT (e.g., total lesion glycolysis, quantitative total bone imaging, MD Anderson bone criteria, and radiomics) to predict clinical endpoints in patients with BD MBC.
III. Evaluate automated image analysis of FDG-PET/CT by AutoPERCIST.
IV. Determine if early metabolic changes in bone metastases assessed by FDG-PET/CT at 4 weeks after start of systemic therapy predict PFS and tSRE in patients with bone-only (BO) or BD MBC.
V. Evaluate the relationship between changes in ctDNA and metabolic response as assessed by FDG-PET/CT and to test the combined.

OUTLINE:
Patients receive FDG intravenously (IV) and undergo PET/CT scan over 15-30 minutes at baseline (within 21 days before start of standard systemic treatment) and at 12 weeks after start of standard systemic treatment in the absence of unacceptable toxicity. Patients also undergo blood sample collection throughout the study. 

After completion of study, patients are followed up periodically for up to 3 years after study registration.