• Men or women with metastatic or locally advanced unresectable breast cancer

• Histologically confirmed ER+ / HER2-negative, breast cancer who is a candidate for endocrine therapy with pathology from the primary tumor or metastatic/recurrent site. Based on American Society of Clinical Oncology/College of American Pathologists (ASCO CAP) Guidelines: ER+: \>= 1% of tumor cell nuclei to be immunoreactive. HER2-negative: HER2 of 0, 1+ by immunohistochemistry (IHC) or negative by fluorescence in situ hybridization (FISH).

‣ In the case of bone biopsy which could yield false negative ER or PR status in patients with historically HR+ disease, a patient may be eligible if the treating physician and the study chair both agree that the patient is a candidate for further endocrine therapy (ET) based treatment.

⁃ Note that baseline PR status by IHC does not influence results of deltaFFNP-PET imaging.

• If premenopausal, the patient has to be treated with GnRH agonist for at least 6 weeks prior to FFNP-PET.

• Disease must be present in at least one non-liver site and measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and be 1.5 cm or greater in longest dimension OR disease can be non-measurable but must be 1.5 cm in longest dimension on functional imaging (fluorodeoxyglucose \[FDG\]-PET/computed tomography \[CT\] preferred).

• No limits to prior lines of endocrine therapy in the metastatic setting including synergistic targeted therapy such as CDK4/6 inhibitors (other than Abemaciclib), PI3K inhibitor, mTOR inhibitor, etc. One line of prior cytotoxic chemotherapy in the metastatic setting is allowed. Washout from prior systemic anti-cancer therapy of at least 2 weeks from chemotherapy or radiation, 2 weeks or 5 half lives (whichever is longer) from oral selective estrogen receptor degrader (SERD), 8 weeks from oral selective estrogen receptor modulator (SERM), and 16 weeks from intramuscular SERD (Fulvestrant) is required. Recovery of adverse events from the last therapy to grade 1 except alopecia. Patients may continue luteinizing hormone-releasing hormone (LHRH) agonist to remain post-menopausal without a need for washout

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2

• At least 18 years of age

• Absolute neutrophil count \>= 1,500/uL

• Platelets \>= 100,000/uL

• Hemoglobin \>= 9g/dL

• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN).

‣ In case of known Gilbert's syndrome, \< 2 x ULN is allowed

• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) /alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =\< 2.5x institutional ULN, or =\< 5 x ULN for subjects with documented metastatic disease to the liver

• eGFR (estimated glomerular filtration rate) ≥ 30 mL/min

• Women of childbearing potential must agree to use adequate contraception (barrier method of birth control, abstinence) prior to study entry and for the duration of study participation

• Ability to understand and willingness to sign an institutional review board (IRB)-approved written informed consent document (or that of legally authorizes representative, if applicable)

• Consent to access archival tumor specimens for clinical sequencing data of tumor tissue and blood