Adaptive capecitabine therapy for metastatic ER-positive, HER2-negative breast cancer

Inclusion Criteria:

* PRE-REGISTRATION: Provide written informed consent Note: Pre-registration should occur prior to screening research blood draws being completed
* PRE-REGISTRATION: Provider anticipates the patient will begin on capecitabine within 14 days or has started capecitabine within the past 42 days and has had a maximum of two cycles Note: Pre-registration should occur prior to screening research blood draws being completed

REGISTRATION - INCLUSION CRITERIA

* Age ≥ 18 years
* Histological confirmation of estrogen-receptor positive (ER+), HER2-negative overexpression or amplification negative as per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, metastatic breast cancer
* Measurable disease. Bone only disease allowed if associated with soft tissue component that is measurable by Response Evaluation Criteria is Solid Tumors (RECIST) 1.1 criteria
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Hemoglobin ≥ 9.0 g/dL (obtained ≤ 14 days prior to registration), no transfusions allowed ≤ 14 days prior to registration
* Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained ≤ 14 days prior to registration)
* Platelet count ≥ 100,000/mm\^3 (obtained ≤ 14 days prior to registration)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 14 days prior to registration)
* Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to registration)
* Negative serum or urine pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Provide written informed consent
* Ability to complete questionnaire(s) by themselves or with assistance
* Willingness to provide mandatory blood specimens for correlative research
* Ability to undergo re-staging CT scans as required by the protocol

  * Note: for patients who have had up to two cycles of capecitabine prior to joining the study, they must have had their initial CT imaging completed within 28 days of their first dose of capecitabine
* Willing to return to enrolling institution at the specified frequency for follow-up (during the active monitoring phase of the study)
* Cohort 2 only: Stable disease, partial or complete response on imaging after beginning capecitabine

Exclusion Criteria:

* Prior chemotherapy or use of antibody drug conjugate in the metastatic setting

  * Note - Cohort 2 only: Patients can have had up to two cycles of capecitabine before joining the study
* Any of the following, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

  * Pregnant persons
  * Nursing persons
  * Persons of childbearing potential who are unwilling to employ adequate contraception
* Any of the following prior therapies:

  * Major surgery ≤ 3 weeks prior to registration
  * Radiation therapy ≤ 2 weeks prior to registration
* Evidence of visceral crisis or impending cord compression
* Evidence of uncontrolled brain metastasis requiring whole brain irradiation or intervention
* Uncontrolled intercurrent illness including, but not limited to:

  * ongoing or active infection
  * symptomatic congestive heart failure
  * unstable angina pectoris
  * uncontrolled cardiac arrhythmia
  * chronic oxygen dependence
  * respiratory failure
  * or psychiatric illness/social situations that would limit compliance with study requirements
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* Other active malignancy ≤ 3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
* If there is a history of prior malignancy, they must not be receiving other cancer specific treatment. Except for antiestrogen treatment (aromatase inhibitors or selective estrogen modulators) for their cancer are permitted if they meet other eligibility criteria. Denosumab and zoledronic acid, are permitted as established adjunct therapies per guidelines
* History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* Patients known to have certain homozygous or compound heterozygous dihydropyrimidine dehydrogenase (DPYD) variants that result in complete absence of deoxypyridinoline (DPD) activity. Test results do not need to be available prior to registration
* History of severe hypersensitivity reactions to fluorouracil or capecitabine