• STEP 1 REGISTRATION

• Patients must have a diagnosis of hormone receptor positive (estrogen receptor positive \[ER+\] and/or progesterone receptor positive \[PR+\]), HER-2 negative, metastatic (M1) breast cancer and must be receiving or plan to receive first-line systemic treatment for metastatic disease. (Systemic treatment is any treatment meant to treat the whole body such as endocrine therapy +/- targeted therapy +/- chemotherapy).

‣ NOTE: Participants are eligible if they have either de-novo metastatic breast cancer and/or recurrent breast cancer from an earlier stage that is now metastatic

• Patients must be registered to step 1 between 14 days prior to and 60 days after start of first-line systemic treatment for metastatic disease

• Patients must have been tested for the following breast cancer specific STMs after diagnosis of metastatic disease and within +/-14 days of initiation of first-line systemic treatment for metastatic disease:

‣ CEA (must be tested)

⁃ CA 15-3 or CA 27.29 (at least one of these must be tested)

⁃ At least one of the tested STMs must have been \>= 1.5 x the institutional upper limit of normal at this time.

∙ Testing all three STMs is encouraged but only two are required. Patients must plan to have the same two STMs tested for the duration that the patient is on protocol-specified disease monitoring.

• Patients must have systemic radiographic imaging prior to initiation of systemic therapy or within 30 days of initiation of treatment for metastatic breast cancer and prior to step 1 registration. Modality of imaging is at the discretion of the treating physician.

‣ Note: the treating physician can order additional imaging tests at any point prior to randomization at their discretion

• Patients must be willing to obtain disease monitoring (imaging and/or serum tumor markers) from a consistent facility in which the registering site has access to the results for the duration of the study intervention (312 weeks after step 2 randomization). Imaging and STMs do not need to be completed at the same facility.

• Patients with known cirrhosis, untreated B12 deficiency, thalassemia, or sickle cell anemia are not eligible as these could cause falsely elevated STM levels

• Patients with known brain leptomeningeal metastases are not eligible as they may require regular radiographic monitoring to assess treatment response

• Patients must not be currently enrolled or plan to participate in a first-line treatment trial for metastatic breast cancer with a defined monitoring schedule

• Patients who are able to complete questionnaires in English or Spanish must participate in patient-reported outcome (PRO) assessments

• Patients must not be pregnant due to the potential harm to the fetus from radiation exposure from radiographic imaging

• Except for breast cancer (and previous history of breast cancer), no other prior malignancy is allowed with the following exceptions:

‣ Adequately treated basal (or squamous cell) skin cancer

⁃ Any cancer from which the patient has been disease free for five years

⁃ Prior Stage 0 or pre-cancerous lesions that have been removed with clear margins

• Patients must not have received prior systemic therapy for metastatic breast cancer, except for their current line of therapy.

• Patients must have decision making capacity and be able to provide informed consent

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; use of legally-authorized representative is not permissible for this study. Remote consent is allowed with adequate documentation.

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

• STEP 2 RANDOMIZATION

• Patients must be tested for the breast cancer specific STMs that were tested prior to STEP 1 Registration between 56 and 140 days after initiation of first-line systemic therapy for metastatic disease:

‣ CEA (must be tested)

⁃ CA 15-3 or CA 27.29 (whichever was tested prior to Step 1)

∙ Testing all three STMs is encouraged but only two are required. Patients must plan to have the same two STMs tested for the duration that the patient is on protocol-specified disease monitoring.

• At least one of the STMs that was previously elevated must have decreased from the assessment at step 1 by \>= 10% at this time.

• Patients must not have known progression since registration to step 1

• Patients must be registered to step 2 randomization between 56 days and 140 days after the initiation of first-line systemic therapy for metastatic disease; This window is inclusive; patients may be registered to Step 2 on day 56 or Day 140. Patients must have been eligible for Step 1 in order to be eligible for Step 2 Randomization

• Baseline questionnaires must be completed within 28 days prior to step 2 randomization; (Note: Those patients who cannot complete the PRO questionnaires in English or Spanish can be registered to step 2 without contributing to PRO research)