Sequential Therapies Modeled on Evolutionary Dynamics for Breast Cancer

Inclusion Criteria:

* Female patients 18 years or older
* Histologically or cytologically confirmed diagnosis of hormone positive HER2 negative metastatic breast cancer per ASCO/CAP criteria (Allison et al, 2020, Wolff et al, 2018), with diagnosis established through either a breast/axillary biopsy or biopsy of a metastatic lesion.
* Hormone positive MBC previously treated with endocrine therapy with either an aromatase inhibitor or Tamoxifen (alone or in combination with a CDK4/6 inhibitor).
* Elevated breast tumor markers which may include cancer antigen 15-3 (CA 15-3) levels above the institutional upper limit of normal (ULN) range of 0.0-31.0 U/mL, cancer antigen 27-29 (CA 27-29) (range \<38 U/mL) and/or elevated Carcinoembryonic antigen (CEA) above institutional upper limit of normal (range 0.0 - 5.2 ng/mL).
* Presence of measurable disease on imaging via RECIST v1.1.
* ECOG performance status 0-1.
* Participants must have adequate organ and marrow function as defined in the protocol.
* A negative pregnancy test for pre-menopausal women of childbearing potential.
* Pre-menopausal women of childbearing potential who are sexually active with a male partner must agree to use adequate contraception prior to the study, for the duration of study participation.
* Inclusion of minorities: patients of all races and ethnic groups who meet the above inclusion and below exclusion criteria are eligible for this trial.
* Stated willingness to comply with all study procedures and availability for the duration of the study.
* Ability to understand and the willingness to sign a written informed consent document or have a legally authorized representative sign on the participant's behalf.

Exclusion Criteria:

* Have previously received Fulvestrant for treatment of their breast cancer.
* History of allergic reactions attributed to the study drugs.
* Documented brain metastasis or active or newly diagnosed CNS metastases, including meningeal carcinomatosis, because systemic treatment would need to be paused for these patients.
* Treatment with any investigational compound within 30 days prior to the first dose of study drugs or during this study.
* Diagnosis or treatment for another systemic malignancy within 2 years before the first dose of study drugs, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
* Uncontrolled intercurrent illness including-but not limited to-ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term, including massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis.
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
* Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen \[HBsAg\]), or hepatitis C (HCV). Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants with positive HCV antibody are eligible if polymerase chain reaction is negative for HCV RNA.
* Concurrent or prior use of immunosuppressive medication within 14 days before the first dose of study drugs, with the following exceptions: premedication with dexamethasone, intranasal, inhaled, topical or local steroid injections, systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or its equivalent; steroids as premedication for hypersensitivity reactions (e.g., premedication for iodinated contrast allergy before CT scan).
* Inability to comply with protocol requirements.
* Pregnant and/or breastfeeding women are excluded.