Biology Guided Therapy Recommendations for Treatment Determination of Hormone Receptor-Positive Advanced, Unresectable or Metastatic Breast Cancer, ENDORSE Trial

Inclusion Criteria:

* Participant must speak English
* Documented informed consent of the participant and/or legally authorized representative.

  * Assent, when appropriate, will be obtained per institutional guidelines
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies

  * If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Age: ≥ 18 years
* Patients must have histologically confirmed, unresectable or metastatic hormone receptor positive, HER2 breast cancer. Hormone receptor positive is defined as estrogen receptor \>= 10% and/or progesterone receptor \>= 10%. Her2 negative per American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines
* Patient must have disease progression during or after prior endocrine therapy meeting one of the following criteria:

  * Disease progression on 1st line endocrine therapy for advanced/metastatic breast cancer.
  * Disease progression on or within 2 years of completion of treatment with a CDK4/6i in the adjuvant setting for early- stage breast cancer
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
* Patient must have at least one lesion amenable to percutaneous core
* Clinically appropriate for biopsy

Exclusion Criteria:

* Prior treatment in the metastatic setting with capecitabine, phosphoinositide 3 kinase (PI3K) inhibitor, mechanistic target of rapamycin (mTOR) inhibitor, protein kinase B (Akt) inhibitor, selective estrogen receptor degrader (SERD), or HER2-targeted therapy, including neratinib
* Known or untreated, or active, brain or leptomeningeal metastases that are deemed inappropriate to pursue therapy guided by systems medicine approach. Enrolled patients may receive radiation or other loco regional therapy prior to initiating systemic therapy on study. History of malignancies other than adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors not requiring active therapy
* Life expectancy \< 1 year
* Pregnant or breastfeeding
* Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures