The goal of this research study is to determine if the investigators can predict which participants will respond to endocrine therapy and a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor for metastatic breast cancer and which participants will not. Investigators will use information from the tumor tissue and serial blood samples. Investigators hope that a deeper understanding of which participants will respond to this combination and how resistance emerges will allow the investigators to better tailor therapies for metastatic breast cancer.

Subjects will have archived tissue or new biopsy collected at study enrollment. This tissue will undergo special molecular testing. Subjects will also have blood collected at study enrollment and periodically thereafter. This blood will also undergo special molecular testing. Information from this testing will not be available to subjects or their treating physicians as the investigators do not know how this information should impact treatment.

The investigators will collect information about which treatment the subjects receive and how their cancer responds.

Any man or woman being seen at Johns Hopkins for treatment of newly diagnosed estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) metastatic breast cancer may be eligible.

Resistance to endocrine therapy (ET) invariably develops in patients with estrogen and/or progesterone receptor (ER/ PR) positive metastatic breast cancer (MBC). Data regarding primary resistance and patterns of emergence of acquired resistance in patients treated with endocrine therapy (ET) and cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors are limited. Understanding these mechanisms could result in improved selection of treatment options and provide new targets for therapy development. In this study, we aim to identify and characterize determinants of intrinsic and acquired resistance to endocrine therapy in patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative MBC treated with the combination of endocrine therapy (aromatase inhibitor or fulvestrant) and a CDK4/6 inhibitor.

Investigators will determine the prevalence of genomic alterations at baseline in the primary tumor, metastatic tissue and plasma tumor DNA (ptDNA), including in the gene encoding estrogen receptor- alpha (ESR1). The mutational tumor burden in the primary tumor, metastatic tumor and blood will be assessed. Blood samples will be collected at several time points, allowing the detection of changes in molecular markers over time. We will further characterize tissue markers associated with progression and duration of response by evaluating these markers in available tissue obtained at progression. Investigators goal is to evaluate the prevalence and role of known alterations determining endocrine resistance in patients with metastatic disease, as knowledge regarding this population remains limited.The investigators also hope to unveil novel markers of endocrine resistance.

Inclusion Criteria:

• Male or Female
• 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Metastatic (stage IV) breast cancer or locally advanced breast cancer
• Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive, HER2- negative
• Treatment naïve in metastatic or locally advanced setting and planning to undergo treatment with endocrine therapy (ET) and palbociclib OR receiving first-line ET and palbociclib for metastatic or locally advanced disease.
• Premenopausal women and men must be treated with concurrent luteinizing hormone-releasing hormone (LHRH) agonist as would be standard-of-care.
• Evaluable or measurable disease.
• Tissue from a metastatic site must be available within past 6 months prior to therapy initiation.
• Ability to give voluntary informed consent

Exclusion Criteria:

• Any pregnant or nursing woman
• No history of another primary malignancy within past 5 years. Patients with prior history of in situ cancer or basal or localized squamous cell skin cancer are eligible.