Patient description: The patient is a 42 year-old postmenopausal woman who had a screening sonogram which revealed an abnormality in the right breast. She had no palpable masses on breast exam. Core biopsy was done and revealed a 1.8 cm infiltrating ductal breast carcinoma in the left upper outer quadrant. Lumpectomy was done and the surgical margins were clear. The tumor was HER2-positive and ER/PR negative. Axillary sampling revealed 1 positive lymph node out of 12 sampled. CXR was unremarkable. She is using “well women” multivitamins daily and no other medication. She smokes frequently and consumes alcohol occasionally. She is in a relation with only one partner and has a history of 3 pregnancies and live births. She breastfed all three children.

Clinical trial eligibility criteria: eligible ages (years): 18.0-999.0,  Advanced Breast Carcinoma Locally Advanced Breast Carcinoma Metastatic Breast Carcinoma Recurrent Breast Carcinoma Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Stage IV Breast Cancer AJCC v6 and v7 PRE-REGISTRATION Women who have disease that is amenable to biopsy and agree to undergo a standard of care and /or research biopsy Note: If a standard of care biopsy was recently obtained =< 2 months of pre-registration, eligible patients should agree to a research biopsy of recurrent or metastatic breast cancer prior to the start of protocol treatment to collect additional core samples for research purposes Patients must satisfy one of the following for prior therapy First line setting: No prior endocrine therapy in the metastatic setting with no more than one prior line of chemotherapy in the advanced/metastatic setting Second line setting: Progression on one prior line of endocrine based therapy monotherapy either in the adjuvant or advanced/metastatic setting; either one or two prior lines of chemotherapy in the advanced setting are allowed Note: Patients receiving bisphosphonate or denosumab therapy prior to registration may continue at the same intervals used prior to study registration First line therapy setting only: The intention to begin palbociclib and letrozole as treatment for locally advanced or metastatic breast cancer Second line therapy setting only: The intention to begin palbociclib and fulvestrant as treatment for metastatic breast cancer (after progression on first line endocrine therapy) Note: Patients who are to receive second line endocrine therapy are allowed to remain on their most recent treatment (tamoxifen or an aromatase inhibitor during the pre-registration period as well as after registration while awaiting insurance approval for the use of palbociclib  PRE-REGISTRATION History of metastatic ER negative or HER2 positive breast cancer Prior treatment in the metastatic setting with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway Uncontrolled intercurrent illness including, but not limited to Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Uncontrolled symptomatic cardiac arrhythmia Uncontrolled hypertension (defined as blood pressure > 160/90) Other active second malignancy other than non-melanoma skin cancers =< 3 years of pre-registration; Note: a second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for =< 3 years prior to pre-registration