This clinical trial examines an investigational scan (64Cu-DOTA-trastuzumab positron emission tomography [PET]/magnetic resonance imaging [MRI]) in imaging patients with HER2+ breast cancer that has spread to the brain (brain metastasis). Diagnostic procedures, such as 64Cu-DOTA-trastuzumab PET/MRI, may help find HER2+ breast cancer that has spread to the brain and determine whether cancer in the brain takes up trastuzumab, which may predict for response to trastuzumab deruxtecan (the standard of care chemotherapy).

PRIMARY OBJECTIVES:

I. Evaluate the feasibility of 64Cu-DOTA-trastuzumab PET imaging in patients with HER2+ breast cancer metastatic to the brain.

II. Evaluate if HER2+ breast cancer patients with brain metastasis who are responders to fam-trastuzumab deruxtecan have higher maximum standardized uptake value (SUVmax) (minimum over all lesions in the brain) than non-responders.

SECONDARY OBJECTIVE:

I. Evaluate if the minimum SUVmax of all quantifiable lesions in a given patient is associated with time to progression in the brain.

OUTLINE:

Patients receive trastuzumab intravenously (IV) over 15 minutes on day 0. Patients then receive 64Cu-DOTA-trastuzumab IV and then undergo PET/MRI scan on day 1. Patients undergo repeat brain MRI every 6 weeks for 24 weeks and then every 9 weeks until disease progression. Patients then receive trastuzumab deruxtecan IV every 21 days in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative
• Women with documented metastatic HER2 positive breast cancer (American Society of Clinical Oncology [ASCO] College of American Pathologist [CAP] guidelines) who have brain metastases
• Age > 18 years
• Eastern Cooperative Oncology Group (ECOG) 0-2
• Patients with leptomeningeal disease will be considered eligible
• Planned therapy with fam-trastuzumab deruxtecan
• Left ventricular ejection fraction (LVEF) > 50%
• Absolute neutrophil count (ANC) > 1.5 x 10^9/L
• Platelets > 100 x 10^9/L
• Hemoglobin > 9 g/dL
• Total (T.) bilirubin < 3 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN
• Creatinine clearance > 30 ml/min (by Cockcroft-Gault formula)
• Activated partial thromboplastin time (aPTT) < 1.5 x ULN
• Prior therapy for central nervous system (CNS) disease is allowed, but at least 1 lesion > 1.5 cm is evident on MRI

Exclusion Criteria:

• Need for immediate local intervention for brain metastases
• Noninfectious interstitial lung disease or pneumonitis requiring glucocorticoids
• Clinically significant corneal disease
• Myocardial infarction < 6 months before, congestive heart failure (CHF), unstable angina, or serious cardiac arrhythmia