[18F] Fluoroestradiol (FES) PET as a Predictive Measure for Endocrine Therapy in Patients With Newly Diagnosed Metastatic Breast Cancer

• Capable and willing to provide informed consent

• Women must not be pregnant or breast-feeding. All females of childbearing potential must have a blood test or urine study within 7 days prior to FES PET/CT scan and \[18F\]-fluorodeoxyglucose (FDG)-PET/CT scan to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:

‣ Has not undergone a hysterectomy or bilateral oophorectomy or

⁃ Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Women of childbearing potential and sexually active males must use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study

• Patient is a postmenopausal woman, man, or premenopausal woman for whom standard endocrine therapy alone (tamoxifen, aromatase inhibitor \[AI\], with or without ovarian suppression or fulvestrant) is planned after FES-PET/CT is completed

• Medically stable as judged by patient's physician

• Life expectancy must be estimated by patient's physician at \> 6 months

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 (restricted to ECOG performance status \[PS\] 0-2 if age \> 70 years)

• Patient must NOT have a history of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-FES

• Patient must NOT be in liver failure as judged by the patient's physician

• Histologically confirmed metastatic breast cancer

• Primary tumor and/or metastatic site must be ER+ and may be progesterone-receptor positive (PgR+) or progesterone-receptor negative (PgR-) by IHC; patients with a history of an estrogen-receptor negative (ER-) primary tumor and a documented ER+ metastatic site are eligible

• The pathology report and either (1) tissue (blocks or an unstained slides) or (2) a photomicrograph of the ER IHC slides from at least one site of metastatic disease and/or from primary breast cancer must be available for central review and analysis

‣ NOTE: if photomicrographs are submitted, the submission of hematoxylin and eosin (H\&E), PR and Ki67 IHC's, if performed, are also to be submitted

• Patient must NOT have human epidermal growth factor-2 positive (HER2+) metastatic disease

• Patient must NOT be planning to receive molecular targeted therapy (such as everolimus or palbociclib) nor HER2 directed therapy in addition to endocrine therapy

• Patient must NOT have received prior endocrine therapy for metastatic disease (i.e., must be first-line endocrine therapy for metastatic disease)

• Patient is not now, and never has received adjuvant endocrine therapy OR patient is currently receiving or has received adjuvant endocrine therapy in the past, AND adjuvant endocrine therapy was initiated \> 2 years prior to diagnosis of metastatic disease

‣ Note: patients who developed metastatic disease while still receiving adjuvant endocrine therapy must have a planned change in the type of endocrine agent used for subsequent metastatic disease treatment; patient is not receiving blocking adjuvant therapy (such as toremifene or tamoxifen) OR patient is receiving blocking adjuvant therapy, but will stop this therapy a minimum of 60 days prior to FES-PET/CT while still complying with the study timeline

• Patient must NOT have a history of \> 1 line of administered chemotherapy for metastatic disease and must be off chemotherapy for a minimum of 2 weeks; prior chemotherapy in the adjuvant setting is allowed

• Disease may be measurable (by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria) or non-measurable but must be present in at least one non-liver site, where presence is defined as 1.5 cm or greater and visualized on PET/CT with \[18F\]-fluorodeoxyglucose (FDG); patients with effusion only disease or disease only in the liver are not eligible for the study

• Patient must be able to lie still for a 20-30 minute PET/CT scan

• Patient must NOT weigh more than the maximum weight limit for the table for the PET/CT scanner at the institution where the study is being performed

• The patient is participating in the trial at an institution which has agreed to perform the imaging research studies, completed the ECOG-American College of Radiology Imaging Network (ACRIN) defined scanner qualification procedures and received ECOG-ACRIN (or current ACRIN) approval