Background: Almost 70% of early BC are endocrine responsive, as defined by estrogen receptor (ER) expression; however roughly 30% of ER+ BC patients will relapse despite adjuvant ET. Moreover, 10 to 20% of BC metastases lose ER expression. The upfront administration of ET in ER+ women with MBC is recommended by major guidelines. However, the early identification of endocrine resistance might improve systemic treatment options, sparing unnecessary toxicities and inactive drugs. 18F-FES, an oestradiol analogue labeled with 18F, may allow to test the performance of ERs, by testing their in vivo linkage ability. In MBC, 18F-FES uptake has been proposed to be a better predictor of response to ET than ER expression itself. The aim of the ET-FES study is to validate the predictive value of 18F-FES uptake at PET/CT scan in metastatic ER+ patients. Methods: This is aphase II, multicentric european comparative study of first line ET vs CT in ER+ MBC with low 18F- FES uptake. The primary endpoint is disease control rate (DCR). Correlative studies include: 1. Optimization of 18F-FES production; 2. Association between gene alterations in ESR1/ESR2 genes and 18F- FES uptake; 3. Development of a predictive score of endocrine responsiveness based on 18F-FES SUV value and clinical and biological information. All patients with ER+ MBC candidate to first line ET will receive a 18F-FES CT/PET at baseline, in addition to standard staging. Patients with 18F-FES uptake (SUV) > 2 will receive ET. Patients with 18F-FES SUV < 2 will be randomized to ET until disease progression (control arm) or CT (single agents) until PD. A total of 220 patients with ER+ MBC will be enrolled. Of these, approximately 50% (n=110) will show a 18F-FES SUV < 2 and will be randomized to ET or CT. The study will have 85% power to detect an absolute 20% difference in the DCR between arms after 3 months of therapy, assuming a 5% two-sided alpha level and a 10% drop-out rate. Current status: The ET-FES study was approved for funding by the ist Join TRANSCAN European call. 18F-FES production is currently on final development (GMP), and the clinical protocol is being finalized for EC approval in the different EU countries. Clinical trial information: 2013-000287-29.