Early prediction of endocrine responsiveness in ER+/HER2 negative MBC: Pilot study with 18F-fluoroestradiol (18F-FES) CT/PET.
Authors: Gennari Alessandra , Brain Etienne , De Censi Andrea , Nanni Oriana , Wuerstlein Rachel , Frassoldati Antonio , Cortes Javier , Rossi Valentina , Palleschi Michela , Alberini Jean-Louis , Matteucci Federica , Piccardo Arnoldo , Sacchetti Gian Mauro , Ilhan Harun , Ruffilli Beatrice , Nardin Simone , Monti Manuela , Puntoni Matteo , Boni Luca , Harbeck Nadia 
Published: June 2023

1024 Background: Estrogen receptors (ER) are considered predictive biomarkers to identify ER+ MBC patients who would likely benefit from endocrine therapies (ET). However, 30 to 40% of ER+ MBC patients fail to achieve a durable response. 18F-FES PET/CT has been shown to represent a valuable and accurate diagnostic tool to determine ER status at the level of metastatic sites and can be proposed as a valid alternative to biopsy of metastatic lesions. In this trial, we evaluated 18F-FES PET/CT as a predictive tool for endocrine responsiveness in ER+ MBC. Methods: ET-FES is an international, multicenter, academic clinical trial, conducted within the JTC-2011 ERA-NET TRANSCAN programme. Patients with ER+/HER2- MBC and first evidence of relapse were eligible for the study. All patients underwent a baseline 18F-FES PET/CT in addition to conventional staging procedures. Tumors were classified as endocrine sensitive if overall Standardized Uptake Value (SUV) ≥ 2; SUVmax was measured in the 3 largest lesions to quantify ER expression and a cutoff value of 2 was used to dichotomize results (endocrine sensitive vs resistant). In the ET-FES trial, patients with SUV ≥ 2 received single agent ET until PD; patients with SUV < 2 were randomized to receive single agent ET or chemotherapy (CT). The predictive role of 18F-FES PET/CT results was assessed for PFS and OS by univariate and multivariate analyses. Results: Overall, 147 patients (142 for ITT analysis) were enrolled from 04/2015 to 12/2020; 113 presented with 18F-FES SUV ≥ 2 and received ET; 29 pts, with SUV < 2 were randomly assigned to ET or first line chemotherapy (CT), following local clinical practice. After a median follow up of 4.6 years, 51 deaths had occurred (54.2%). Median PFS was 18,0 months (95%CI 11,2- 22,9) in the overall population and in 18F-FES SUV ≥ 2 versus 12,4 months (95%CI 3,1 – NR) in patients with SUV <2 treated with ET and 23.0 months (95%CI 7,7 – 30,0) if treated with CT. Median OS was not reached in the overall patient population and in patients with SUV ≥2, treated with single agent ET. Median OS was 28.1 months (95%CI 14,2 – NR) in patients with SUV <2 treated with ET versus 52,8 months (95%CI 16,1 – NR) if treated with CT. The Kaplan–Meier estimate of OS at 48 months was 64.4% (SE +/-5%) in all patients and 66% in 18F-FES SUV ≥ 2; at 60 months was 54.4% (SE +/-6%) and 57% (SE +/-5%), respectively. Among the 113 pts with SUV ≥ 2 treated with ET, the Kaplan–Meier estimate of OS at 60 months was 73.0% if treated with aromatase inhibitors versus 35% in case of fulvestrant or tamoxifen (p< 0.0005). Conclusions: ET-FES is the first prospective trial to assess the efficacy of ET alone in patients selected for endocrine responsiveness on the basis of whole body molecular ER imaging by 18F-FES PET/CT. These results suggest that the efficacy of ET may be maximized by using the appropriate assessment of endocrine responsiveness at the different metastatic sites. Clinical trial information: EUDRACT 2013-000-287-29 .