Kumar M, Salem K, Jeffery JJ, et al. - In breast cancer, how an activating ESR1 [estrogen receptor (ER) α-gene] mutation can impact pretreatment ¹⁸ F-fluoroestradiol ( ¹⁸ F-FES) uptake as well as early evaluation of endocrine therapy response employing ¹⁸ F-FDG and ¹⁸ F-fluorofuranylnorprogesterone ( ¹⁸ F-FFNP) PET/CT imaging of tumor glucose metabolism and progesterone receptor (PR) expression, respectively was assessed here. Tumor xenografts were generated in ovariectomized female immunodeficient mice supplemented with 17β-estradiol by using ER+, PR+ T47D breast cancer cells expressing wild-type (WT) ER or an activating ESR1 mutation, Y537S-ER. Estrogen-independent growth was demonstrated by Y537S-ER xenografts, whereas growth of WT-ER tumors was evident only with estrogen. A significant decrease in tumor volumes for WT-ER was brought about by fulvestrant treatment for 28 days, whereas this treatment only stabilized volumes for Y537S-ER. There was no significant difference in baseline ¹⁸ F-FES uptake between WT-ER and Y537S-ER tumors. Based on this study’s findings, experts suggest the likely utility of molecular imaging of PR expression dynamics as a noninvasive approach for early detection of decreased effectiveness of endocrine therapy resulting from activating ESR1 mutations.