Longitudinal Molecular Imaging of Progesterone Receptor Reveals Early Differential Response to Endocrine Therapy in Breast Cancer with an Activating ESR1 Mutation

Activating mutations in the estrogen receptor (ER) α-gene ( ) result in constitutive transcriptional activity in the absence of estrogen and are associated with endocrine resistance in metastatic ER-positive (+) breast cancer. It is not known how activating mutations may alter the predictive values of molecular imaging agents for endocrine therapy response. This study investigated the effect of an activating mutation on pretreatment F-fluoroestradiol ( F-FES) uptake and early assessment of endocrine therapy response using F-FDG and F-fluorofuranylnorprogesterone ( F-FFNP) PET/CT imaging of tumor glucose metabolism and progesterone receptor (PR) expression, respectively. ER+, PR+ T47D breast cancer cells expressing wild-type (WT) ER or an activating mutation, Y537S-ER, were used to generate tumor xenografts in ovariectomized female immunodeficient mice supplemented with 17β-estradiol. Tumor growth curves were determined in the presence or absence of estrogen and for ethanol vehicle control or fulvestrant treatment, a selective ER degrader. Pretreatment F-FES uptake was compared between Y537S-ER and WT-ER tumors. Longitudinal PET/CT imaging with F-FFNP and F-FDG was performed before and 7-9 d after the start of endocrine therapy with fulvestrant. Radiopharmaceutical uptake in Y537S-ER and WT-ER tumors was compared between baseline and follow-up scans. Statistical significance was determined using paired testing for longitudinal imaging and 2-way ANOVA for the F-FFNP tissue biodistribution assay. Y537S-ER xenografts showed estrogen-independent growth, whereas WT-ER tumors grew only with estrogen. Fulvestrant treatment for 28 d significantly reduced tumor volumes for WT-ER but only stabilized volumes for Y537S-ER. Baseline F-FES uptake did not significantly differ between WT-ER and Y537S-ER tumors. Fulvestrant treatment induced a similar early metabolic response for both WT-ER and Y537S-ER tumors. F-FFNP uptake in WT-ER tumors was significantly reduced after 7 d of fulvestrant treatment; however, this reduction did not occur in Y537S-ER tumors, which showed no significant change between baseline and follow-up PET/CT. Molecular imaging of PR expression dynamics could be a noninvasive approach for early identification of reduced effectiveness of endocrine therapy resulting from activating mutations.