ER Imaging for Estrogen-Related Tumors Is Bothersome but Useful

Recent developments in molecular imaging methods have greatly contributed to the field of clinical nuclear medicine in terms of personalized cancer therapy as well as appropriate diagnosis of various diseases. Theranostics, the combination of therapy and diagnosis, is now not just a concept but a fusion of biologic diagnosis and its therapeutic application aiming at the goal of molecular imaging in oncology. The basics of theranostics are to elucidate specific biologic events or phenomena using molecular probes developed by molecular imaging technology. Conventional methods of assessing glucose metabolism and perfusion can be used to delineate the features of alteration in energy metabolism and blood flow; however, these are the results of pathophysiologic alterations caused by various diseases. Because the targets of molecular imaging are disease-specific biomarkers and phenotypic changes, the images delineate pathologic features of the disease. Imaging of amyloid and tau for diagnosis of Alzheimer disease is a good example of molecular imaging for pathogenic substances. Prostate-specific membrane antigen imaging and nuclear medicine therapy, a representative example of radiotheranostics, is now available in many hospitals and cancer centers for treatment of prostate cancer. Estrogen receptor (ER) imaging, used for breast cancer and uterine tumors, is also a good example of molecular imaging that can well delineate features of cancers. In breast cancer studies, ER expression in cancer is important information not only for diagnosis but also for determining the suitability of hormone therapy (1). Conventional CT and MRI diagnosis can detect the size of lymph nodes, and F-FDG PET can delineate the glucose avidity of tumors and metastatic lesions; however, these images cannot differentiate lymph node metastases from reactive lymphadenopathy. 16a-Ffluoro-17b-estradiol (F-FES) is a representative PET ligand for ER imaging and has been applied for decades in the diagnosis of breast cancers (2). Many studies have shown the usefulness of F-FES PET, and its accumulation correlated well with ER expression in tumor tissue (2–4). F-FES accumulation in enlarged lymph nodes indicates the presence of ER, that is, metastatic lesions from an ER-positive breast cancer, which improves the diagnostic ability in terms of staging of breast cancer. F-FES has a 6.3-fold absolute affinity preference for ERa over ERb (5), which is important information to estimate the prognosis of ER-related malignancies. F-FES PET is also useful in diagnosis of uterine tumors such as endometrial cancer and leiomyosarcomas (4,6). Previous studies have shown its beneficial application for differential diagnosis and for prediction of prognosis (3,4,6). Since F-FES accumulation correlates well with ER expression in endometrial cancer and sarcoma (3,4), SUVs can detect ER density in tumors. However, ER expression tends to be decreased in malignant tumors (4,6), and accumulation of F-FES alone cannot improve the ability to diagnose malignancy because negative accumulation cannot distinguish between normal tissue and high-grade malignancy. Since this tendency is the same as for metastatic lesions, the diagnostic ability of F-FES PET for metastasis is not so sufficient. Furthermore, in the endometrial tissue of a normal uterus, substantial F-FES accumulation is observed in premenopausal women, and the intensity of accumulation varies according to menstrual cycle (7). Therefore, F-FES PET scans in premenopausal patients should be performed during the secretory phase of the menstrual cycle to minimize the effect of normal endometrial uptake (8). Another problem with FFES PET in abdominal-to-pelvic scanning is excretion of the tracer to the intestine. The tracer shows high accumulation in the liver, where F-FES is metabolized and excreted into the bile ducts. PET scans are usually performed about 60 min after the tracer injection, as is the case with F-FDG PET scans. During this waiting time, F-FES is metabolized and excreted into the intestine. Patients often show a strong intestinal accumulation of F-FES due to excretion of metabolites, which may sometimes prevent observation of abdominal and pelvic lesions. This F-FES accumulation in the abdomen and pelvic cavity has made it difficult to apply the useful tracer to gynecologic tumors. However, in previous F-FES PET studies for these tumors, scans were performed after a substantial fasting time, and clear images were obtained in the pelvic regions (3,4,6,8). The combination of F-FDG and FFES PET can provide useful information for evaluation of prognosis (8,9). In clinical practice, additional MR scanning is essential to delineate features of the primary tumor (10), because it is difficult to make a correct radiologic diagnosis of gynecologic tumors on the basis of PET/CT findings alone. To improve image quality and contrast for assessment of ER expression, a new PET ligand, 4-fluoro-11b-methoxy-16a-F-fluoroestradiol (F-4FMFES), has been developed as a homolog of F-FES and applied to diagnosis of breast cancer (11). Paquette Received Sep. 28, 2021; revision accepted Oct. 4, 2021. For correspondence or reprints, contact Hidehiko Okazawa (okazawa@ u-fukui.ac.jp). Published online Oct. 14, 2021. COPYRIGHT 2022 by the Society of Nuclear Medicine andMolecular Imaging. DOI: 10.2967/jnumed.121. 263170