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 18F-FDG PET can delineate the glucose avidity of tumors and metastatic lesions; however, these images cannot differentiate lymph node metastases from reactive lymphadenopathy. 16α-18F-fluoro-17β-estradiol (18F-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 18F-FES PET, and its accumulation correlated well with ER expression in tumor tissue (2–4). 18F-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. 18F-FES has a 6.3-fold absolute affinity preference for ERα over ERβ (5), which is important information to estimate the prognosis of ER-related malignancies.
18F-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 18F-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 18F-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 18F-FES PET for metastasis is not so sufficient. Furthermore, in the endometrial tissue of a normal uterus, substantial 18F-FES accumulation is observed in premenopausal women, and the intensity of accumulation varies according to menstrual cycle (7). Therefore, 18F-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 18F-FES PET in abdominal-to-pelvic scanning is excretion of the tracer to the intestine. The tracer shows high accumulation in the liver, where 18F-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 18F-FDG PET scans. During this waiting time, 18F-FES is metabolized and excreted into the intestine. Patients often show a strong intestinal accumulation of 18F-FES due to excretion of metabolites, which may sometimes prevent observation of abdominal and pelvic lesions. This 18F-FES accumulation in the abdomen and pelvic cavity has made it difficult to apply the useful tracer to gynecologic tumors. However, in previous 18F-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 18F-FDG and 18F-FES 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-11β-methoxy-16α-18F-fluoroestradiol (18F-4FMFES), has been developed as a homolog of 18F-FES and applied to diagnosis of breast cancer (11). Paquette et al. compared 18F-FES and 18F-4FMFES PET images directly in a phase II clinical trial study for breast cancer and found that SUVmax was similar and image quality was better with 18F-4FMFES PET than with 18F-FES PET. Because of the improved tumor-to-background ratio with the new tracer, the image contrast has been improved, compared with the conventional one. Therefore, the new tracer seemed to be promising for diagnosis of ER expression of breast cancer. They also applied 18F-4FMFES PET to endometrial cancer of the uterus and compared its diagnostic ability with that of 18F-FDG PET (12). After tumor biopsy, patients with ERα-positive endometrial cancer were enrolled in the study and underwent 18F-FDG and 18F-4FMFES PET within an interval of less than 2 wk. They compared the diagnostic performance between 18F-4FMFES and 18F-FDG PET. Since high-grade endometrial cancers tend to reduce or lose ERα expression (3,6), the diagnostic performance of 18F-FES or 18F-4FMFES PET alone is not expected to be superior to that of 18F-FDG PET. However, SUVs and diagnostic performance were preserved or surpassed in this study because only the ERα-positive cancers after tumor biopsy were enrolled. If PET scans are performed without tumor biopsy, the 18F-FDG/18F-4FMFES ratio would be the most sensitive parameter to determine the grade and prognostic value of the tumor (6,8,9,12). The investigators added an evaluation of the effects of loperamide or butylbromide administration before tracer administration to reduce tracer excretion to the intestine. In the study of gynecologic tumors, the intense abdominal uptake may affect the diagnosis of uterine tumors, including metastatic lesions. Allowing for a substantial fasting period before scanning may be a more effective and less invasive method for improving image quality than is administration of antimotility medicine. The timing of the scan should also be chosen appropriately according to the patient’s menstrual cycle so as to minimize normal endometrial uptake, which may impair discrimination between normal tissue and cancer. Since breast cancer and gynecologic tumors have different features, the study protocol should be determined in accordance with the tumor characteristics. 18F-4FMFES PET has shown good image quality in breast cancer studies and would be promising for uterine cancer or sarcoma studies with proper preparation and scanning protocols using PET/CT plus MRI or PET/MRI. Information on ERα expression is essential for application of hormonal therapy aimed at theranostics.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
Footnotes
Published online Oct. 14, 2021.
- © 2022 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication September 28, 2021.
- Revision received October 4, 2021.