Estrogen receptor(ER) is a vital biomarker in the development and development of breast cancer, and its status has great clinical value in clinical treatment strategy, endocrine therapy efficacy prediction, and breast cancer prognosis. By specifically combining
18F-FES with ER,
18F-FES PET/CT imaging uses standard uptake value(SUV) to semi-quantitatively reflect the distribution of ER and its biological activity in patients, and assesses the expression of ER in breast cancer patients about primary and metastases before or after treatment, to provide a basis for personalized treatment of breast cancer. In this review, we will review the imaging principles of a new ER detection method
18F-FES PET/CT, and the research progress in the clinical application of breast cancer, and compare its diagnostic and treatment value with non-specific tumor imaging
18F-FDG PET/CT in breast cancer.
<sup>18</sup>F-FES <sup>18</sup>F-FDG PET/CT Breast Cancer ER1. Introduction
Breast cancer is the most common cancer in women. According to the statistics of the World Health Organization, among the global new tumor cases in 2020, the number of breast cancer cases is 2.26 million, accounting for 11.7% of the total number of new tumors in the world. It has surpassed lung cancer (11.4%) to become the malignant tumor with the highest incidence in women [1] . Breast cancer is a hormone-dependent tumor. About 70% of breast cancer patients are positive for ER [2] . The treatments for breast cancer include surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, etc., among which endocrine therapy is widely used because of its definite curative effect, low toxicity and low price [3] . According to the guidelines and norms for breast cancer diagnosis and treatment of China Anti-Cancer Association (2021), breast cancer patients with positive ER and/or progesterone receptor (PR) should receive postoperative adjuvant endocrine therapy. So most breast cancer patients in China need endocrine therapy [4] . In terms of molecular mechanism, the expression activity of ER can regulate the expression of PR, and the endocrine therapeutic drugs used in clinic also take ER as the main therapeutic target [5] . Therefore, the expression status and expression rate of ER have become the most important factors affecting the efficacy of endocrine therapy for breast cancer. Thus it can be seen that the detection method and accuracy of ER are very important.
At present, the routine method of ER detection is puncture biopsy and immunohistochemistry (IHC). Its advantage is that a single biopsy can obtain multiple molecular phenotypes and provide multiple supporting information for treatment decision-making, but it also has some limitations: 1) Breast cancer is heterogeneous. About 20% to 35% of patients with metastatic breast cancer have phenotypic changes [6] . The puncture results can only reflect the pathological condition of a single lesion. 2) During the treatment, the epitope may be lost in the focus [7] . Therefore, it is necessary to dynamically evaluate the expression of ER, but it is difficult to achieve repeated biopsy in clinic. 3) Puncture biopsy is an invasive examination method, the tolerance of patients is poor, and affected by the location and size of the focus, it may be difficult to biopsy. 4) There may be some deviation in reflecting the true pathophysiological state of the focus due to sampling error, decalcification treatment and other factors. Therefore, we urgently need a new detection method to evaluate the expression of ER in patients more accurately, omni-directionally and dynamically. This article will describe the imaging principle of the new non-invasive ER detection method 18F-FESPET/CT, and focus on its research progress in the diagnosis and treatment of breast cancer, and compare the value of 18F-FESPET/CT and 18F-FDGPET/CT in the diagnosis and treatment of breast cancer.
2. Imaging Principle of <sup>18</sup>F-FES PET/CT
18F-FES is an estrogenic derivative, which is obtained by replacing the 16 α H of estradiol with 18F. Fluorine is a small halogen, and its spatial structure and chemical properties will not be significantly changed after replacing H, so 18F-FES has structural characteristics similar to estrogen and can specifically bind to ER. The metabolism and excretion pathway of 18F-FES is also similar to that of estrogen. After being injected into the body, it is quickly absorbed by the liver and metabolized in a short time. The blood clearance rate is fast, about the stable level of 20 min - 30 min, and the background is basically stable after 30 min. The metabolites in the blood circulation cannot be combined with ER directly or indirectly, so it has little interference to the imaging. Metabolites are mainly eliminated through the kidney, some of them can enter the intestine with bile, excreted from feces, and a small amount can be reabsorbed through hepatointestinal circulation. Therefore, its physiological uptake is mainly concentrated in the liver, kidney, bladder and intestinal tract [2] [8] . Radiation dose studies show that the organ dose of 18F-FES PET is similar to that of other commonly used nuclear studies, and the potential radiation risk is within an acceptable range. The recommended injection dose is 6 mci or less [9] [10] .
3. Research Progress of <sup>18</sup>F-FES PET/CT in Clinical Application of Breast Cancer
At present, 18F-FES is the most widely used ER targeting probe. Non-invasive detection of ER expression in the whole body can be realized by 18F-FES PET/CT, which provides a new basis for diagnosis, staging and curative effect prediction of breast cancer, and brings epoch-making significance for endocrine therapy of breast cancer [11] .
3.1. The Value of <sup>18</sup>F-FES PET/CT in the Diagnosis of Breast Cancer
18F-FES is a specific tracer for ER, while ER is highly expressed in 70% invasive breast cancer. Therefore, we can diagnose breast cancer by detecting ER [12] . In 2019, Sun Young Chae et al. verified the accuracy and safety of 18F-FES PET/CT in evaluating the status of estrogen receptor in recurrent or metastatic breast cancer [13] . In 2021, Jin A Mo statistically analyzed the data of 7 studies. The comprehensive sensitivity and specificity of 18F-FES PET in the diagnosis of ER+ breast cancer were 0.86 and 0.85 respectively [14] . As for false negative patients, they are usually patients with low expression of ER [13] . In this part of patients, due to the low expression of ER in the lesions, the radioactive intensity produced by binding with 18F-FES will be lower, so false negative can be seen in 18F-FES PET/CT imaging. It also shows that IHC is more sensitive than 18F-FES PET/CT in detecting ER. Although the pathophysiological status of patients with low expression of ER is similar to that of patients with negative ER, endocrine therapy is still recommended [4] . Therefore, there may be blind spots in these patients with 18F-FES PET/CT. The false positive patients account for relatively few benign lesions, such as breast fibroadenoma [15] . And as a specific imaging agent, 18F-FES imaging can help identify the second primary tumor [16] [17] . And guide the treatment plan [18] . It is worth mentioning that 18F-FES is a specific imaging agent for ER rather than breast cancer, so other estrogen-dependent tumors such as endometrial cancer and ovarian cancer should be excluded when used in breast cancer [19] [20] . Generally speaking, 18F-FES PET/CT is a safe and reliable non-invasive in vivo ER detection method, which can provide omni-directional information about the distribution, density and activity of ER+ cancer cells in breast cancer foci. It is expected to fully reflect the expression of ER in breast cancer patients and provide help for the formulation of clinical individualized treatment. However, this imaging cannot recognize and distinguish ER− breast cancer and ER+ benign lesions, so there are still some shortcomings in the diagnosis of breast space occupying lesions alone.
3.2. Prediction of Therapeutic Effect of <sup>18</sup>F-FES PET/CT on Endocrine Therapy for Breast Cancer
The prediction of curative effect and the evaluation of prognosis are the key factors in deciding the treatment plan in clinical treatment, and the expression of ER is undoubtedly an important predictor for endocrine therapy of breast cancer. Therefore, as a targeted probe of ER, 18F-FES PET/CT plays an important role in predicting the efficacy and prognosis of endocrine therapy for breast cancer. For patients with high expression of ER, endocrine therapy is often effective [21] . The high expression of ER on 18F-FES PET/CT is mainly reflected by the increased radiouptake, that is, the SUVmax value of the foci. Therefore, we can predict the efficacy and prognosis of endocrine therapy by the SUVmax value of early 18F-FES PET/CT imaging in patients [22] [23] . ER is not only the main target of endocrine therapy, but also the marker of hormone-dependent tumor cells. When the drug takes effect, it can lead to the decrease of physiological activity ER, so we can also compare the change of SUVmax value between baseline scan and treatment for a short time, that is, ΔSUVmax, to achieve the role of early efficacy evaluation and prognosis evaluation [24] . In addition to endocrine therapy, some scholars have also explored the role of 18F-FES PET/CT in predicting the efficacy of neoadjuvant chemotherapy. Although 18F-FESPET/CT is not directly related to the prediction of the efficacy of neoadjuvant chemotherapy, the results show that, contrary to endocrine therapy, patients with lower 18F-FES SUVmax are more likely to benefit from neoadjuvant chemotherapy [25] . The study also found that patients with positive pathological ER but negative 18F-FES PET/CT imaging were more likely to benefit from neoadjuvant chemotherapy than neoadjuvant endocrine therapy [26] . In other words, the effect of endocrine therapy in patients with low expression of ER is not as effective as that of adjuvant chemotherapy, which is consistent with previous studies. However, 18F-FES PET/CT is not perfect, it cannot identify mutant ER, and gene mutation may cause endocrine drug resistance [27] [28] [29] .
3.3. <sup>18</sup>F-FES PET/CT as a Pharmacodynamic Biomarker of Endocrine Therapy for Breast Cancer
ER is the main target of endocrine therapy for breast cancer. As a targeted probe of ER, 18F-FES PET/CT plays an auxiliary role in the research and development of drugs targeting ER. First of all, for ER antagonists, when the drug acts on the focus, it can lead to the decrease of ER with physiologically active function, the metabolic activity decreases and the SUVmax value decreases on 18F-FES PET/CT. Therefore, the time, intensity and scope of action of the drug can be directly reflected by 18F-FESPET/CT [30] . Through the imaging of patients taking different doses of drugs, we can select the best treatment dose of drugs, so that patients can achieve the best treatment effect while minimizing the side effects caused by excessive drugs. For other types of agents, such as aromatase inhibitors and cyclin inhibitors, the drugs do not act directly on ER, so they cannot achieve the effect of immediate imaging, but when the drugs take effect for a period of time, the pathophysiological changes of tumor cells can also be shown in 18F-FES PET/CT. In summary, 18F-FESPET imaging can be used as a biomarker of pharmacodynamics of ER-oriented drugs, which can show the performance of drugs reaching the target or taking effect in time, and provide an important basis for drug research and development, testing of the optimal therapeutic dose and duration of drug action [3] [30] .
3.4. Effect of <sup>18</sup>F-FESPET/CT on Treatment Decision of Breast Cancer
The most important way to measure the clinical value of an examination lies in its impact on treatment decision-making. The main reasons for the influence of 18F-FES PET/CT on treatment decision-making are: 1) reflecting the heterogeneity of lesions [31] . Heterogeneity of estrogen receptor expression in about 10% of 20% of breast cancer patients [32] . 18F-FES PET/CT can reflect the expression of ER in patients with systemic lesions, so it can identify the heterogeneity of lesions, and the visual contrast effect is more obvious when combined with 18F-FDG PET/CT imaging. Studies have shown that endocrine therapy is effective in patients with ER+, but not in patients with heterogeneity, and the effect is inversely proportional to the level of heterogeneity [32] [33] . Therefore, for patients with heterogeneity, the effect of single endocrine therapy is often not good. When 18F-FES PET/CT finds the heterogeneity of patients’ lesions, adjuvant chemotherapy can be recommended. 2) the effect on tumor staging of patients. Some studies have shown that 18F-FESPET/CT is more sensitive than 18F-FDG PET/CT for breast cancer lesions and can find more metastatic foci, so it can have a certain impact on the staging of the disease, thus further affecting the treatment plan [34] [35] . Generally speaking, the influence of 18F-FES PET/CT on breast cancer treatment decision-making mainly comes from the identification of lesion heterogeneity and the influence on clinical stage.
4. Comparative Study on the Value of <sup>18</sup>F-FES PET/CT and <sup>18</sup>F-FDG PET/CT in the Diagnosis and Treatment of Breast Cancer
PET/CT is a new imaging technique which integrates anatomical imaging and functional imaging. It has been widely used in all kinds of tumor and non-tumor imaging. The commonly used tumor non-specific tracer is 18F-FDG, which plays an important role in the diagnosis, clinical staging, guiding treatment and evaluating the curative effect of breast cancer [36] . As a specific tracer of ER, 18F-FES may be comparable to or even better than 18F-FDG in the diagnosis and treatment of breast cancer.
4.1. A Comparative Study of Diagnostic Efficiency
In previous studies, the comparative study of 18F-FES and 18F-FDG in the diagnosis of breast cancer is still controversial. Some studies have shown that 18F-FES, as a specific tracer targeting ER, is more sensitive and can detect more lesions [34] [35] . Other studies have shown that the diagnostic efficacy of 18F-FES and 18F-FDG in breast cancer is almost the same, even slightly lower than that of 18F-FDG [37] . According to the comprehensive analysis, the main reason is that 18F-FES reflects the expression of ER, while 18F-FDG reflects the level of glycolysis. When ER expression is high, 18F-FES imaging is easier to find some subtle lesions, while when ER expression is low, it is close to 18F-FDG, even due to the existence of tumor heterogeneity, only part of ER+ lesions are shown. For some subtypes of breast cancer, such as lobular adenocarcinoma, the level of glycolysis is low and the effect of 18F-FDG imaging is poor, while 18F-FES imaging shows relatively obvious advantages [38] . Therefore, the diagnostic efficacy of 18F-FES and 18F-FDG in breast cancer is affected by many factors and cannot be generalized. Therefore, we can try to combine the two and learn from each other’s strengths to offset our weaknesses. For example, the physiological uptake of 18F-FDG in the head is higher, while the uptake of 18F-FES in the liver is extremely high, so the combination of the two can make up for their respective defects [39] [40] [41] . And due to the existence of ER-negative lesions, the information of 18F-FESPET/CT imaging alone is limited, so it may be an inevitable trend to combine 18F-FDGPET/CT at the first examination.
4.2. A Comparative Study on the Prediction of Curative Effect
Different imaging agents have different basis for predicting the prognosis of the disease. 18F-FES imaging reflects the expression of ER in the lesions, and the expression of ER can predict the effect of endocrine therapy. If it is high expression, the 18F-FES uptake will increase, indicating that the effect of endocrine therapy and prognosis of patients are good. 18F-FDG imaging can reflect the invasiveness of the tumor, and the 18F-FDG uptake is increased, indicating that the tumor has strong invasiveness and poor prognosis. However, studies have shown that patients with high 18F-FDG uptake can also have high 18F-FES uptake, and for these patients, progression-free survival is longer than those with high 18F-FDG uptake and low 18F-FES uptake [42] . To sum up, we can find that 18F-FES and 18F-FDG have different angles to evaluate the prognosis. 18F-FDG imaging reflects the invasiveness of the tumor, which is a comprehensive situation, while 18F-FES imaging predicts the effect of a single treatment (endocrine therapy), and the two evaluation angles are completely different. Therefore, in clinical practice, we should choose the corresponding examination scheme according to the actual needs, especially for patients with recurrent and metastatic breast cancer and multiple metastatic foci, it is of irreplaceable value to evaluate the expression of ER by 18F-FESPET/CT before endocrine therapy.
5. Summary and Prospect
At present, the effective rate of endocrine therapy for breast cancer is far from perfect, and 18F-FES PET/CT imaging, which is closely related to endocrine therapy, has become hot for a while [43] [44] . A large number of studies have shown that 18F-FES uptake is closely related to the pathological results of ER expression, which can be used to evaluate the systemic ER expression of patients. Based on this principle, 18F-FES imaging can be used in breast cancer diagnosis, efficacy evaluation, prognosis evaluation, drug development and other, and has achieved good performance in clinical trials [45] . In addition, 18F-FES imaging has unique advantages: reflecting the heterogeneity of lesions, so it is more in line with the needs of personalized treatment. With the research and application of 18F-FES PET/CT imaging, it is expected to break through the bottleneck of endocrine therapy for breast cancer. However, with regard to the specific clinical application of 18F-FESPET/CT imaging, there is no relevant guide recommendation and expert consensus, which may need to be studied and promoted on a larger scale.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
Cite this paper
He, J.H. and Pang, H. (2024) 18F-FES PET/CT Research Progress in the Diagnosis and Treatment of Breast Cancer. Journal of Biosciences and Medicines, 12, 105-114. https://doi.org/10.4236/jbm.2024.121010
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