Comparative study between 18-F FDG PET/CT and 18-F FES PET/CT in estrogen receptor positive breast cancer patients

Comparative study between 18-F FDG PET/CT and 18-F FES PET/CT in estrogen receptor positive breast cancer patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative study between 18-F FDG PET/CT and 18-F FES PET/CT in estrogen receptor positive breast cancer patients Suchita Chowdhury, Rajeev Kumar, A K Dewan, Manoj Gupta, Vaishali Zamre, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6446808/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: 16a-[ 18 F]fluoro-17b-estradiol (FES) is a promising synthetic estrogen analogue which when used as tracer for PET scan, provides an in vivo estimate of tumor estrogen receptor (ER) status in breast cancer. This study aims to investigate the diagnostic accuracy of FES PET scan in diagnosing ER positive lesions in breast cancer patients. Method: In this single centre prospective study, 57 ER positive breast cancer patients underwent both FDG PET and FES PET during the study period of two years. The number of lesions suspected for disease by either modality were calculated and their sensitivities were compared. Results 251 lesions were identified using FDG PET/CT and FES PET/CT; eight were proven to be true negatives by biopsy and were excluded. FDG PET had better sensitivity for detecting lesions, both overall (80.25% vs 61.32%, p < 0.001) as well as non hepatic (80.08% vs 63.14%, p < 0.001). However, FES PET exclusively identified 48 lesions and also helped characterize 18 FDG-PET positive lesions. Hence 18F-FES had an incremental value in 66 out of the 236 non-hepatic lesions (27.9%) either by characterizing 18-F FDG positive lesions or by exclusive detection of lesions not identified by 18-F FDG PET and resulted in change of management of 21.05% of patients. Conclusion 18-F FDG PET displays overall better sensitivity for detecting lesions. However, the value of 18-F FES PET lies in the exclusive lesions it identified and the number of FDG avid lesions it helped characterize, both by its negative as well as positive findings. FDG PET FES PET Estrogen receptor Breast cancer Figures Figure 1 Introduction Testing for estrogen receptors in breast cancer is done by immunohistochemistry (IHC) and ER expression in breast cancer guides endocrine therapy in neoadjuvant, adjuvant and metastatic settings. However phenotypic discordance has been reported between the levels of ER expression in the primary tumor and recurrent or metastatic disease; the discordance rate of ER expression as per available literature is approximately 20% [ 1 ][ 2 ]. This may be due to biological drift of tumor cells following previous endocrine therapy or due to presence of small sub clones which were previously undetected. The occurrence of such heterogeneity in ER expression can have therapeutic implications; it might lead to decreased efficacy of endocrine therapy in a patient whose primary breast tumor was ER positive but the metastatic disease is ER negative. Similarly, in case of positive conversions, the patient might be a candidate for anti-estrogen therapy. The NCCN recommends IHC testing for estrogen receptor (ER), progesterone receptor (ER) and human epidermal growth factor receptor (HER)-2 for all new primary or newly diagnosed metastatic breast cancer patients. However, IHC fails to provide information regarding the functional status of estrogen receptors and their responsiveness to hormone therapy. It has been estimated that 55–60% of patients with ER positive breast cancer and 5–10% with apparently ER negative disease respond to anti-estrogen therapy [ 3 ][ 4 ]. Positron emission tomography (PET) scan has emerged as an important tool in staging and monitoring treatment response in breast cancer. The most commonly used radiopharmaceutical for PET can is 2-[ 18 F]-fluoro-2-deoxy-D-glucose (FDG). 16a-[ 18 F]fluoro-17b-estradiol (FES) has emerged as a promising estrogen analogue, which can be used as a tracer for PET for quantitative radioimaging, because of its high affinity to ER positive tissues [ 5 ][ 6 ]. Previous studies using FES in ER positive breast cancers have also established correlation between the FES uptake by cancer cells and the ER concentration measured by IHC [ 7 ]. FES PET CT scan has also demonstrated ER receptor heterogeneity in metastatic sites following previous endocrine therapy [ 8 ]. Considering these promising aspects, attempts have been made to formulate an appropriate use criteria for 18-F FES PET in breast cancer [ 9 ]. However, no clear guidelines have been established till date. This study was conducted to investigate the diagnostic accuracy of 18-F FES PET scan in diagnosing ER positive lesions in breast cancer patients and also to compare its sensitivity with the current standard, 18-F FDG PET scan. Materials and methods Institutional review board permission was taken for this study (RGCIRC/IRB-BHR/112/2022, issued 06.10.2022). This is a single centre, prospective observational study. Fifty-seven patients (n=57) who underwent FDG PET CT for the following indications during the period from September 2022 till September 2024, were included in the study after informed consent. Sample size has been calculated based on the following assumptions and formula: 5% level of significance (α) Power = (1-β) is 95% Considering π 1 and π 2 from previous study by Manoj Gupta et al [10] π 1 = estimated sensitivity of 18-F FES PET scan = 75.3% π 2 = estimated sensitivity of 18-F FDG PET scan = 92.2% Inclusion Criteria: Biopsy proven ER positive breast cancer patients, who are undergoing FDG PET CT for initial staging. Known ER positive metastatic breast cancer patients who are undergoing PET CT scan for response evaluation. Recurrent breast cancer patients who are undergoing PET CT scan for restaging, whose primary disease was ER positive. Treated high risk ER positive breast cancer patients undergoing PET scan for follow up. Eastern Cooperative Oncology Group (ECOG) performance status </=2 Patients aged 18 years and older Normal liver and renal function Exclusion criteria: Patients with poor performance status. Inability to give consent for participation in the study. Breast cancer in pregnancy. Patient with diabetes, chronic infection or chronic inflammatory condition. Institutional 18F-FDG PET CT scan protocol was used. Patient was asked to fast following a light breakfast in the morning and to maintain adequate hydration. Following a fasting period of 4 hours, 4-5 MBq/kg body weight of 18F-FDG is injected. Thereafter they were asked to rest in a silent, dimly lit isolation room for one hour and to drink one litre of plain water. The scan was performed in GE Discovery Mi 28 slice PET/CT scanner, in three dimensional mode starting from base of skull till mid-thigh. At first, all patients were subjected to a low dose CT scan (40 mAs and 120 kVp) for attenuation correction and anatomical localization. These patients underwent 18-F FES PET scan, within one week of their FDG PET scans with no change in treatment or intervention in the intervening period. Same pre-scan protocol, as for FDG-PET scan were utilized for FES-PET scan. Patients were injected approximately 200 MBq of 18F-FES and image acquisition was done after one hour. PET images were processed and corrected for radioactive decay of the tracer. Uptake of 18F-FDG and 18F-FES by suspicious lesions were analyzed. The maximum standardized uptake value (SUVmax) corrected by body weight was calculated for both 18F-FDG and 18F-FES for biopsy proven lesions. This is given by the formula SUV= A/(ID/BW) , where A is the tissue tracer uptake in microcuries per gram for the hottest pixel in the tumor (SUVmax), ID is the injected dose in millicuries, and BW is the body weight in kilograms. For the purpose of the study, any lesion showing significant uptake (defined as more than the adjacent background) is taken as positive. In case of an indeterminate lesion on 18F-FDG PET-CT, 18F-FES positive lesion was taken as a reference and as a true positive for disease. For extensive and uncountable lesions involving a single organ (liver and lungs), an arbitratory maximum number of 10 lesions were taken for analysis. The number of lesions suspected for disease by 18F-FDG-PET and 18F-FES PET were calculated out of a total number of lesions seen by either of them together and their sensitivities were compared using the McNemar test. Since it is not possible to demonstrate hepatic metastases on 18F-FES PET scan because of the high physiological uptake and resultant high background activity of the liver, sensitivities were also compared after excluding the liver lesions. Sensitivities were compared for the lesions with lobular histology and for the skeletal metastases. Incremental value of 18F-FES scan was also calculated; this is defined by the percentage of lesions exclusively seen on 18F-FES scan and also the number of indeterminate 18-F FDG lesions that 18-F FES helped characterize. Correlation between ER expression and SUV max on FDG or FES positive lesions were determined by the Spearman rank test. The corresponding P value was calculated using Kruskal-Wallis test. Results Fifty-seven patients underwent both 18-F FDG PET and 18-F FES PET during the study period, within one week of each study. Of these, 56 (98.2%) were female and one patient was male (1.8%). Twenty-nine (50.9%) of the patients had cancer of the right breast, 25 (43.9%) had disease in the left breast and three patients (5.3%) had bilateral breast cancer. The reasons for referral for PET scan included response evaluation in metastatic breast cancer in 26 (45.6%) patients, staging in a newly diagnosed case of breast cancer in 30 patients (52.6%) and restaging in a recurrent setting in one patient (1.8%). Most of the patients had infiltrating ductal carcinoma, NST (82.5%), five patients had invasive lobular carcinoma (8.8%) while 5 patients had special type of cancer like mucinous (3 patients), medullary (1 patient) and neuroendocrine (1 patient). Only estrogen receptor positive patients were included in the study. Of these forty-eight patients (84.2%) were progesterone receptor positive and 6 patients (10.5%) were HER 2 positive. The various clinicopathological characteristics of the study population are summarized in the Table 1. Table 1. Clinicopathological characteristics of study patients Age (median) 50 years (Interquartile range=15) Gender Male Female 1 (1.8%) 56 (98.2%) Side of disease Right Left Bilateral 29 (50.9%) 25(43.9%) 3 (5.3%) Disease status Known Metastatic Newly diagnosed Recurrent 26 (45.6%) 30 (52.6%) 1 (1.8%) Histology Infiltrating ductal carcinoma, NST Invasive lobular carcinoma Mucinous Medullary Neuroendocrine 47 (82.5%) 5 (8.8%) 3 (5.3%) 1 (1.8%) 1 (1.8%) Estrogen receptor Positive Negative 57 (100%) 0 Progesterone receptor Positive Negative 48 (84.2%) 9 (15.8%) HER2 neu Positive Negative 6 (10.5%) 51 (89.5%) A total of 251 lesions were identified using 18-F FDG PET/CT and 18-F FES PET/CT. Of these, 8 lesions which were proved to be true negatives by biopsy, were excluded. Hence a total of 243 patients were included in the study (n=243). Of these 243 lesions, FDG PET picked up 195 lesions (sensitivity 80.25%) and FES PET identified 149 lesions (sensitivity 61.32%) and this difference was statistically significant (Table 2). Table 2: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for all lesions FDG+ FDG- Total p -value FES+ 101 48 149 < 0.001 FES- 94 0 94 Total 195 0 243 Considering the known limitation of FES in identifying hepatic lesions because of inherent high background activity in the liver, we analyzed all the non-hepatic lesions separately. Of the 236 non-hepatic lesions, FDG PET identified 188 lesions (sensitivity 80.08%) while FES PET identified 149 lesions (sensitivity 63.14%); again this difference was statistically significant ( p < 0.001) (Table 3). Table 3: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for non-hepatic lesions FDG+ FDG- Total p -value FES+ 101 48 149 <0.001 FES- 87 0 87 Total 188 48 236 A total of 33 skeletal lesions were identified in our study of which FDG PET picked up 20 lesions (sensitivity 60.61%) while FES PET picked up 18 lesions (sensitivity 54.55%). Interestingly this difference was not statistically significant ( p =0.05), showing that FES PET has non inferior accuracy in identifying skeletal metastases (Table 4). Table 4: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for skeletal lesions FDG+ FDG- Total p -value FES+ 15 13 28 0.05 FES- 5 0 5 Total 20 13 33 Considering a previous study which had shown greater sensitivity for FES PET in identifying lesions in invasive lobular carcinoma, we analyzed 16 lesions in five patients with invasive lobular carcinoma, included in our study. It was found that, in this case FES PET picked up more lesions (13, sensitivity 81.25%) than FDG PET (10, sensitivity 56.25%), though this difference is not statistically significant (Table 5). Table 5: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for lesions with invasive lobular cancer histology FDG+ FDG- Total p -value FES+ 6 7 13 0.09 FES- 3 0 3 Total 9 7 16 It was also found that FES PET exclusively identified 48 out of the 243 lesions (n=48, 19.7%) which were not detected by FDG PET. These included lesions like supraclavicular lymph node, posterior cervical lymph node, skeletal lesions and in one case a breast primary in a patient presenting with an axillary lymph nodal mass. FES-PET also helped in characterizing eighteen FDG-PET positive lesions (n=18, 7 mediastinal lymph nodes and 11 lung nodules) which were clinically suspicious for being inflammatory or granulomatous. Hence 18F-FES had an incremental value in 66 out of the 236 non-hepatic lesions (27.9%) either by characterizing 18-F FDG positive lesions or by exclusive detection of lesions not identified by 18-F FDG PET. As a result of this, FES-PET impacted clinical decision in 12 out of 57 patients (21.05%) (Table 6). Table 6: Percentage of changes in management after following 18-F FES PET Changes Number of patients (n=57) Change in management Yes No 12 (21.05%) 46 (78.95%) Change in surgical management Yes No 3 (5.2%) 54 (94.8%) Change in staging or course of treatment Yes No 9 (15.78%) 48 (84.22%) We also analyzed the correlation between ER expression of a lesion and the corresponding 18-F FDG SUVmax and 18-F FES SUVmax. Spearman rank test was utilized for this analysis. Biopsied specimens with IHC was available in 30 patients for a single lesion. No correlation was found between ER expression and the SUVmax of either FDG or FES, though the p-value for FES was approaching significance ( p =0.094) (Table 7). Table 7: Correlation of ER expression with 18-F FDG SUVmax and 18-F FES SUVmax 18-F FDG SUVmax 18F-FES SUVmax ER expression Pearson Correlation 0.099 0.306 p -value 0.597 0.094 We utilized the Kruskal-Wallis test to analyze the correlation between the level of ER expression and the SUVmax for both 18-F FDG and 18-F FES. We subdivided the lesions into two categories based on their level of estrogen receptor expression: /= 80%. P value was found to be significant ( p =0.031) for the level of ER expression and the 18-F FES SUVmax but not significant for 18-F FDG SUVmax ( p =0.28) (Table 8, Figure1). Table 8: Correlation of level of ER expression with 18-F FDG SUVmax and 18-F FES SUVmax SUVmax (mean+/_ SD) Estrogen Receptor Expression p -value /=80% 18-F FDG SUVmax 5.7+/-4.2 9.5+/-1 0.281 18-F FES SUVmax 2.2 +/- 0.7 5.9+/-4 0.031 Discussion This study was aimed at analyzing the diagnostic accuracy for 18-F FES PET/CT in comparison to 18-F-FDG PET CT in detecting lesion in estrogen receptor positive breast cancer patients. The results are widely variable in literature. Gupta et al [ 10 ] demonstrated a significant ( p = 0.004) difference in sensitivity favoring 18-F FDG PET (92.21% for FDG-PET and 75.32% for FES PET). However the difference in sensitivity was found to be insignificant when only non-hepatic lesions were considered (91.18% for FDG PET versus 85.29% for FES-PET, p = 0.21). Liu et al [ 11 ] reported sensitivity of 90.8% for FDG-PET and 82.8% for FES when they conducted their study on newly diagnosed ER receptor positive breast cancer patients. In our study, FDG-PET detected more overall lesions compared to FES-PET (sensitivity 80.25% versus 61.32%, p < 0.001) which is in accordance with the findings of the studies by both Gupta et al and Liu et al. However, unlike the study by Gupta et al, even after excluding the hepatic lesions, FDG PET identified significantly more lesions than FES PET (sensitivities 80.08% for FDG and 63.14% for FES, p < 0.001). This might be attributable to the heterogeneity of the study population which included metastatic as well as non-metastatic diseases, untreated patients as well as patients who have received previous systemic therapy (chemotherapy, immunotherapy and endocrine therapy) and also HER2 positive patients and a variety of histologies leading to an array of confounding factors. Liu et al had reported that 18F-FES PET had better diagnostic sensitivity than 18-F FDG PET in detection of ER positive skeletal metastases [ 12 ]. Our study was not powered for subgroup analysis but we compared the sensitivities of 18F-FDG PET and 18-F FES PET for detecting exclusively skeletal lesions. Interestingly, both the investigations were found to have equivalent sensitivity in diagnosing skeletal lesions (sensitivities 60.61% for FDG-PET and 54.55% for FES-PET, p = 0.05). Though the number of skeletal lesions analyzed (n = 33) was very less to draw a definitive conclusion, this can have implications in directing future studies comparing the two investigation modalities in patients who have exclusively skeletal metastases. A study from MSKCC [ 13 ] had reported that in patients with invasive lobular cancer (ILC) histology, FES PET detected more lesions than FDG PET. Similarly in our study, we found that when the 16 lesions in 5 patients with ILC were exclusively analyzed, FES-PET picked up more lesions (13, sensitivity 81.25%) than FDG-PET (10, sensitivity 56.25%), even though this difference is not statistically significant (p = 0.09). Again, the small number of patients and the small number of lesions in this subgroup does not allow us to draw any conclusion. But it does point towards a better accuracy of FES-PET in detecting lesions in lobular histology. We also analyzed whether ER expression in tissues measured by IHC has any correlation with FDG or FES uptake. Dehdashti et al [ 10 ] in their study had documented that there was no significant correlation between ER expression measured by IHC and FDG uptake in corresponding tumor tissues but there was overall good agreement (88%) between IHC assays and FES-PET. Gupta et al [ 12 ] demonstrated a positive correlation between ER expression with 18-F FES uptake but no correlation was found with 18-F FDG uptake. In our study, we found no positive correlation between ER expression with either 18-F or 18-F FES uptake. However when we analyzed the correlation between the level of ER expression (as reported by IHC) with the mean FDG SUVmax and mean FES SUVmax, we found a statistically significant correlation (p = 0.031) in favour of FES PET. This is in accordance with the study by Gupta et al who demonstrated a positive p trend of 0.011 with 18F-FES PET SUVmax and the level of ER expression. This indicates that FES-PET might have better diagnostic accuracy in detecting lesions which are strongly ER positive (> 80%) compared to lesions which have lesser proportion of ER positivity. An important aspect of our study was determining the incremental value of FES-PET with either the number of lesions exclusively identified by FES-PET or by the number of FDG-positive lesions that FES helped characterize the lesions. The latter is specifically important in the context of the Indian subcontinent where granulomatous infections are prevalent and might lead to detection of false positive lesions on FDG because of inflammation. In our study, FES PET had an incremental value in 66 out of 234 non-hepatic lesions (27.9%) either by exclusively identifying 48 lesions (19.7%) or by helping characterize eighteen other FDG positive lesions. Liu et al [ 11 ] had reported that addition of FES-PET changed the management in 26.3% of patients while in the study by Gupta et al [ 10 ] the value was 20%. In our study it was found that clinical decision making was impacted in 12 out of 57 patients (21.05%) either by changing the intent of treatment or course of treatment or by leading to further investigations like biopsy. The small sample size and the heterogeneity of the study population is the primary limitation of our study. We had included HER 2 positive patients in our study, however, the effect of HER2 positivity on FES uptake has not been studied and hence it emerges as a confounding factor. There is also the issue of inherent high background uptake of FES in liver which makes detection of liver metastasis quite difficult. Finally, in spite of promising results, no definite conclusions can be drawn from subgroup analyses (for example skeletal lesions and lobular histology) because the study was not powered for these analyses. In summary, our study demonstrates the utility of 18-F FES PET when used along with 18F- FDG PET in ER receptor positive breast cancer patients. 18-F FDG PET maintains significant overall sensitivity in detection of lesions. However the value of 18F-FES PET lies in its ability to characterize FDG indeterminate lesions and also to detect exclusive lesions in certain scenarios which might change course of clinical management. Especially when 18-F FDG PET fails to detect metabolically active lesions in the background of high clinical suspicion, 18F-FES PET can be used as a problem solving tool. Also, in case of an FDG avid but a FES non-avid lesion in an otherwise non-suspicious scenario, biopsy should be done to rule out non-neoplastic inflammatory lesions. Conclusion 18-F FES PET CT can be a valuable investigation in strongly ER positive breast cancer patients along with 18-F FDG PET. Considering the findings of our study and existing current evidence, it can be used for better characterization of FDG indeterminate lesions for providing better specificity. Its additional value in detecting skeletal metastases and in lobular histology needs to be investigated with further studies. Abbreviations IHC - Immunohistochemistry ER - Estrogen Receptor PR - Progesterone Receptor HER2 - Human Epidermal Growth Factor Receptor 2 PET - Positron Emission Tomography 18-F FDG - 2-[ 18 F]-fluoro-2-deoxy-D-glucose 18-F FES - 16a-[ 18 F]fluoro-17b-estradiol NCCN - National Comprehensive Cancer Network SUVmax - Maximum Standardized Uptake Value ILC - Invasive Lobular carcinoma MSKCC- Memeorial Sloan Kettering Cancer Center ECOG- Eastern Cooperative Oncology Group MBq- Megabecquerels mAs- Milliampereseconds kVp- Kilovoltage peak Declarations Funding The authors state that this work has not received any funding. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Author contributions: Study conception: Dr P S Choudhury, Dr Rajeev Kumar Data collection: Dr Suchita Chowdhury Data analysis: Dr Suchita Chowdhury, Dr P S Choudhury Manuscript preparation: Dr Suchita Chowdhury Manuscript review and editing: Dr Rajeev Kumar, Dr A K Dewan, Dr P S Choudhury, Dr Manoj Gupta, Dr Garima Daga Project administration: Dr A K Dewan, Dr Vaishali Zamre, Dr D C Doval, Dr Pankaj Goyal, Dr Sumit Goyal, Dr Ullas Batra Data availability : Data will be available on request. Ethical Approval: This study was performed in line with the principles of the Declaration of Helsinki. Institutional Review Board approval was obtained (RGCIRC/IRB-BHR/112/2022, issued 06.10.2022) Consent for participation: Written informed consent was obtained from all subjects (patients) in this study. Consent to publish: The authors affirm that all participants provided informed consent for publication of the data from research in this study References Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, Adamoli L, Munzone E, Sciandivasci A, De Vita F, Goldhirsch A, Nolè F. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014 Jan;50(2):277-89. doi: 10.1016/j.ejca.2013.10.004. Epub 2013 Nov 21. PMID: 24269135. Hilton JF, Amir E, Hopkins S, Nabavi M, DiPrimio G, Sheikh A, Done SJ, Gianfelice D, Kanji F, Dent S, Barth D, Bouganim N, Al-Najjar A, Clemons M. Acquisition of metastatic tissue from patients with bone metastases from breast cancer. Breast Cancer Res Treat. 2011 Oct;129(3):761-5. doi: 10.1007/s10549-010-1264-6. Epub 2010 Nov 27. PMID: 21113656. Harris JR, Lippman ME, Osborne CK, Morrow M. Diseases of the Breast. Lippincott Williams & Wilkins; 2012 Mar 28. Ravdin PM, Green S, Dorr TM, McGuire WL, Fabian C, Pugh RP, Carter RD, Rivkin SE, Borst JR, Belt RJ. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. Journal of clinical oncology. 1992 Aug;10(8):1284-91. Kiesewetter DO, Kilbourn MR, Landvatter SW, et al; Radiochemistry and radiopharmaceuticals. J Nucl Med 25:1212-1221, 1984984 Mathias CJ, Welch MJ, Katzenellenbogen JA, Brodack JW, Kilbourn MR, Carlson KE, Kiesewetter DO. Characterization of the uptake of 16α-([18F] fluoro)-17β-estradiol in DMBA-induced mammary tumors. International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology. 1987 Jan 1;14(1):15-25. Mintun MA, Welch MJ, Siegel BA, Mathias CJ, Brodack JW, McGuire AH, Katzenellenbogen JA. Breast cancer: PET imaging of estrogen receptors. Radiology. 1988 Oct;169(1):45-8. Dehdashti F, Mortimer JE, Siegel BA, Griffeth LK, Bonasera TJ, Fusselman MJ, Detert DD, Cutler PD, Katzenellenbogen JA, Welch MJ. Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays. Journal of Nuclear Medicine. 1995 Oct 1;36(10):1766-74. Ulaner GA, Mankoff DA, Clark AS, Fowler AM, Linden HM, Peterson LM, Dehdashti F, Kurland BF, Mortimer J, Mouabbi J, Moon DH. Summary: appropriate use criteria for estrogen receptor–targeted PET imaging with 16α-18F-fluoro-17β-fluoroestradiol. Journal of Nuclear Medicine. 2023 Mar 1;64(3):351-4. Gupta M, Datta A, Choudhury P, Dsouza M, Batra U, Mishra A. Can 18F-fluoroestradiol positron emission tomography become a new imaging standard in the estrogen receptor-positive breast cancer patient: a prospective comparative study with 18F-fluorodeoxyglucose positron emission tomography?. World Journal of Nuclear Medicine. 2017 Apr;16(02):133-9 Liu C, Gong C, Liu S, Zhang Y, Zhang Y, Xu X, Yuan H, Wang B, Yang Z. 18F‐FES PET/CT Influences the Staging and Management of Patients with Newly Diagnosed Estrogen Receptor‐Positive Breast Cancer: A Retrospective Comparative Study with 18F‐FDG PET/CT. The oncologist. 2019 Dec 1;24(12):e1277-85. Liu C, Ma G, Xu X, Song S, Yang Z. Can 18F-FES PET Improve the Evaluation of 18F-FDG PET in Patients With Metastatic Invasive Lobular Carcinoma?. Clinical Nuclear Medicine. 2024 Apr 1;49(4):301-7. Ulaner GA, Jhaveri K, Chandarlapaty S, Hatzoglou V, Riedl CC, Lewis JS, Mauguen A. Head-to-head evaluation of 18F-FES and 18F-FDG PET/CT in metastatic invasive lobular breast cancer. Journal of Nuclear Medicine. 2021 Mar 1;62(3):326-31. Additional Declarations No competing interests reported. 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Choudhury","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYHACNiBmTgASjI/BfGbmBqK1MBszMBgAKUbitbBJg7UwENBizn/42YOPbdZ5/LPPmFUXVPyJ5m8HavlRsQ2nFssZaeaGM9vSiyXO5ZjdnnHGIHfGYcYGxp4zt3FqMbjBwybN23Y4seEMj9lt3jaD3AagFmbGNjxazp+BaJkP1FIM0jKfoJYDORAtG4BamEFaNhDSAvSLmeSMc+mJG8+wFUvznDHO3QjUchCfX0AhJvGhzDpx3hnmjZ95KuRy550/fPDBjwo8DkMwORDsAzjVo2phf4BP4SgYBaNgFIxgAAAe11cR1i0dGQAAAABJRU5ErkJggg==","orcid":"","institution":"Rajiv Gandhi Cancer Institute and Research Centre","correspondingAuthor":true,"prefix":"","firstName":"P","middleName":"S","lastName":"Choudhury","suffix":""}],"badges":[],"createdAt":"2025-04-14 14:08:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6446808/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6446808/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82299922,"identity":"65d4051f-3eae-4d13-b457-98d20c799ec0","added_by":"auto","created_at":"2025-05-08 20:38:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38044,"visible":true,"origin":"","legend":"\u003cp\u003eTrend showing correlation between the level of ER expression with corresponding 18-F FDG SUVmax and 18-F FES SUVmax.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6446808/v1/184d7d2fe9b3b04566212b8b.png"},{"id":82317712,"identity":"2a38225d-a190-483d-a4c3-71ac85841dcd","added_by":"auto","created_at":"2025-05-09 04:01:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":594365,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6446808/v1/7a96de7f-a2bc-42cf-93e6-b6361616f777.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative study between 18-F FDG PET/CT and 18-F FES PET/CT in estrogen receptor positive breast cancer patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTesting for estrogen receptors in breast cancer is done by immunohistochemistry (IHC) and ER expression in breast cancer guides endocrine therapy in neoadjuvant, adjuvant and metastatic settings. However phenotypic discordance has been reported between the levels of ER expression in the primary tumor and recurrent or metastatic disease; the discordance rate of ER expression as per available literature is approximately 20% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This may be due to biological drift of tumor cells following previous endocrine therapy or due to presence of small sub clones which were previously undetected. The occurrence of such heterogeneity in ER expression can have therapeutic implications; it might lead to decreased efficacy of endocrine therapy in a patient whose primary breast tumor was ER positive but the metastatic disease is ER negative. Similarly, in case of positive conversions, the patient might be a candidate for anti-estrogen therapy. The NCCN recommends IHC testing for estrogen receptor (ER), progesterone receptor (ER) and human epidermal growth factor receptor (HER)-2 for all new primary or newly diagnosed metastatic breast cancer patients. However, IHC fails to provide information regarding the functional status of estrogen receptors and their responsiveness to hormone therapy. It has been estimated that 55\u0026ndash;60% of patients with ER positive breast cancer and 5\u0026ndash;10% with apparently ER negative disease respond to anti-estrogen therapy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePositron emission tomography (PET) scan has emerged as an important tool in staging and monitoring treatment response in breast cancer. The most commonly used radiopharmaceutical for PET can is 2-[\u003csup\u003e18\u003c/sup\u003eF]-fluoro-2-deoxy-D-glucose (FDG). 16a-[\u003csup\u003e18\u003c/sup\u003eF]fluoro-17b-estradiol (FES) has emerged as a promising estrogen analogue, which can be used as a tracer for PET for quantitative radioimaging, because of its high affinity to ER positive tissues [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Previous studies using FES in ER positive breast cancers have also established correlation between the FES uptake by cancer cells and the ER concentration measured by IHC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. FES PET CT scan has also demonstrated ER receptor heterogeneity in metastatic sites following previous endocrine therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Considering these promising aspects, attempts have been made to formulate an appropriate use criteria for 18-F FES PET in breast cancer [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, no clear guidelines have been established till date. This study was conducted to investigate the diagnostic accuracy of 18-F FES PET scan in diagnosing ER positive lesions in breast cancer patients and also to compare its sensitivity with the current standard, 18-F FDG PET scan.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eInstitutional review board permission was taken for this study (RGCIRC/IRB-BHR/112/2022, issued 06.10.2022).\u0026nbsp;This is a single centre, prospective observational study. Fifty-seven patients (n=57) who underwent FDG PET CT for the following indications during the period from September 2022 till September 2024, were included in the study after informed consent. Sample size has been calculated based on the following assumptions and formula:\u003c/p\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003e5% level of significance (\u0026alpha;)\u003c/li\u003e\n \u003cli\u003ePower = (1-\u0026beta;) is 95%\u003c/li\u003e\n \u003cli\u003eConsidering \u0026pi;\u003csub\u003e1\u003c/sub\u003e and \u0026pi;\u003csub\u003e2\u003c/sub\u003e from previous study by Manoj Gupta et al [10]\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026pi;\u003csub\u003e1\u003c/sub\u003e= estimated sensitivity of 18-F FES PET scan = 75.3%\u003c/p\u003e\n\u003cp\u003e\u0026pi;\u003csub\u003e2\u003c/sub\u003e= estimated sensitivity of 18-F FDG PET scan = 92.2%\u003c/p\u003e\n\u003cp\u003e\u003cimg 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v3ATePe+972Hu971rm2JDKJIAwppvqaU0T6c4sUipMuVsNXtKi8h3qkPJ9U5azLiEjF029vedrjf/e7XxGDSIfFbk+ueEkWLRB726dxyJ2H0UEOfcd5mWY+MhXjTm940HHroocNb3vKWNnNHg5yHIkJqnPF0mMmFfnsmdCEJ25Zbbtmm4EPF5E38vPPOa+E0bTbxmKu/q0ofp5lc6LenQ9qqoKSzSkkXmsG64psBkTP5M36/+d5/nPgxyS1nko4qcW4Sk+I0yc1Gf47nyYBVgsi4sIggYfnIRz4yvOMd7xg+8YlPXG2w91IxHq/p3GyIi/RVRg1g90yyyLFi9nXDpHqiZy736hk/vw/zbG4mEs6cJx6ePYL2Tne604rZn0QDa7UJH29729tWdGkvJePxms6Ffnsm8ryoQ3WJylPLfsRK1jNbvi5XShQtEH0hy69CMcmhPzfbywnhVJmZ9i18+sqZwGHwtWUKTjzxxOHYY48dXvSiFw0ve9nL2gKP3gS9QWE8btnu02FV6P0hfIwL0dWnrxsGdaqcTAk+6qijhuc85zmtoUn4sBhp38e7j/NiEP/ljYZHF6c8sH+h0nku5F7jDn1aZHt1IlwJh21ixP9eePRhRuIyF6aLY8SXwamsRBrPjGEyzkZZNdPzda97XVsv6b3vfe+KtZI8i4uF8C5GfEOO+xioGazqD8/mdPThCfk/6dh09OfOJz6Y6R7xi3XEs2b5BmIP4vbtb3+7LQdiuQwLqMZyi7mGfb70cV3ZOM8V/uYeupyJIuVU3PMMLda9l4ISRQuAAqIQ9IVlpkLRn5vt5UIKtbegT33qU23wLsvDwx/+8GaJ0Ie+7777tqmnRx555PCqV72qWWd0W5mWesQRR6yYYRKLRUh8Q+I+nQv99nQYq/C0pz2tNTYaH/cmgB760Ie2/R//+MfbdH0Pb29JSX4tFH2exu+EP/unc6Hfnok+PVkaLPqnMtaYGmwuHbhJDer4/eZz/z7dZrNgxO8+XVY3fboJv/RJWvWMhznb07nQbwdv1p4JopXV0suEAbqsm/LNC8Yee+zRZkx65nQvKa9J36T3QjOeFn1csj2dC/32JHJcnSIdnve85w3HH3982yfNHe/jN8n//B8/1sOPxCfb+Y9cO5ML/XbgF3KM6FH/2S9viQLr9+gqfPWrX92s0l4qWftybcK0kPAv4e+3ke3pXOi3ZyP3gF8WI+X5X//1X9u4McjX2eqG5UqJogVAwUhht815EFRqBsD6ZclgofCWmNkJKVjLCXEIKmbhF1YzSKypovAbG2AMy8Ybb9zM/wcffHDrsmImVgmkEc5D4ZfrG53+PrMxl3OlsT5tSFcigYh7/vOfPzzhCU9o3UtBBYbk1UKR/M92n8e2+3jMFKe5xBd92KUty4P8kgfEXx+WmXB8rvcEf+O3+xKZVrTl3FsY3N8zoKw73od1dZK4JjxXXnnl8PKXv7x1f/zTP/1T25d868NsX8980gu53nWeqzSWEQqep2c/+9mtvJqNJs3kZ1jo9OvTIWWzfz5XNb6T8Ny5h2dV/OH+M/mdcM7l/skz5wq/eyVO49fP5t+k4+P7TGiw1pS6xjHWonve856tPO26667Nuq4uTLjQby8E7hv/xvNs/GVotjivDNJXOZWfXobzwonFuN9SUCtaT0MKm4I1lxWt+/M1Ct4CmcIzhZ1zTMOx7bbbNhHBbJ7kX8gHZVVQQSe81icSd4LuwAMPbAvcmfLubZbZP+JCejz60Y9u3WesSE9/+tPbcW/FKn1+wX+LfXmjyqcMxJuTDpxG1FgLC2XGJJ20nUSOeUvRoPg8wxve8IY22Jpf7u+Nzcd8jdPwBveUpzyl5ctCp33C0oeXCLaGyec+97kV9xRvaeeXSzisSn3rW9/6atfPhPPkl0qZGd8Yhmc961ntkx+vfOUrWxlTTp3TN7BQFoVBpS59dDnqfpP2wpQ8mwn317CzEsYyJdzC41eYxOeOd7zjii5N18zF78XC/fswfPWrX23lWflR5qSLsDuu/GRRR91bylKudY5zlX1vyptssslw+9vffsUaUXk2gvOkC0GkO/cZz3hG605ibVCneB4CS8MFF1ww/MM//EP7FpsxK7l+IRGXID7y8vzzz2/dQp5VZSbx5cRLmngujSWRt9PFN7jeNc4zuJxl5f3vf3/7RpbtnANhQF/+WHihLOsido7zc+4k+uPKtzWoUhclf5H7OkaISvc8J5PuIVz2ZT/LHgu1wcbGVnp+Enb71TWe/Q9+8IPDjjvu2K6ZLezzJf71/nrutD+68XRviTOSh8IIa0hZaJJ4m+szH1K3+trBYYcd1tpG5UEbYHmJ3CvlwrZ6SDlY7itaS8xiAqNC0n5HGTk1KtRTIyEz9clPfrLtGxWIFcdhO/9Hgmjq9NNPn9p7772ntthii6m73e1uU6OHZmqU+VOjhmFq1DBOHXTQQVMjZT01KghXu3Y5IL7ChXPOOWdqJDSmnvzkJ09dddVVbV9I2J0/qnimdt9996nRQzI1EkRTo4exnfOb3/ymHcdIWE2de+65U7e97W3VRFOjyqf9cqOHecU2t8EGG0yNKpN2HRKeSSTtRkJoatSgT2266aZTo0an7Rs1ZO1Xvu25557N71FFtWL/YqQ9/xJecT/77LOnHvawh7V7jxq1FXHt4x931FFHtetmim+PeymLGL2lTb31rW+dGlUwU6OKbmokVKZGDWk7ljwI/Jc3OO+886ZGb7VTo8Z56pJLLmn7XDdTGHLMeSOxN/Wc5zynPR93vetdp0ZidGok7qY222yzFifpLi9TrsbDstT0+QNx3mqrraZOOeWU9l+cUiZGYnFq1FBOjV5erpZPowq/5WX+3+xmN5t63vOeNzVqjNp1o0a2/fYkn0YvRVMnn3zy1OilYWokFqfOOuusq53vPOmnnhi9aEz99Kc/XbF/oRHPPj/k5V3ucperxY1TZvvyOhIQUwcffPCKsI3EVPudhHskfhdeeOHUSIA2P6QXktb5RV+/7rXXXs197Wtfm7Y8j5Nrf/jDH7ZnYiQM2j0TL/GRh4kPNxItU6MXmHYdJpV//vbhfOQjHzk1auTb8/Pd73637ctzdcwxx7Ry5bg8Dv31CwU/E17l6+1vf3srW+Ll/onjeL6ORHnLEyRt50ryXBl4yUteMjUSylPbbbfd1Pe///0VYenTUJ6lHIxeTludeMYZZ0yNRFXbt7rrhZ7V98q2lhGVzozIGmJlU+M7RgW0fWhyn332aSu7smIY5+KtZ1SY2zW5djlA4QuXN9qYhk299IuEGaPy0359ABGUvi61zEQQL/sMIDXzy5sv/3VreTPbaaedWreFt2z7mJ6333779u0gbzhhMdNHHBIPcRs9nO0taFRJtN/pnOOjh75dFz/ijzh6g9LV+MxnPrN1O7IOmjovbsqB5e1ZFsSXVUtaGLCIlY3v+HX5n3BBmBN+iLP8kk/i7txJ8evJf5aF4447bsUbonLuvwHt4sVy98QnPrFZFdwn5WF1Igx9Osmr/n/KvrEhurNYieQVS4U4sSaIj5lG3rK96SrDnhFvzuDndPT36rd7ptuPPi9mK6O9G39u/efkue4sExFYr4zJY+X1QVPl1DMpvtJAfMVVl7nu6LnEd5zxuI2nvTjFCRvLgvv0z2Vc0iK/iSM/jX00+eOf//mfW96Ig3GQ8s/SFen6V0/LQ9t9PFYmb+ZLH+7EbzonvvlNPMEPTthHwrFZPA3S1yMhr9Sz8tC2AeHbbLNN+xakfeocVk7MJw/HWcg0WQ6UKFoA+kJBIChw1qxgTlV5mKquG8UD6VtcCqprVqUgLgYeNuHy4On601XGnCzcKiaNZB7CPIgaOSvzatCZk5mJpQG/Yor2TSDfyTHzxLgNH4fUEOvG2n333dsD6wF90pOeNOy///7Dk5/85Na1APdxX5WG3/EKYVUR3+Sf+AizuBKBfqdzjqeB7/M/2xoaA73FefRW1L5rpVIy1uBxj3tcKwMPeMADhqc+9anDv/zLv7TKW2WNPs7cfOM80znCrKsmQpb4tM2Ezowt/Lr5NEaT4of8lwbGwhB68p84Mq7A2DINkLVbVMIpB8nDVWFS2iS+K5M2/BK+PIviJu80MLpV5AtBq2E1No1QIhYIXAP4zS5SbqWDcpHw9PcZv2f/fzxtw0z7c/1sZbR3fV0TP/zKY4NjPaPSQvx0v3pR8awaFE20q8d8rNZMU0KXiODvXOI7iUnnC6M4KX/8li+2lUvdr7YdV379Jo0mpdWFF17YXsZ03YqHz1Koj72kqJuVy4c85CGtq18eekZTTsUp5UuazDducyXh7uud6Vzy2u94XsYfAl4XJZGnLlanGk7w2Mc+dthtt93a9t5779262NU5XtSNFQU/xG382Qrzifek/FiTKFG0QCg0HOWtAHoAWQtYCd7znve0isebZsbJKHQp3Av5oM2VhDcOeQiIokwP9rDGUuS8NJTCLg76rc2c8XapkdCwEzz8yrn882bGgqAi0mDqdyYQNajSSiXsrc24Dg+zhjph6x989GEO4+esDN7ENIjGPBlEOZ1zXH4aazUdwmJ5ABXP4x//+BZnlZIGhshU0Usr297AOdaHxDd+ZHtSnCfRXxN6P7xBJn7GvrEGsvgYMyNORI3Bx5zjk0i5VUnLQ9/EIyCMRXn3u9/dVrdVZsRZAyZdlaPxcM01TtOdN+7fJHJtf/24X/3bt7jZJnrETf6Ji7wh5uWfeCnjxpJwyqvyLT34nXI/HX0ejYclTLcfrhVGY0eSV+NlNM4xItXA93H4I6z8En4WbOM8iFvxFX9xE3+C5L73vW9LA/s876kT+kZ6rvR5l/gIY8LLYqVsesaUT89l4so5rv5B0qpPU/6xiLBWelETXuXUcyb/iHjWP/GRh17MpEX8Eqfev7hJzHRsJnKN+GkrxFvcJuUjl3pHOvX3Szjlh3wkeLx8ibO4PvCBD2wi0AuQ+la+qmeJez0W8Su//OvjPldW5prlSImiBUAhSIGgtDUC9nnbNAjNxx733HPPVkBVwHk7zXW5drFJYfUrDMKS8PRxUCEYhEeYTFfBO9cgQgOwmd41EioZXQ/8zHX81ZB4AyWIDLI0S4y1xH1UerocveWo5J3PqqZSS5j4Feca4YVjzoH904V1JtyHg3DpBhLWV7ziFS1ufuMMXuZUtLpBDUp1f44fCQ9HAL30pS9tDYjKzmKXtok/YoMIsa6Se4oPUSHdMCnO8bePc09/3Pl9WIJ7GOAofroWmNkNejRIWr4wvdtvUoEZNAaoht6f+CvO4gF551rl2vINGlCIG7EgPI71eWQfNxPuk/OyzY/4lbgi53Dwq+H0PPblKeeDRYwQ7EWDxkT53GuvvVoXuHyRb/FXg5yGm7/SVTwTNq6/R7+NhIHrwzsXcq50112pjL3kJS+5WjmNM5BZXrLuyOM8N8Lcp5t6ifVHfA0Qtl/XLgEN4kSDnPhKq/nEN/TxdH9knzQ04F+5e8ELXrAiDizMBrvb79kTF3E++uijm0BA4tXf91GPelSziLAQKeNeQgyoh/DLcy906h756/4Ji7AlXpz/4j0erxxfGfiXcHv5fNe73tXiLS/lW5+P4q0u8lLpM0ZeOpRp8EO4OT0UnkEvnNLSS4qXLvW4OoewdC/Cy/2JscQ5ZWI83nCOuOc+49iXa/N/TaZE0QKQhyWFQyNw0kkntQrG2wpRoKJVgBWcFLCVpb/WNn8V6uy33f/Pr/va71ejIpyc7T5MfnNeCnrIMeg28zAzPetigAcwjWD8ywPmTeb4449vVigPq0XNmO1VWKxrxi3knn5do/Fh3mYCt4I2IZbwavD8QuWWSjv75ovwCb+uOxY9lh6/485xYSYEkfuJr22/wq7BlTcqdh9N9DaqobH+E9HkTc1Yh6RP4qXSJqZ1L2oMpLN4OScV6Ti5XmWpwUwj36eFbWJX+PPxSrPNxJtFx3YfT+eOkzgi/ll3x/efvKV66yaOU07ELeOrDjrooOGMM85o184V9+BPf19+6GbVeJhlQ4gj5dJ5OV/c0hUYv4KXFjPBdG2yhsA5EafS03OsnBnz5k375JNPbmmty0waJd3dT74qo9JCWbQPCX+2vQgQ/vIyeT5X4o9rxvNrkpPH8tszGfr79fGVVvLJPl0wyoTnVRzTpd3H18wwjbTxgr1VMWEcx7W593j59Ot+wpuuXOFP/eS5THz8snDI03HcmxMXeBbESd4ZJ0VgqSvkpzpIGvI/5YNTpggqXafqcHVQ7tXHzYuAfMx1K4s4ik/inrwbd6l3lOf+fraVK+nLoud5M9uV+FEvGwbhpVOe6q3Qje9ccVIGXW9bPAlt3aSeL59jSdz6Z6vHf+lHYCnXfZ08XTlY7pQoWiAUAAXNry4zal5BZ57VWHhIUxD9riopcApg/ExhtN3/9+v8PDgeZGLEVFGDwr/xjW+08xIu/nlQFXRvUIEfuR9zrjc1gs+4GNYw/msMvIF5E8t9/aoEWVZUTt5CVXIGQ3p7yQPvjVSF5aGHh9Q1Hk6OuDBWQNg9gPEfRIZKzwOaB3gu8IODCpIfxvqIlzcvv3H+c6wg1mpyzxA/0G/r45cW3lidryEWD+M2pHe6CKSpcKvIfGCREGJFkjdEh/+xykxCZSSvdAsYr6TyRNIf0kYXQrpANArGhhhXoCtPhakL037HWRDG4Zdw+uVYIIRP/rpOOSCU3Df5SKhJA9YoyzykEUbybzpy3L0ISpYb3bXKLeubBkyaQbiS94mz9M4yENJImvuFsiQ8RH0fV3khLY0FJLh0JelSsl8clGHdE4SuZ0C6alw8V8orIeV+ied4HhgfY4yOPJJu42mQtM12T/57Pols+cX15bQvr8lP98zzHf/dV3oJk7Arl8KsO1sZclwdQfx7JggK5VVdJr7KrXFzhIN0SNr38em3+e0caa17EjnOT421cOvaSRyEW5nOs+eYOHl+5AMSr5A0UkfJDy+kGa9HuIqPeznPOeo595cXBITyzMrCkmu5CeVEXaQcx2+ox+SjtEjc5wp/Em71n7FP6hVxE8/En/NfF6DnVr3DEqQsIvmYcBGnwuu4uszLjzwilCz5IZ/koWdAvjtP3qtnvCCIv7irw13HsiTefT72iLd0k5/SmLANfVqtSax661xcrVCqDK3ZQPF700/DqULgFMacP59C0xfKXGcf/xTqvuB6yN2rvybnQkG36rFuIOsKedMjToKHnPPQenDG4bd1f1xjBevEUeOkEtUFxXyLhEGFa80V6xkZY6OBU9GIi3CprIjJLMDoOusK+Q6UAa5Zf4d1yXfWWJs80MIJlSXzs4ZYWsyVPh+IIpYbgoCFTwXkd9ypqLyBaTxyrbSyLdz5VfkIq4pCV5WGzBubCkqlrFFn9YiAlI8aed9L4j8LmS5HwkqFJe6pSJOu+VUxyQ9vgyrWdPdwuUZeatwdZ6UyzoCIiSgyWJhTeRqMSsyHxBO5JwGsrBMQuiv4pXFJ4+dX/khX95Rf8lw8+wZ0Nif8fpVb69sQxe6lsVQOPHO9X+A/ga2ce+NXJp2LlBlhkR/SRB65xjHppHGwRhfRSHwQ7Z4rDaXyKs5WdHc97NMIyVdlO41tSFlVPqU7oUJ4yPuEByk7icc4yQdlSUMqH+XXpHKq/DqmQZXHfR7CPYRb2DSkulaNuRE+woEIl2aeJ3mmm7yPr/MIRnFgNclzNx72/OeHMuH519AjcVVuhFG583wph8JPFLEgp0yKLyetY8kcfyYSTyuDs+zpbnO9/BYfYkp4dQ/L51i5lBcWWvFR37CYGCNKWBHP0oPf4g4DmI3B8uz1eTgTiS9/Em7CxUuTNBG3SfWOfeolZVGayDPk2fCrTHo2vFSpK9WbwmqfdCfCjznmmBYf50I4CCUCX/3LgqZdEDdxJnilS84NSWv+Sy/pa3YxgQfPUn/+mkSJogUgBcQbqT5h/fMeFhUpFA6LxBEFHlIPJxSoXDsbKWAKWwqcSkaj6mHS55w3Zg2wCkzlzH8PrPNtR7R4y1NZqNi8/ZqV4OEAC45uMW8mxhm43j1VXB4A4xQMHmeW1kg5RxeEcRj6vVnJUnF4eL3d20/gsJ6pcDUOGm5iyL28kXvzyhuk8LIOqbAIBFYMXRyuS8MK4RIvFQv/IJxIpaMBSToLT9/tlet7lzSezcXP8euh8fClfnEXjpQF8VOJ6g6URiovM9Sco1FRAckHDbUKMBY4QkoapRy4T7aRSjJdfhr2PjzBf/mZSlFlKS0JqliihMs5ubb/db57EW/KgfIj/1WmgV+sOcZdaXSkt7zhhK1vQMRbPCY55N7Cy1//CTCDSTWiwpJz4L90JCAtjChuZjgS8Z4J+/M2K1wslul+ExbpRvh4UTj88MPby403cwgT/3WP6Qr0zCiT8se14iaOxDLsh+scF07b7slfjXOOBfeXPgSV81NWk789KYdzcX0aIc+nZ0XdJE66TpRFwg7CoqxaVsR4s3Qz8k94pL/4Ei2wH8m7kHsnr1hXXIs+XLY5ZSz7pYP8Uf6zvy+byLb7597yRz3Iwpr4EOeE6NFHH90EoDzwMqBOcq3jBJt89VwSZuKmPPWWv8RTPnPSUh2D5JNf53E5FoQ3Lv9z7myuvw62E2dtgbDLT2JO2REO1mFWPksuiK/ubcf4B+lAdHlBNghbfctpI7Qp8iD36MMM5Uf85SeBrMyE8XKwplCiaBXpC6gHx9slha1SJYIMktN4mJXj4VLppKJTaOZTcBTinK+SIDKYOL1JKPwedtYF53mLJiASPtc5R+H1htl3kXjjZ7XIm57/3i4UchWK/fyyjxWDiPGwECfetlgxvFEIi4fRG50Hz8PiuAqVedb01wgX8NdDJaxmRagsNRR50P1qMFKpSLfs79M9eCCFizg19kjjxpJh3AMrA3/EU2VpP/EhTfo8mOTvbPTXCy+h59Mn3r6NscmgY0gT50tbokeFlUY693bc2ABID2Ecj7Nt+SzOGn73Em/7s/bIdORa+FXZc9k3fq8+fjmHQCGM5LnyII+VdS8F0la3mgaFSIN8Fk9xQfzk3yTX3x/CpzHkp7JI8EtL5UZD7Xxpz19OWWFN8GwoV7oEdKW5Ljhf+qWx4z/RJO8Ie1Y3oi/pyV/30R3D3xwT3ggbYRPXPs0mQUApf16SlFljQIgwdYV6RFpp0L21Gygcy6t79aJyZXC9fNDYuYd6yq+XKxYL4iCIr4ZffFnNWBvG4ysNx+PruuSj9NAdo55Qh7gm5Ts4L7+u4yCsKZ/9OdkOiZM0Je4IYJYkM2KJHrhGmbFfmZG/6uPUL9Jc3eiFRJyEm5NOk9Lc+cIpTup95YtV1zOgPvRC53oWbwOmtQH8SdqtDH28bae8e9FVftTdlsKQj3BM2klv8SL05GcfBsfs81IaAaneEVZ1dJ/efu2Xh+oAzz/BJY1mq3fWFEoUrSJ9ZeCNUveLBkEDRbQwVar4mGtVLBS4hsLDqWCmwKXQTUd/3Bs90zCTpwrMgFMPOTHGepPxIhFfeQA86Co2szCYqB0nXrwVKeQeaGZ/cfKwJ265t64tjYZ46g5xDw2PB41Fw9uGAZnMqCobjbXK3tumc1UMeeuGCoNp39uNcPWCCCqd/i0rD6iw9o1rwsc/XXnMwCw00klFLD/clziR7gaISr9YmwK/pNVcXcI5jvupKOWDdVGIn1hmhF2FpbKWXn3jwD95JM6phMXZfnEbjzMnHLrpWGQIQenO5bzxMPrPH/5BI6cy1NBLfzjOjV8L9wNxreyohKU3C6SxGN7AxV/lShB6M0+DJg0iCv2XRkSqZ4TzaQvOPuUscVcWCQdlU1pq+NxTGCO8pFfCKw11MRgrpKGXHp5L5YEVNMIolX6uEzYvG8Ilj+SdOCqHcD/lnTXBbFIWH7g+fogjlzIZ/M854qNrUjg1KsS7BlX6Ka8aL93Bwq2cShNxDvG7L4uzudw71/ov/iy/7u/5MyvRS5JwQXwJPxZg0/UnxVf65bkch//280/c1FfKP39S/uJP/BRW57s3vDRwyqb9znHMecG+3F/eEuvKta56XUjJP+epL9VPZkgq88KDpJNnz33ESZor30SVPEld5LzcT1yIAeXefaXn6aef3sqRsqMOkL7aAvVrxB6EJ7+5/1xcruvxIqY+Y502xtNzJw4QRvWvl1LthPgJf9KNn/b5BQuR+sQz7CW2r6Ocn2eY0NVVRxy5h7RNuqDfXqMYBbyYwKjwtt9RAZj1Mx9hVPm3peLH3agyvtonL3pcw78c4+8kv0cVTPsdKfKp0Vvs1P3vf/+p0Rte24c3v/nNU6NKfGr0htI+IYLx+/X+2uYXzjjjjKmRqJkaCYf2uQefphg1Ju0TEMh5/BMP8ZkUR7/OzX1yj8Q/+wL/HJcGcKw/PhIO7XMpibv0f/GLX9w+KzF6aNu+/nrbo0ZvavSmNDWqGNo+9x69sbX7j4c1/i408jP3Gr9HH+fEN/k0Es7t8wAjwdk+uYCRGGifWTnggANWlD+4PvH2OYqRMJ4aVfbtcwgYNcxXS8vpEL4+PHMlZSHxjEva5hlJ3Nxnr732avkyqkTb/eTlhhtu2D4PMHprb5+YsD1qrKYOPPDA9ukSfjj/iCOOmNpjjz2mRiJi6l3vetfUK1/5yvZZFPEeiah2D37mfkjay3/PxWabbdY+A/OhD32o7T/kkEOmRmJg6nvf+177D36kvPZ+QVjsT7r7nzhKQ4ze1qce8pCHTI0ayRWfMBAO52U7z8JIuLdPAB133HHt8wj8Sfr16TkpLAtBwu4+08VXOZKX+T8e30MPPbTFYSRSp37xi1+0fUl35+Ra9cpIoLS8GwmXti/pOBP84JJ+s5H0lW4JY+CH8NifuPb+2k6YlL3RS9zUSChOve9971sR71yX35FoavmoPlYHQ/0rLYSjz0dpuRgIG79zjz5O6OPsWO8gzRJv54xe6Kd22223qRNPPHHFp1xybV9+tRPq6Be96EWt3sV0eeX6xL8+87EOMErH5qht1pdxR2l7W8nbD/prxq0Ak94Esm9U4Fa8Fcdc6b+uLG/So4J3tbeR3Ifr/c0+eEPwRsTc682JeXl84CQ/hVE8xGdSHP16m3Kf3M//xB99GPiXN7M+PMFbn7eWvMEIl2uEc/QQt339NY7pH/eWaL/xOe7tLcb9x8PK31w/fu+VgR+c/My9+nugj3OfTpDG8k+c81YqrPJ3VBE1EzVyDT/AUuRtzduhuM4V/ghfH57snw7HuJSFxDMuaSsNEj+4j/yTN8qt+2Wsj+5M3UZ+07Vpdpe48MP5xpXoQjImS/cAy4a3VG/zk8JtO89BrBL8GFW+zcqlbAsTi1LSEbZTXsURibP72O+c/B+/tziyXHnLlg7IsZBrjDPTbWH8mbx1v6Rfn57jYVlV+JHw89d9pouv+kD65b4JexBf+cMSK6xwrrRXrlwrbinT0iVlG/F3nOx3Ltffd6Zr5Km4CIvr7Mv5/BAe+8XV/vibc+StupDVxzHWZVZ14Y//ORfupTxJQ8+oYywmLFuO9fkYq1R//arCL+Hkd+7hf3+PPs49OU+c8gywwJp1aUVsXYn8VNc6B64RL3ieRoKv5X26KMfvvSZSomiBUBigQMzkck7ONxtCt5SGPsdnwnWcwqiLwbVMp8bsMHnqqrOt0s+Dn+vQ3yP7nKeCVrA92CoAD3oKf+4J13MqvWxP+j9+flzPdPuDBtTDyvxsnIWB1x5Q4fSQw33ywPJHpaA7T2Nn5pc0EieN4XgYuYRzoZgU7/wP48eCeKQCFVeVs24Vosi+5AfcR7xUYMaDOG4GSM5JJTcd7j0e1rkyKY7TOXGSZ4QbZ2yPuImTLioDO7OiNxO/X2tW6e6Sl86LX6M34ZanyoP9xolpkAnh0Oena+Bc4XAuxx8DwQlQ99KwI/cZd5gtrezT+OvmU1aVO8/0OPxJ46QxkWeeN42wZ1laKaeTyupCM+5/XJhunzj4lX5exsRZfDWSwXFxkRaGErhGnho/mLTMczsTuT83Eznenz/pmknHsq2cKJtmLBoTpFx5sUrXrudN2OVNwu7XeeocdfJpp53WhLqywL+lyEdMukf/2+8P2SeM6hpd4OLtGdWNajyofX2+ipP/xhF5Do2NNHi773pP/q6pXHP0hnbA77eLMfLwe5PTt6+f3xiGPBTJ/L4Q2J7J8c8vbBv7Yi0MD5E+boWK/zkn9NcpwMYOaWSIH42DAqoBNfXdWBWDSzUq8SvXjvsrHgq6+xNT0EgYm2M8Qawuqcjj12wuTLcf0x3LtodPxavvmuCTD8JrXIeHljhK2JI+xIH+fw2NB1waqLS8veec3oV+e2UZ92/chUn7gviykBmbYIwQ0QMCwtiKWILERSNqECcrkbE2ZgtGSBBFk/wPk8IT5nvddE445A1x4A2UYM+UaBWpsCq/yui4i/+OE/3KgEbJrEcNMZErDYwZ0tjK91wTl//xU2XPD431oYce2p4RU68JSX5xea7HXRjfJ462/RqL5Hk2dsY9lFGNRs7Nde4h/J4tZdVzJ689z2bxSZfxa/r/q0rv53yddPQrrYzPIgI0kP4bJ+VlBOKonjKOhsiQR+pPae5Yn9aTyP7ctz9v0jX9eZNcGN8vHNmvDjSo3WQSeclCpJ41iFkd4hlUN6ZcSwtWGHULi5+XE9ZLL5gG0jt3ujK1UMSvcf/jZjombH49Y/LSoH7iVviVT0ucqEe9qHi+xMPzo6055phj2suFNDJW1nHXSBd+juNe0ku9pKwr88ahak+9CCadlgMlimYgBWc2UbQyxG+VisXeNH4WSEujNqmAuCb7FVaF0rkaBgOfVageUOFUGaeATgpn75cHWLeEQZ5mMbHCGHTJ1C2M/FkK+nDa1qhoQKU9ASCc3sis5SGe8JAJI1wjb4TfcXlFWLEOiMtC5NtCIyycOKhgVUgaF7OfdBcJr3JhlpUGJ/kh3zU6KheDOQ1Yd8z5ydfVHc80HnmzVLblIRFiwoHKMPnhvIQ9+zj5a7CsX7PbvIUr28qBKeIaW2Wkvy74LwwwaFn6qvQ1dESnNPUCkeck9NuzoUy5XtprFAlawlXciHdlMP7lN3noWs5Ad8+ydNLwunb8muVCH1+NG8ErTz1zBhazfgkzJ6845Vb5VMeMN5zLIX4JA1HEIqScyhNlRPkxEUWd6qVVGRJ31yhftp2jjiFyOS826VKSXs5dDvHsEW5OHFi4WPSI8oTbtrIr3uIv3uIgbiyDhJQXMYIocUy5mBRX+51XomgNR+bKrIUURbkmv94mKG+Nvkpeg+EtM/ced/DQquS9dbEeKFy2PbR+Nar85cdsYUyBVlhNXfdGrmH2GYM0KktdWBN3D5kHVFwIJJUuC4O3Nsdy7ng8bXvQdAFqMMUnFpbxc5cD4ppwqXw0MvJYfoqzvn1xTj4k/NKA+IsFiT8pl8shjn04lGuiXaNvRou4KXM5p3fwywKm68Vbu3WqvJUq9+LLD42t9JqpfEYURRB5jllT7dfw8VODnvui354LCbdw6B6KVU8YMy5q3E//k+/SRjkVN41Sny7LkYRLfFmUiT+zmtQ74tEj/uokQjaCYrmV0R71hnJBCMgLz5+p+yx6rCF9uPtrxUldpa5Jl65nOMeWG4kHJ09S32hL5CUB68XDf/VRH1f5KG0yhrGvv9CfG5yzpoiia4wCc/WOxqKRjFZ5WoOCdjQA1ANCtKTiWhn43RcCi6Mx0R533HHtwcrbVI97JatW9r7j9P6xOpiqymKlG8a6MwprRNFC3XMm+vDYdm/pMH7vPkzOy/FsR+j11/XnLTcSNr/cpMqhP5bzg//SRJm0jeUS1/Gw9kwX1uS77mDfEvPMsepk5fTgzd55KSOT7uVZsl9FzirLSmSMCAuHxep0GSjn010/V2aL5/ixfp/6RPiCY1jZsCwF08U3YUd/3DPpmLya7trVxcqmd39dymzPcovnJOYTxknner7UO5jJL+njXOJLF6UlDB7zmMe0Z5t1bVL6rS6Wn4Rdy8mDlIZP5cwcmUoD/ZtiHLLtPOZLjYJfBcr1Cp19/jsnLvTbiL8gxgg/K9vus88+7e0V/f0Xm9xHOG2nkR+Pax6enBds25e0zYMYkTQe/+VCwuZX2IV3PM4YF0TO06Dal7RyLMdXNwmPX+FMnGwnT3K8J+FXWeoa5giipEvSRAXbV6ST4u14zjFGzqq+xhMZi2WGDT8mXTdXhD3xFKY+34QXiWMfz9zTPoJIOU1eOpZrlhuJx6T4+p+wJ/z2iZv/8iHXLhcSnoQ35TRu/BmE89Bfl7glvvE35y5H+jAmL8fjnrjAuUi945rl+CK2qpSlaBoki0yW8QtpKRovQESRzyFYUNDnNgxko6It9mVqJ9N+GhG/TJoWj0PfsGBVCqdr3TsF3dvzckC4Ei/08Z2N8evWFBJnLvGdFP7xc5YzEQhhLmFW3o3R0R2RypfDysQ5woODZ2tVRVFPHz7MJ4y5NoJ+TWC2+I4fWxMYL6dhrnmZOK8p8Q3jeQn/xWO8TObcuaYJIhbLUlTMikKiclbwOIWDSjegjVLvnX2p0OH8vlDOp5CO4zp95vqIl4sggnAlbcbjOxtJj/lcsxxInFUSM8U5560J8Uv+xc0lzCwoGT+WF4D5XD9OxD6rKMcaupBp14dvvmHMtWsSs8XX/7g1hT4+vZtrHNa0+AZhHo9z6p9xcu6aGM+5UJaiaYgSXmhLEZLkrucXS5F7mLrKOmSJeMIoyrnPIhU58eIc1zpnUhbap1ExSC4FO3Hq6cMirtl2TX+sKJaKlFO/vRjqj82VvgzHv/jRu/68oigWlrIUFdMyXkkb4Gz6o5k2FgqD7gIzUbwlEzV+ucymMn3S922s+utbN8ZG+JaPlX7NYOMsSufL9Kb6zkQaBeTNIA1Qf6woloqUOb/jb6vzLY99GY5/fTnvj2W7KIrFgwBKN+VyfOZKFM2BVKYRNAsF/4wjstibsUW2LTCnsnbMfVN5c/Cri8vy84SQTyUQRYSQ2WP+++Cr7Uw3DnMpgNUwFGs7yniV86JYPbAW6fHQxi10m7oQVPfZNESUMPnp2so3mQx0XpXus/gLavllL3tZW6hPt5m1PIgba/HoPpvuHuP7orz7ab1FURRFsRzou88sQePzIY961KPaUhvWWnPcC//KtKkLTVmKJkC49FqRCLLabPb1x+aLTI//CoF1UowlMhXeuCWLvjmWwdfOT0HJb0yP8BFYa6+85S1vaTPWzCADPxTCnlUJd1EURVHMl76rzBARi7FasNh/PTBYTm1TiaJpiAAhTIznsWqrby5Z+n18evB8yDXxn3WHAOJsux/G/XZ+9ilkpir7zs5RRx3VLFlnnXVW+4DfGWec0b4vRcj11yD3LIqiKIqlIFYgGGCtZ8TY2KxmDW3TcmmfShRNIJlDUMhMH/szhsfy5Oedd17bR5iMC5e50md+zIqcbX7OVjgcZ7kifihvS9H7HpiCduaZZ7aVgA2wzjiolQ1nURRFUawKadO0mb4P6LNN2iuiiCHA/oim5UCJomlIJsJ3XmQihWtQNBzL8fkwLngIF5YnznaOj58X7FeA/BqDdO9733t45jOfOey3335tm2nS98t8MBYliIqiKIrVQf+Sn/bStwF9R9Qsa9g/XXu3OihRNA29mLBooq4z+/LBw9WRif09Tdk36Jszcw2EFYSzxFBRFEWxOtFmRQzlG4NXXXVVG1PUi6Hl1F6VKJqBZBgLjjWCtt1227bvU5/61IqFE1fGWrQqKDzCQADl69pW5/XVYd17vkjt69xmsyFxKIqiKIrFphc42kfjZY2BvfDCC9t/X9fXRuXlPT0fy4USRdMgkzJ2SL/nLW5xizZ9kBg66aST2hgg52SGVzJ4MRkvbO5t6j5L0TnnnDNcfvnlrQtts802a6LIGCVhLGFUFEVRLCXaq7RBvsBw7rnntvbTDGvjYNNmLqfxRChRNAsyTaYSRllPwQKLfkPO4WwvFv093J+1SNfeCSec0MYSUd8PechD2mw5LDcFXhRFUay9pC3MdtBO+XKDfT5TpW1azLZyVbjmARbHWY0kEf1yLCB94599ORc5lsRfLHIPv0RIBob5NIc+UZ/gWH/99VeED4sdNn67H0EkDKbjf+ITnxh23nnnFpajjz66naNLTeFL2BY7rYqiKIp1E20O0s5oLwkfQ0y8sFsyxmxpX1ywvE2Wn1mOL+7LwlIUEZFEtJ1Ezr7VlYDul3sav7PNNtsM97znPYdvfvObw8c//vFmNUr4FhtpknShvIkhIsg0x8suu6x1oR1zzDHDd7/73T8SkkVRFEWxGPTtsjZHm+iXEPLi7nudO+6447DVVls144L2abytXy6sdlEU0SGRslZPb93wXz+kY9mPPhMWi9zDL8uMsOia8k0x0wq//OUvDyeffPLVProqgxcrbPGbALM+0be+9a0myowfspq1xRtZi252s5u176NhKdKpKIqiWLfR1vQC5yc/+Un7nMdXv/rVYcMNNxwe9rCHtTWKtKMsRWG5tVGr/dtnhI5G3lfiLToo0TbYYIMV42IuvfTSNh2eurTY03rrrdcStA92ElVic7MRYRE1O1OmjN9HeHMfH3A1ov6Wt7zlcL/73a/N/Mp5M/m5qgiT+xvRbz2ipId97ivtzExbzDAURVEUBcbbSV1mei4uuOCC4RGPeETrXdHmjveoLMc2arWOKZKQnISiKj/2sY8NRx55ZBNGt7/97dvq0aeffnqzgEhcgsQ4HgIps7/6RI7QmYvLdbNliuNxwTYhIizC/6UvfaktpMhK44N3OWex4LfwGzMkLViFjCFiMeKEbTHvXxRFURRBexOH888/f/jc5z7XZkNvv/32rU1PWz9+7nJjtVqK3Jp1Q9eUbqD3vOc9w2GHHTbssccew5Of/OThne98Z7MgOUZ53vnOd25f1r373e8+/Pa3v23XETggmHQp+fyF/eB/n/D+Zx8hkbV8piPnT8JUeNYYYo7FyOCx2972tlebCr/YiDOXeyWs0mS5FriiKIpi7ebDH/5wG97x1Kc+tf3XXvY9PNqn6drWmXDdYrdty6b7zIdWL7744rbmjs9UXHnllc0Ksueee7aVMI8//vg2mFg3le+QEUUafwJIFHwd3sdQDT7WxWZfHzUJ6V4sTDLHStD8gfOS0P22sUyumYRziB/ki/bx37H+3kVRFEWxLqD90zZrA00I0kZrHxeiTeR33xPSt9cLxWq3FEWkfOYznxle8pKXtEHCRI3uqF122aVZdAzUInaM3bGA4m1uc5sV4iOJ/+tf/3o49dRT29Q/6wnZ10fNub0oYm3adddd2zHn9Qk7/r8oiqIoirWf1S6KWGNYWnzd/fGPf3yb1WXNHTO8rHxpvA5THOvR4x73uOF2t7tdE0LpIop44Y9PXZiOrlsLfdSc538sU8SXxQ5hf/zJNv8uuuiithKna3K/cT8x6T5FsS4w6Rko/sBM6TNTXVH1SLE2sFD1A3/0DjF4+NxWxu4uBqtVFBEbuqBYbiwBvv/++w877LDD8NCHPrQNtBY0lh+CydgdY8J9sV7ijCeKc/VbEjPJiJlwT2JsnIgmY5NYrogyYYzQKoqiWEjGq+C51F9Fsa5htjWjyIEHHth6k+DZWejnZdlYioif5z//+cNrXvOaNlo9Ef3kJz/ZZqWZlv+CF7ygTcsniiJonMcfIubwww9vg7VvdKMbtWMETnAecZP7+RzGk570pHasT9hsE1g+/EqM2TfJUlQUxe+oZ+OPGU+T/v/4NhdSb41fXxTrKp4F7b4Z3/RB3xvUPzsLwbIRRabf77vvvsMb3/jG4W53u9vvzxja4GsLE+o+e/GLX9zWMJokigzosnKmqfsGaNs3HjX/CSMDv+50pzsNO+2004pzxhPWfoO+hQ8LnfBFsTaQ52L8WSv+QOqoSbBKq+AzeJQgMj5yrhbvolhX8Gx4Tiw/47lZLFabKHLb3Nq3xFiDDJTeb7/9mmAhXFh/dKsZhG3VaN1qxhlZ80CFEQcJRiyx8MxlpLvut8XslyyKopgN9ZRPIVh6hBBSJxnrWHVTUaweVpsoMgvMrSm/F77whW2Q9NOe9rRhyy23bIsSsvwY6OwL8MTR1ltv3bqyzBq7xz3u0cRPpvotJEmOvLUVRXF1WFvTnezL1ywdZonmBaX4HdLDivPqrxve8IatrlLv+VW3SEeC6A1veEP7jqKXQ7NujZnwnSh1kfMqXYviD3ge8kx4Rhb6+VitogiEzcte9rI2a+wZz3jGcOtb37p1jTnuo6vGGV1++eXDYx7zmLZ4o2+opAJeiMSZ6brVlDRFsezwjHgeuFhidWm/9rWvHe5617u2BVeLqyPNWMDf+973Ngv4Zptt1tIuE0UMDWAdtxI+MaTbX9eZVfy9HD7hCU9owok/SfOiWNdZmXZ+Pqw2URQrjIfdW5LVqE21890uQkmwvGUdd9xx7W3Um5M1ipxPMDmnZ77RSMK6brETuSjWBjwrGmm/vkno20ZeWCyhwdWz9DtSF0kLnzo46aSTmuAhHokddZ8FaX3r0UQSwwWshq9ug7GO1mQ76qijriaKiqJYfFbrQGuMV6R9hTJOf2z8uqIoFgfPWp69WHB9/frzn//88PKXv3y4+c1v3o7VM/kH+rqKZYgVXBfaAx/4wGHTTTdtwwZ6oRPxY1yRr4lvtNFGwyGHHFKiqCiWmNX6pKUS9evtKf+5oFLg+r71qnyLYunwrOUZ1LV9yimntO8RPvGJTxxucIMbtHPSeHs2uXWVxD9pAVbtpz/96U0c+Z6jrjMix7hI59hvjJaxR8cee2xbWNYYSlQ9VxRLy2oVRXN54HNO/1sVRVEsHRpujTjhoyv705/+dPvY43Wve93WmOeciIF1+flM/JMeHHwo2vccdZextBFCIIyIJPt8WPoLX/jC8IAHPKB94xH8KitRUSwdy+Jpy4M/qTK1PzNdiqJYWjTqusw8gz66fP7557dZoOn+ydjAej7/GGmSdCEozdIzq/bss89unw9idXOchcigax+8NtHEeCKCE5WuRbG01CtIURQzEuGj8fbJHUvsW2DVejq6htK1XQ34H0h6xHrm80Q+YWSdNYvMsrhB2ll2xEw+K/U+5SlPaaLJvhyPtakoisWnRFFRFNOShh26eawhdsc73nHYYost2gyqwGrkvPm40G8vNeNhmo/rr59ERKLj0seUfMuKsBhZlde3nA477LC2Ur/PExFCpuFbp8gabbl2Ov+Lolh4ShQVRTEtLBW6ynSdmYZvGrlG3UyqScRCMheH1dngj997UhhncqHfHqe/h+82mZpvTbYvf/nLbTkDQpPINFXfoHXpbWmSzTffvF0zk99FUSw8q31KflEUyxMNtLEwRJGB1WZGvfKVrxye+tSntplnus8cR8YEusYChD7L0w/CTuNum3O+cTME1uog1Z5wJXx+TYn3zUPxiPVrPOz+Gw/E2pNjk8j5nLTQZXb88ccPz372s4dHP/rRwyMf+cjhNre5TbunAdd+cf3rX78tUOseuV9RFEtDiaKiKCZCGBhkrXFmIXrHO94xHHTQQa1Rf9KTntQGBBNFziOccNVVV7XzDj/88LZKs+pFY0/88MtAY9cQFM997nOH+9///u1/RNVSI3zCT7SYEeY7i/vvv3+Lx41udKO2gKz4C5/jBJ+4+tzQq1/96nZM+CMAx+n9N7ja6tY+fG0F8Cc/+cltQceck6rYuSWEimL1UN1nRVFMy3jjrOFO4w3bGnGWDoOFDz744OEtb3nL8IMf/GC45JJLWpfb17/+9eFLX/rS8NWvfnXFf1PQWWTmy/i9CZK5uF50jP8SPFbU98kNgsi0eF1burh8k1G4bROGnPBfccUVVwvLXHGNsKAXUsJg0DrXp/nK3KMoipWnRFFRFLOioU4jrqHuBQVnmv773ve+4ayzzmoN+y677NIWIWQJue9979s+37PNNtsMD37wg5uVxO8tbnGL5ge/V8Yy4prcfzY3fo+EP/vOPffctk4QseazG8b5WFX6oQ99aJsmL6zWDhL2hz/84S1e/MV8w+783hrEksaKFsFUQqgoVh8lioqimBUNeC8k0qBHGLCsHHPMMe0bhcYd7bXXXsMd7nCH4ZnPfGb7T2AYR3PooYcOb3/729usq7vc5S7t2vgxF3LfkLDMxYVs55cl6bTTTht++MMfDq961ata99Y973nP9j23N7/5ze1bZATdK17xiuFtb3tbc1aoTpfhfMLfk/u7nvM/v6HfLopi8SlRVBTFSkNQwPo7PmBqEPYGG2zQus8IId9FM+7G2BxjaozJGYd1JIONOX5GgI1bTdL1ZGySrq0Pf/jDrdvrIx/5yPChD33oas4xYucDH/hA676zzhIS5sBqQ7y9/vWvb+sv6UqzLx9pFbaf/exnzQViRdgc43o/52rpmet5RVEsHSWKiqKYE70Vo2/Qdf0YOG0quWnlVmb2dXj/zTAzc81nLkzj99+1ron44SerC/HE9d1040QUGfT8ne98Z/jEJz4xfOxjH2vdX7Z7Z5/FJi2GaCyQGXGIH3APjgAyLZ54+9SnPtWmyutGM+Ca6BF2XYBwvfAn3FzCjNmsO47HFUWxvChRVBTFrEQ8TMJ+AodQ+OIXv9gGKhtEbaFCCxQSSFtttVUbm2OqOdJlFFhxfvrTn7bz+RMIh5nuS6Bw/Xa/L/vH/ej/x8qjC/DCCy9s6wgZDyW8RBUhF8GXsUDC7jrhFlfCafwes5Hz53tdURSLR03JL4piIsQEgcJ6Y/aVWWVveMMb2lR608l1jTnuPNYSYsFX4FlwrHi96667DkcccUT7gOzznve8Jpiuc53rtEHKLEsRRbqlnEc8ESP77LNPEyT8Izx6C1VwT11tLEaqMOdMqsrsc+24FQqO8SfhN8ssX6k3UNx14rn33nsPG2+8cQufMVMbbrhh88cYpKOPPrp15Ynrpptu2ixM0sRg8/4eztctd9xxxzU/DTTfb7/9mn8ElXvlmqIoVh9lKSqKYiIa6ggXXUe6l253u9u1/ZlOH8Gha+p1r3vd8O53v7uJlXvd615NCOg2IxqMN/rKV77SBILGn7+6qqwLdOSRR7bxRsYi2f/BD36wfU2e1SiMCx7nWfuI/1aJJrJsjzvH/PokSS+IwE/7CCJjkl7zmtcMn/3sZ9vMM2swOcY65FtlJ554Youj+4qza8Xjxz/+cbvm4x//+IrxUuIY+nC7nmAisLbeeuurzb5LOhdFsXqpJ7EoiolorAkDlgziIN88I0Z89gOO6/YynZ0ViVi61a1utaKbjCghEggL+1iAsoo1sWTMzve///0muEx3Z0Xy3S9iieAgFgiLiIteZLAiCRsR5neSy+BtYqT3g+O3YyxYZsMZm8T6ddOb3rSdRyytv/767Qv2BnWLu091RBTpVjOYnOCydhG/0Iexx3HpZRVr3XFEkTAKR4miolge1JNYFMW0EABEjUabILDKMwsJkRF0CVn0kCXkaU97WhM3GdSsy4hIuM997jPsvvvubUBzuol0pRFavgy/2267tSn6Zn8RDwQRS5L7R4TAdoiVh6XK7ySXbjP37K8NusBMrzd2yBiol770pU3sQBytv+Q7ZA972MPaNH0iL2EhhlzD6uMeYfw+OZ9/jrG6EVvCT9hNCldRFKuHax4w4vfbRVEUV0ODruEmKnQPGVdjmjuxYHYWYcPyw4qy5557NkuP7ioNvUZftxYrEEHBAmNfRIJtX91fb7312jbnOlYn3//yVXkiLCykeIhfxB4rmDE+HMuPcNhPVLEcGfcjDkQQhN/1nMUeWYlYvXz6Q3pkHBRyHsuaMVnWcpIOxB9xRCgl3kVRrH7KUlQUxYxotEHAEDesImZq6TbT/WOcEUFx73vfe8W0dYICuojSVWRfP96GcCC2Ys3RjXbGGWe08TwWfvTttJy/WKKBiDGoWvhvf/vbt32xZBFBFm0UP8KNGIogCgZ6c8IZsRf6c1nOfAaFsGQ1Y3XDdBasoihWDyWKiqKYFg22hpv40a1kAPU97nGP1v1j1hgx4HjGCUU4hL7Bj0iI89/1rCWEhXFEFl3cbrvthh122KHdYzFEUe7NEWaxACH3C+P3Hf8v7sRe/Az9efbrRiTACESfDhE33YQliopieVGiqCiKWekbfV1ahIT1fLIvlhLnjQsE2/2x7EOsRaeffnrrimJtIrp0u+lyWgzRMCksccKTsKE/Nn4+CEXjjAwij3UsxwI/WYn86jrL8YWOV1EUq06NKSqKYlbSgBM/N77xjduvWWLGzxAExhGFXnBg/H9EhX26zHxI9uSTT25Cy0Bs3xu78sor21if6bqtVoVxf/J//Bfj+yJowHp2/vnnD+edd14bsG2BSmOhnMsRQZYasE6TT46Yiq+bTpxyDvJbFMXqpyxFRVHMSAQJZ9uYn+233759+sJ6QgYa9/TCYSZ0m/kEiDWALPhoOj+/TjjhhPatMsf5NVf/VoWZhEl/LGmBhNd0fbPlxMEK16xbCbOxVz45QvCZXUf0BaKpKIrlRT2VRVHMSMQQNPgsJGZpPeMZz2hjiSyyGLEwk7iA8ziCwJgafhl0bCabfcYV6UIzdslA6/g5m79LReLpN8sOEIebbLJJW0LAvj6s0sY+0/7NYBNfaYj4VRTF8qE+81EUxZxJdaEx13V2xRVXtHE1uoSyf664nmWFlSUz0yIaCKX+UyDLhQgZYc16SmaUCb/w6kr0qY+cx5qkC43Ac06ffkVRLD9KFBVFMWd6UWA70/UxnwY//qyJzBb2HO/PIwBtE3lrctyLYm2nRFFRFPOib9RZdmz3XUKYqdHP9X6JK2OHxiG2sqjhXPxcKvq4Czux49c+gmc8zI5x/cy05RCPoigmU6KoKIrVyqQqaE0RDn3YpwtzCaGiWHMoUVQURVEURTGiZp8VRVEURVGMKFFUFEVRFEUxokRRURRFURTFiBJFRVEURVEUI0oUFUVRFEVRjChRVBRFURRFMaJEUVEURVEUxYgSRUVRFEVRFCNKFBVFURRFUYwoUVQURVEURTGiRFFRFEVRFMWIEkVFURRFURQjShQVRVEURVGMKFFUFEVRFEUxokRRURRFURTFiBJFRVEURVEUI0oULRBTU1PNZft///d/m8v/HCv+QJ9e//M//9PSq99XFEVRFEvJNUaNT7U+q0iS8BrXuEb79b/fRv4XV6dPK1R6FUVRFKuLshQtEBpxDXoa+V/96lfDz3/+8xXHij8mafXf//3fw3/8x3+035C05IqiKIpiKShRtABE9Pzf//3fikb84x//+HDyySdf7VjxB6STLjP8+Mc/Hk455ZTh61//+vDb3/62pVnS0nYJo6IoimIpKFG0iqTB1sBf85rXbI34m970puHcc88d/vRP/7Qa9DnCSvS2t71t+NCHPtT+R0yWMCqKoiiWihJFCwCrBgH07//+78NHPvKR4eKLLx7+7u/+bth8882vZvEo/oD0ICKlzXWuc53h7//+79v2Zz7zmeGcc85pg67/5E+qeBZFURRLRw20XkkidPwSPhr4E088cTj66KOHRzziEcOOO+443PCGN1zRuJcomoy0i/j5zne+M7zzne9sovKQQw4ZbnnLW7b9SeuiKIqiWExKFK0CBA8xhMMOO2z43ve+N2yxxRbDzjvvPPzt3/7t1RryatT/mHFhafvb3/72cMEFFwznnXdeE5c77LBDO45Kw6IoimIxqf6JVUBDHgys/slPfjLc4x73GNZff/1m/UhDvxwac8JiuetfaXarW91q2GqrrYZPfOITw+WXX972J/2We/iLoiiKNZsSRStJun3+67/+q1mIWDg02je5yU3asRzviTCZyS0Us/m3MveKnzO5+UDs5BoWt0zJ/6u/+qvhP//zP4dLL710uOqqq9q+oiiKolhsShStBARPZpt961vfGp797GcPl1xyyfDnf/7nrZHX2EcQ+e98XW2zOedFJMxXYIwzbqGa9H82hCHhiNCbFO5xN584JFzOTZr5f7Ob3azN4nv+85+/Yl8fnqIoiqJYaEoUrQQaaAIBLEVXXnnl8IQnPGF45CMfebXGu2/sCSgz1GZyznEN8rsQCCvLyy9+8YsV4Z5NXCT8cM1ix8G5EUVm7r3mNa8Ztt566+Hf/u3f2r6wkOlSFEVRFD0lilaSNM6Ehm6fu93tbq0RDxFGaeiJp5/97GdtlWurN8f5byq/7V//+tfN0rIQ5P4Qxs997nNtMUnbmMt9cr242ha+6eLA8dviixFeK4P7/MVf/MVwpzvdqU3T59dvfvObdqwEUVEURbGY1OyzeSK5NNQaaFaM0047bTj44IOHf/mXfxl222234frXv3477jzncMTCN77xjeGyyy5rDX72c+ly+rM/+7NhvfXWa0KApST34FaG/nrjnUx1J4re//73DxtttFETL8IyE/HD7w9+8IMWfqtP93FIeojDta997TamapNNNhn+8i//su2PKJwLfZjx2Mc+dvjKV74yHHjggcM222wzXPe61523n0VRFEUxV0oUzZOIGOOHPvCBDwxvfOMb22KDRx111PAP//APbb/jSVZWICs1n3TSSW3ckYbdMWOSNPDXuta12rZ9BMVBBx007LTTTq27i18rKwD4F3FhIPhxxx3XVot++9vfPtziFrdoliv+T4ew8UNciCrhMsOOpUgchJmDOLDmXO961xvufve7D/vvv/+w8cYbtzhEQM2FpFnOf/SjH93EnGn5RxxxxHCb29ymWeUIyKIoiqJYaOqVe56k4YbuJKIn3+syngYEhfE1v/zlL4dPfepTw/HHHz/89Kc/bd1rLC32E0Dbbrvt8P3vf78JDdYVFhyCA3MVEkiYImIiWDhhsY9/wuQ/+nMc73GO/eJzxRVXDKeeemoTfn/zN38zbLrppm2qPP9YtTj/iRVCaIMNNlghtuYTh0kkXmagZWZaURRFUSwWJYrmSd/Q6yL667/+67aPkIjgSGOe6frECOvP0572tOHOd77z8OAHP7htP+lJTxq233771u32ghe8YHj605/exBFcszKiwjUcC1O2iRv/hS9+Zl/OGSdxINjMsLN+0J577jk8/vGPH253u9sNj3nMY4ZnPetZw1577dXWFdp7772H5zznOc1aZuFKrGwcQq61MnhZh4qiKIrFpkTRKkBkpKusFxfp8vJNL91Jutge9rCHDb/61a+Gu971rsNTnvKUtsijdXjMWDMe6T73uc+w3XbbtTFJ6GdxzUbO8+vero2zzxgl/hIWGUfkN+cmvMH/iJCb3vSmTfj867/+a7MSsXI96lGPGp785Ce3z3CwdD3zmc8cnvGMZwz3ute92vfeiEXweyEoK1FRFEWxFJQoWgQiMoy10SVmkDDh9NGPfrQNRr75zW/eBmkfe+yxrfuJpQUREc4dd/3+Hv91dYFVyto+++6777DPPvsM//RP/9QsUkTLe97znjZQmkXKf1YpxwmcN7zhDa0bsL9P4mDw95ZbbtmsQ64XB+JI95//xind8Y53bPFEhFjCOu7mQ8TefK8riqIoipWhRNEC0Tf6GnNWJAKB1cR09W9+85vNyqJ77EY3ulGbkWZmFeEE1hBuXADwK+Igv+PkGuKIuPnRj37UnLE4xjCZOUaE6c4ztumHP/xhc475dU26/hD/7GMxEgfjhr773e+uEHrg/9e//vU21giZjt/HIeGPG4/fTOTc6eJdFEVRFAtJiaJFQrdautdOOeWU1lXGIuTr+SCAWFxi5SE+YmWJCJgkBsb3+R8L041vfOPW1fWyl71seOUrXzm86EUvGl7ykpc0y5AxTVaJ1s31ile8YnjhC1/Y3Gtf+9o2y8unNcbvm7ARcyxQ4rLHHnu02WtgTTIjLOJFHOxz/Xg4c47ffnsu9NcURVEUxWJRomie9I0z0cD6gr7h9ksQEQgEi+nqhAWM7Tn88MOHE044YTjkkENWLFCICAr0omI2QZCuLuOEzP4yKJpFym+cwcrputtwww2bmGHx8UtMCWfu4969xYd1yIBrcTU7juXouc99bus+e/e7390sRc5NmHt/QACyIvmdLo4Yj2f+S7/xY0VRFEWx0JQoWgnSQBMSsY4QCpmK7jiBYp2eCy64YPja177WxuDssssubUYWMaFLy9f0iaOzzz57xXWxMJnu75jFFnW9RTjldxJEBv+FibOdMNrmEsbx81wbkSIctsXBl/+FwX+DqLfYYot2jm4zXXH8e+tb3zpcdNFF7RxCURw43XPHHHPM8NKXvnR43vOeN7zqVa9qXXDTkfsHYQNRNn6sKIqiKBaaEkXzhACKZYbQYekxLZ8VJVYjEAUXX3xxswoZAG2gsgHL0MgbU3TGGWcM5513Xvt2GlwDVhXT4A899NC26CIBFTE0yWLS77Pt3IgrEGesLcLX38PxuPjhl3Oe8z/ykY+0OLAGWVeJkAPBJF4Wpfz0pz/dBBL4JX2IKULJgo/c+eef39ZsOvPMM9t1yL16evHDsuR+PqFiYUiUOCqKoigWixJF80SDz7JCaBgjZAyP7igC6Etf+lI7h3WGCDAO513velfr0srgZDju3COPPLLNDrP+D3FAUDjme2IEBIuS/abURwxMEgX9PtvC2O/jB1GkCywiJOfF+e9YwuF8s+MIImEV/qw/BGH8xCc+0axcLECWFIjg4p8xVGam7b777k3YEU662qSH6f3oxRiyzdpkELrp/oSkMVAEqOPSviiKoigWgxJFK0lEh5lkd7nLXYbTTz99OPHEE1tDTxwQAWZsWezwH//xH4db3/rWzfIBIueBD3zg8LrXvW7YbLPN2r40+K416Nk6RhZ2NAbJzLFePMwF4UsYWaYMsiYwWHiQYz3uQdDAPT/zmc+0tZYs0mgNol4UGYtkgLaxRcYkgZ8RLbe97W3bdH+LVTqe+0WEjdPHz6w2A8R1vxGehCLmmwZFURRFMR9KFK0kGn+NtK6zBz3oQU1EGPujwbffgOb73e9+baHGfMw0jbrPfRAUD3jAA9rgZ0IoYsG2fQZKs0ARNMYXrYog0PVEXDzkIQ9pggsRGpMgYIgn44esUE3csBTZR/Thvve9bxN8vmYv3PYnDsJqYLf1i/KB3MQRk+Lins4B8fixj32sCcldd911xfnOWZV0KIqiKIqZqA/CrgIa7wwGZvkxVd1CiJI0AgBp7MeFCLGgoY8VxXW6jvhpzI/FFfHQhz60rYxNiEV8LBYpDglTiKgZ3y8NhKuPg+0IIdv2JU6WBiC2jJcaTxfHCS/ikmC0ZAArG8bTqiiKoigWmkW3FKWRhYYtA5I1ppNcPxgYru/9WC4IUxpzQsa4IA36y1/+8rYPxh1FGMSCgggGpJF3rG/w+c2tigjI/fz290SO9SQMnG3x4lw7buWJf30Yc71f50fEEUQGkx9wwAHtUyYsa3Cu650TQWT8knFHxij5jAjib1EURVEsJosqivpGEhpKU7g5DeUk55iGMte4fr4NYq6F7fm60G+PI0wROpwxNxp8g5lNUc/qzxr8xGE8HjPFq783P2YKy3TM5P9MxyaR8Oc64bEdsRSyX5ghPwkdg60N3jbw2ngpuJaw8ksQfe5zn2uDs60A7ltxxiXFn/7eRVEURbEYLJoomtSIGxtjRpXp5t/+9rebG9/WdUJYrEkNIBFnELKp46atm5FlGrrPZ4yLBtg3bgXKdtItIsC5491Tk9J2JuKPe85E7gHb7stNigO/xvf3YbRN8MhL0/Cta6TrzCBzFsGcBxY1M81OO+20NjjdmKt8HLcPU1EURVEsJos6pojXXBpPg2ef/exnt4G/LAMaTZaAHPdfA/nEJz5xeOxjH9v2JXjLsXHsky5jgaxc/eEPf7jNRjMzzXR154kbgTEbug9ZV1xjTJG0MaaI2CJE+DObuFndJA7S4sUvfnHLb4PODcoWJ2OvfG5EXrOmEUyWJ9CFptvMeCLpKe4pG8u5HBRFURRrB4suivJ7xBFHtDVvvvzlL7eGjUDQ8DlGTEQgwerHvt2F+LHcG8Ne3FnI8POf/3wL8z3vec+2rz8+HdJDupiKTkD6hhnLCQvLwQcf3GaAEUTSZLmKxIhDFkFdZq9+9avbOk1ZCZsFzcy7Aw88cIV4MnNP15kFIsUxM9bEkVuu8S2KoijWLhZNFPUNGYuARQ5ZUO5///u3rpIrrriiCQDWAw2iFZB9INXnMkwBNxUcCd5cG0Xna1CJB42tRQCN77FPY+13HGLFfo20T1mYDm/qet8w9yRMfRxt5z//iDzdRCxiOX86XOMcgoJIsE7PWWed1bqdiCJCgYXFwOMIyIRrNr+XCmGRXuIgzj5tcuqpp7ZFKK11ZJmBfBbkwQ9+cBsz5Fxplbi7DvxJWobZBGVRFEVRrCqLLor8+qSFbhQN3+tf//pmQfjCF77QVikmlkzP9ikLX3O3KCA0jGkw0TeQM+F84kYDe8kllwxHHXXU8MEPfrB1zejGEYZxCA3XCOe+++7bBBkBEvGRcCQ+vZuOdJVNut90JI7xlx+2pQVmut9yYVIcIpYck9bIf/hNGkcQhZyTLkPHsq8oiqIoFpIlWaeIxYTgMPDYd6985sEMJGNlDjrooNZdsuOOO7aByuONn18NJYECjadzcgzjjWSuJYQM9DW2xb6ZrA25j7BYkDGNd1EURVEU6waLLop4H0FirIwp1yeffHJblM+Ch7vttluzDj384Q9vg4kjTjJ2BpMsA/0x29MJo4Ui/hF4poz/6Ec/+qNwFguL9JXmut5uetObruiKXMh8LYqiKIqwqN1nwTarzWc/+9nhlFNOGW5wgxsMu+yyS5vG/s///M/tcxY+52AadixCERsaQGOSWJk0krrAuPFg9w1lrtNF86tf/apdb1+6aMZxrv1cxr+k+wv2RwD5EKqPnfoYqi63fKajWFjkiTIjH8ziMxZNeZEPM1n8iqIoimJlWVRLUcSEBs4aRb6S7kOf1qPxIVQzrHxE1TRsLoOb0/BxBIcv0LuGCNHFpquNGOE/1zeS/rtGY8qaY6CvsUX2sTRMEjDEjv3EE/99OLWfAYX4aUD4BRdc0L4g73wiaj7jhorZkeacxR6l+cYbbzzst99+bQyatO4Fa1EURVEsFIsiinipUctgWqLjoosuarPPdKHtv//+bXbSe9/73uEOd7hDsxxZ1M/Ubc54Ht1UrDIXXnhh+1q7hR0JEw0j0XLXu951WH/99dtsJkS8uLf78sPMLfdkoeKfmW3TiSLHNcIsVvz2QVPn8jcWJtuEmVltZtARTbFoFQtPRCnhaQaeNY2SD0VRFEWx0CyaKILGS8PGUvOmN72pWYss2mfNmjPOOKPNQjOeiAXnxje+cfuquq40/1lhLOrnO1hECAsOC4H1f3Sl+dYYcWRQNPFCnMC9I1b6KfmEEgE1KbqxSBE8wpYp+X08itWP/Ki8KIqiKBaLRR9oTZD42rk1ayxk+P73v7/tJ27e8573NEsOIcJCQ/hYwI8oYrXRTXXYYYe16fGve93r2nW+K+a6xz3ucW1RQ9YigocIWswGMw2yX6LLPYulQbqz/CX9SxgVRVEUi8GCj1jVaEUwWIDQJzuOOeaYNv3eWkUGz8IMLl9Ov+51r9s+62BBP11osfiAONJ1Mj6GJIOhM5ZovJGMzvPLAsQJ02zOeQRPf33IPfy6L6tTuaVxEURJ/6IoiqJYDBZlGk8aLrPEttlmm7Ygok875FMP0F1mRpEBtNtvv30TQ721J+IjLvT750Lv32wuZLvf19Nfsya5nknHl7MriqIoisVmwUWRBiyCxXihpzzlKe07VwYvw5s/fBT0QQ96UFufiECKVadvAO2LC4731pxJxI+EJYJrLm6uYmu506fbeBoi+yYdK4qiKIp1kUVRABElBiubTaa7i5Dhcow4MpsIaZSJkmznN+cHfhQz06ddL3j8j0PEZf7b7s8viqIoinWJRRFF4w1xfrnxRjeN8qRjpsmbhdYLIZYcs8S4nD9+3brMeHpGiHLS05iunDNuGct5RVEURbEusqh9RWmU+4a5ZyYx41wDrFmUNOSm15uRZu0i+/vBt8Uf0wsfX6e3UOarX/3q5qwPZakC36MjLnVbFkVRFMW6zjUPGPH77QUjYsVvXBjfnvSf01ATQ2aosRbZvuyyy4bvfOc7bRHGO9/5zu3zD2aoEQBry1igVUXaRWxm2yzAww8/vLmzzz67CSKfP3GMwDSTj/jsryuKoiiKdY1FX6doZYh1SdCuuOKK9hFZaxMRRve+972Hhz3sYe3TDxm0zRpS/I5e2LCsffGLXxze+c53tgU0je2yErc0ZXGz8OWzn/3sYY899mgfXM1A9xKYRVEUxbrIshRFfcMOK1tbyNGYmM0337ytfK37DMRTNeK/Q7pxSQ9CKEsemP2XT59YQPP0009vazNZO+oJT3hC+3yKtESlZ1EURbEusuxaP406McSlkb71rW/d1jnSeG+77batcY8lSQMeEVVcHV1kX/7yl1ua7bzzzsMOO+zQrEIWyrR+VMZslaWtKIqiKJahKCKGeosH8ZNZaJyBwb11KCKq+F3aJf2Qz6P4lps01GVGULK0EUosRf3svhKXRVEUxbrMsuwnSeMO4oclQ2POsW7kWH9e8Tv6NPEdufvc5z7DzW9+87ZP+oGwlI53v/vdW3ek8wijSs+iKIpiXWaNGDwSYcTZroZ7bhA+17/+9dsMPenmvy618847r3WrEUWbbrppm82XQdaVtkVRFMW6yhohioq503eBpeuRZYgo4kzH/+hHP9oGYW+99dbtEyuorrOiKIpiXadE0VoGS08ETqxDsf6wtBFDLEMGXm+33XZtm3BK15prSyAVRVEU6yLLckp+sTBE4BBHv/zlL4eLLrpoOP7444eb3exmwy677DJsttlmK8RQhJPzqwutKIqiWBcpS9FaSgSRLjTjhS699NLhzDPPbB/p3WmnndoMtEzF761LJYiKoiiKdZWyFK1l9Nlp23giq1qfe+65beHG5zznOcMGG2zw+zOG4Wc/+1mbmn+9612vrVkUUVTiqCiKoljXKFG0FjI+vd6nPK666qph3333HdZff/22zzEiyKfvFIFnPetZw0YbbdTGILlel1tRFEVRrEuUKFoLiagxgNonUh7zmMcMP/rRj4Z99tmn/fqGXNZ9Ou6444bb3/72w2GHHdYWeyxRVBRFUayrlChay0h2sgSxDh155JHDscce28YUxXrEET7O3XLLLVd8QuVa17pWO5bri6IoimJdokTRWobsjKD5wQ9+0D7z4VMe1772tVdYf/wafP3rX/962H333dsnP0zNz7UliIqiKIp1kRJFayERN1av/sIXvtBWtCZ6Inb8shQZYL3xxhs3wYQUhRJFRVEUxbpIiaK1kPmKG+dzsSTZLmFUFEVRrGuUKFrL6AVNrEHT4dx8U841KQoliIqiKIp1kRJFazGydrbsJYBKBBVFURRFiaKiKIqiKIpGLUZTFEVRFEUxokRRURRFURTFiBJFRVEURVEUI0oUFUVRFEVRjChRVBRFURRFMaJEUVEURVEUxYgSRUVRFEVRFCNKFBVFURRFUYwoUVQURVEURTGiRFFRFEVRFMUwDP8PIVQFWLVvjX4AAAAASUVORK5CYII=\" width=\"581\" height=\"234\"\u003e\u003c/p\u003e\n\u003cp\u003eInclusion Criteria:\u003c/p\u003e\n\u003col style=\"list-style-type: lower-roman;\"\u003e\n \u003cli\u003eBiopsy proven ER positive breast cancer patients, who are undergoing FDG PET CT for initial staging.\u003c/li\u003e\n \u003cli\u003eKnown ER positive metastatic breast cancer patients who are undergoing PET CT scan for response evaluation.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRecurrent breast cancer patients who are undergoing PET CT scan for restaging, whose primary disease was ER positive.\u003c/li\u003e\n \u003cli\u003eTreated high risk ER positive breast cancer patients undergoing PET scan for follow up.\u003c/li\u003e\n \u003cli\u003eEastern Cooperative Oncology Group (ECOG) performance status \u0026lt;/=2\u003c/li\u003e\n \u003cli\u003ePatients aged 18 years and older\u003c/li\u003e\n \u003cli\u003eNormal liver and renal function\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; Exclusion criteria:\u003c/p\u003e\n\u003col style=\"list-style-type: lower-roman;\"\u003e\n \u003cli\u003ePatients with poor performance status.\u003c/li\u003e\n \u003cli\u003eInability to give consent for participation in the study.\u003c/li\u003e\n \u003cli\u003eBreast cancer in pregnancy.\u003c/li\u003e\n \u003cli\u003ePatient with diabetes, chronic infection or chronic inflammatory condition.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eInstitutional 18F-FDG PET CT scan protocol was used. \u0026nbsp;Patient was asked to fast following a light breakfast in the morning and to maintain adequate hydration. Following a fasting period of 4 hours, 4-5 MBq/kg body weight of 18F-FDG is injected. Thereafter they were asked to rest in a silent, dimly lit isolation room for one hour and to drink one litre of plain water. The scan was performed in GE Discovery Mi 28 slice \u0026nbsp; PET/CT scanner, in three dimensional mode starting from base of skull till mid-thigh. At first, all patients were subjected to a low dose CT scan (40 mAs and 120 kVp) for attenuation correction and anatomical localization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese patients underwent 18-F FES PET scan, within one week of their FDG PET scans with no change in treatment or intervention in the intervening period. Same pre-scan protocol, as for FDG-PET scan were utilized for FES-PET scan. Patients were injected approximately 200 MBq of 18F-FES and image acquisition was done after one hour.\u003c/p\u003e\n\u003cp\u003ePET images were processed and corrected for radioactive decay of the tracer. Uptake of 18F-FDG and 18F-FES by suspicious lesions were analyzed. The maximum standardized uptake value (SUVmax) corrected by body weight was calculated for both 18F-FDG and 18F-FES for biopsy proven lesions. This is given by the formula SUV= A/(ID/BW) , where A is the tissue tracer uptake in microcuries per gram for the hottest pixel in the tumor (SUVmax), ID is the injected dose in millicuries, and BW is the body weight in kilograms. For the purpose of the study, any lesion showing significant uptake (defined as more than the adjacent background) is taken as positive. In case of an indeterminate lesion on 18F-FDG PET-CT, 18F-FES positive lesion was taken as a reference and as a true positive for disease. For extensive and uncountable lesions involving a single organ (liver and lungs), an arbitratory maximum number of 10 lesions were taken for analysis.\u003c/p\u003e\n\u003cp\u003eThe number of lesions suspected for disease by 18F-FDG-PET and 18F-FES PET were calculated out of a total number of lesions seen by either of them together and their sensitivities were compared using the McNemar test. Since it is not possible to demonstrate hepatic metastases on 18F-FES PET scan because of the high physiological uptake and resultant high background activity of the liver, sensitivities were also compared after excluding the liver lesions. Sensitivities were compared for the lesions with lobular histology and for the skeletal metastases. \u0026nbsp;Incremental value of 18F-FES scan was also calculated; this is defined by the percentage of lesions exclusively seen on 18F-FES scan and also the number of indeterminate 18-F FDG lesions that 18-F FES helped characterize. Correlation between ER expression and SUV max on FDG or FES positive lesions were determined by the Spearman rank test. The corresponding P value was calculated using Kruskal-Wallis test.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFifty-seven patients underwent both 18-F FDG PET and 18-F FES PET during the study period, within one week of each study. Of these, 56 (98.2%) were female and one patient was male (1.8%). Twenty-nine (50.9%) of the patients had cancer of the right breast, 25 (43.9%) had disease in the left breast and three patients (5.3%) had bilateral breast cancer.\u003c/p\u003e\n\u003cp\u003eThe reasons for referral for PET scan included response evaluation in metastatic breast cancer in 26 (45.6%) patients, staging in a newly diagnosed case of breast cancer in 30 patients (52.6%) and restaging in a recurrent setting in one patient (1.8%). Most of the patients had infiltrating ductal carcinoma, NST (82.5%), five patients had invasive lobular carcinoma (8.8%) while 5 patients had special type of cancer like mucinous (3 patients), medullary (1 patient) and neuroendocrine (1 patient). Only estrogen receptor positive patients were included in the study. Of these forty-eight patients (84.2%) were progesterone receptor positive and 6 patients (10.5%) were HER 2 positive. The various clinicopathological characteristics of the study population are summarized in the Table 1.\u003c/p\u003e\n\u003cp\u003eTable 1. Clinicopathological characteristics of study patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eAge (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e50 years (Interquartile range=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003cp\u003e56 (98.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eSide of disease\u003c/p\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29 (50.9%)\u003c/p\u003e\n \u003cp\u003e25(43.9%)\u003c/p\u003e\n \u003cp\u003e3 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eDisease status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Known Metastatic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Newly diagnosed\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Recurrent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26 (45.6%)\u003c/p\u003e\n \u003cp\u003e30 (52.6%)\u003c/p\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Infiltrating ductal carcinoma, NST\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Invasive lobular carcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Mucinous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Medullary\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Neuroendocrine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47 (82.5%)\u003c/p\u003e\n \u003cp\u003e5 (8.8%)\u003c/p\u003e\n \u003cp\u003e3 (5.3%)\u003c/p\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eEstrogen receptor\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Positive\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57 (100%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eProgesterone receptor\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Positive\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e48 (84.2%)\u003c/p\u003e\n \u003cp\u003e9 (15.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003eHER2 neu\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Positive\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 319px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (10.5%)\u003c/p\u003e\n \u003cp\u003e51 (89.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eA total of 251 lesions were identified using 18-F FDG PET/CT and 18-F FES PET/CT. Of these, 8 lesions which were proved to be true negatives by biopsy, were excluded. Hence a total of 243 patients were included in the study (n=243).\u003c/p\u003e\n\u003cp\u003eOf \u0026nbsp;these 243 lesions, FDG PET picked up 195 lesions (sensitivity 80.25%) and FES PET identified 149 lesions (sensitivity 61.32%) and this difference was statistically significant (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for all lesions\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eFDG+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eFDG-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eFES+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026lt;\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eFES-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e243\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eConsidering the known limitation of FES in identifying hepatic lesions because of inherent high background activity in the liver, we analyzed all the non-hepatic lesions separately. Of the 236 non-hepatic lesions, FDG PET identified 188 lesions (sensitivity 80.08%) while FES PET identified 149 lesions (sensitivity 63.14%); again this difference was statistically significant (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001) (Table 3).\u003c/p\u003e\n\u003cp\u003eTable 3: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for non-hepatic lesions\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eFDG+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eFDG-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eFES+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eFES-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eA total of 33 skeletal lesions were identified in our study of which FDG PET picked up 20 lesions (sensitivity 60.61%) while FES PET picked up 18 lesions (sensitivity 54.55%). Interestingly this difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e=0.05), showing that FES PET has non inferior accuracy in identifying skeletal metastases (Table 4).\u003c/p\u003e\n\u003cp\u003eTable 4: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for skeletal lesions\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eFDG+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eFDG-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eFES+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eFES-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eConsidering a previous study which had shown greater sensitivity for FES PET in identifying lesions in invasive lobular carcinoma, we analyzed 16 lesions in five patients with invasive lobular carcinoma, included in our study. It was found that, in this case FES PET picked up more lesions (13, sensitivity 81.25%) than FDG PET (10, sensitivity 56.25%), though this difference is not statistically significant (Table 5).\u003c/p\u003e\n\u003cp\u003eTable 5: Comparing Sensitivity of 18-F FDG PET/CT and 18-F FES PET/CT for lesions with invasive lobular cancer histology\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eFDG+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eFDG-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eFES+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eFES-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIt was also found that FES PET exclusively identified 48 out of the 243 lesions (n=48, 19.7%) which were not detected by FDG PET. These included lesions like supraclavicular lymph node, posterior cervical lymph node, skeletal lesions and in one case a breast primary in a patient presenting with an axillary lymph nodal mass. FES-PET also helped in characterizing eighteen FDG-PET positive lesions (n=18, 7 mediastinal lymph nodes and 11 lung nodules) which were clinically suspicious for being inflammatory or granulomatous. Hence 18F-FES had an incremental value in 66 out of the 236 non-hepatic lesions (27.9%) either by characterizing 18-F FDG positive lesions or by exclusive detection of lesions not identified by 18-F FDG PET. As a result of this, FES-PET impacted clinical decision in 12 out of 57 patients (21.05%) (Table 6).\u003c/p\u003e\n\u003cp\u003eTable 6: Percentage of changes in management after following 18-F FES PET\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003eChanges\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003eNumber of patients (n=57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003eChange in management\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (21.05%)\u003c/p\u003e\n \u003cp\u003e46 (78.95%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003eChange in surgical management\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;3 (5.2%)\u003c/p\u003e\n \u003cp\u003e54 (94.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003eChange in staging or course of treatment\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 213px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;9 (15.78%)\u003c/p\u003e\n \u003cp\u003e48 (84.22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWe also analyzed the correlation between ER expression of a lesion and the corresponding 18-F FDG SUVmax and 18-F FES SUVmax. Spearman rank test was utilized for this analysis. Biopsied specimens with IHC was available in 30 patients for a single lesion. No correlation was found between ER expression and the SUVmax of either FDG or FES, though the p-value for FES was approaching significance (\u003cem\u003ep\u003c/em\u003e=0.094) (Table 7).\u003c/p\u003e\n\u003cp\u003eTable 7: Correlation of ER expression with 18-F FDG SUVmax and 18-F FES SUVmax\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"665\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 333px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e18-F FDG SUVmax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e18F-FES SUVmax\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eER expression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003ePearson Correlation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e0.306\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e0.597\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWe utilized the Kruskal-Wallis test to analyze the correlation between the level of ER expression and the SUVmax for both 18-F FDG and 18-F FES. We subdivided the lesions into two categories based on their level of estrogen receptor expression: \u0026lt;80% and \u0026gt;/= 80%. \u0026nbsp;P value was found to be significant (\u003cem\u003ep\u003c/em\u003e=0.031) for the level of ER expression and the 18-F FES SUVmax but not significant for 18-F FDG SUVmax (\u003cem\u003ep\u003c/em\u003e=0.28) (Table 8, Figure1).\u003c/p\u003e\n\u003cp\u003eTable 8: Correlation of level of ER expression with 18-F FDG SUVmax and 18-F FES SUVmax\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"665\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eSUVmax (mean+/_ SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 333px;\"\u003e\n \u003cp\u003eEstrogen Receptor Expression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u0026lt;80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u0026gt;/=80%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e18-F FDG SUVmax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e5.7+/-4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e9.5+/-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e18-F FES SUVmax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e2.2 +/- 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e5.9+/-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study was aimed at analyzing the diagnostic accuracy for 18-F FES PET/CT in comparison to 18-F-FDG PET CT in detecting lesion in estrogen receptor positive breast cancer patients. The results are widely variable in literature. Gupta et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrated a significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) difference in sensitivity favoring 18-F FDG PET (92.21% for FDG-PET and 75.32% for FES PET). However the difference in sensitivity was found to be insignificant when only non-hepatic lesions were considered (91.18% for FDG PET versus 85.29% for FES-PET, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.21). Liu et al [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] reported sensitivity of 90.8% for FDG-PET and 82.8% for FES when they conducted their study on newly diagnosed ER receptor positive breast cancer patients. In our study, FDG-PET detected more overall lesions compared to FES-PET (sensitivity 80.25% versus 61.32%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) which is in accordance with the findings of the studies by both Gupta et al and Liu et al. However, unlike the study by Gupta et al, even after excluding the hepatic lesions, FDG PET identified significantly more lesions than FES PET (sensitivities 80.08% for FDG and 63.14% for FES, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This might be attributable to the heterogeneity of the study population which included metastatic as well as non-metastatic diseases, untreated patients as well as patients who have received previous systemic therapy (chemotherapy, immunotherapy and endocrine therapy) and also HER2 positive patients and a variety of histologies leading to an array of confounding factors.\u003c/p\u003e \u003cp\u003eLiu et al had reported that 18F-FES PET had better diagnostic sensitivity than 18-F FDG PET in detection of ER positive skeletal metastases [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Our study was not powered for subgroup analysis but we compared the sensitivities of 18F-FDG PET and 18-F FES PET for detecting exclusively skeletal lesions. Interestingly, both the investigations were found to have equivalent sensitivity in diagnosing skeletal lesions (sensitivities 60.61% for FDG-PET and 54.55% for FES-PET, p\u0026thinsp;=\u0026thinsp;0.05). Though the number of skeletal lesions analyzed (n\u0026thinsp;=\u0026thinsp;33) was very less to draw a definitive conclusion, this can have implications in directing future studies comparing the two investigation modalities in patients who have exclusively skeletal metastases.\u003c/p\u003e \u003cp\u003eA study from MSKCC [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] had reported that in patients with invasive lobular cancer (ILC) histology, FES PET detected more lesions than FDG PET. Similarly in our study, we found that when the 16 lesions in 5 patients with ILC were exclusively analyzed, FES-PET picked up more lesions (13, sensitivity 81.25%) than FDG-PET (10, sensitivity 56.25%), even though this difference is not statistically significant (p\u0026thinsp;=\u0026thinsp;0.09). Again, the small number of patients and the small number of lesions in this subgroup does not allow us to draw any conclusion. But it does point towards a better accuracy of FES-PET in detecting lesions in lobular histology.\u003c/p\u003e \u003cp\u003eWe also analyzed whether ER expression in tissues measured by IHC has any correlation with FDG or FES uptake. Dehdashti et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] in their study had documented that there was no significant correlation between ER expression measured by IHC and FDG uptake in corresponding tumor tissues but there was overall good agreement (88%) between IHC assays and FES-PET. Gupta et al [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] demonstrated a positive correlation between ER expression with 18-F FES uptake but no correlation was found with 18-F FDG uptake. In our study, we found no positive correlation between ER expression with either 18-F or 18-F FES uptake. However when we analyzed the correlation between the level of ER expression (as reported by IHC) with the mean FDG SUVmax and mean FES SUVmax, we found a statistically significant correlation (p\u0026thinsp;=\u0026thinsp;0.031) in favour of FES PET. This is in accordance with the study by Gupta et al who demonstrated a positive p trend of 0.011 with 18F-FES PET SUVmax and the level of ER expression. This indicates that FES-PET might have better diagnostic accuracy in detecting lesions which are strongly ER positive (\u0026gt;\u0026thinsp;80%) compared to lesions which have lesser proportion of ER positivity.\u003c/p\u003e \u003cp\u003eAn important aspect of our study was determining the incremental value of FES-PET with either the number of lesions exclusively identified by FES-PET or by the number of FDG-positive lesions that FES helped characterize the lesions. The latter is specifically important in the context of the Indian subcontinent where granulomatous infections are prevalent and might lead to detection of false positive lesions on FDG because of inflammation.\u003c/p\u003e \u003cp\u003eIn our study, FES PET had an incremental value in 66 out of 234 non-hepatic lesions (27.9%) either by exclusively identifying 48 lesions (19.7%) or by helping characterize eighteen other FDG positive lesions. Liu et al [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] had reported that addition of FES-PET changed the management in 26.3% of patients while in the study by Gupta et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] the value was 20%. In our study it was found that clinical decision making was impacted in 12 out of 57 patients (21.05%) either by changing the intent of treatment or course of treatment or by leading to further investigations like biopsy.\u003c/p\u003e \u003cp\u003eThe small sample size and the heterogeneity of the study population is the primary limitation of our study. We had included HER 2 positive patients in our study, however, the effect of HER2 positivity on FES uptake has not been studied and hence it emerges as a confounding factor. There is also the issue of inherent high background uptake of FES in liver which makes detection of liver metastasis quite difficult. Finally, in spite of promising results, no definite conclusions can be drawn from subgroup analyses (for example skeletal lesions and lobular histology) because the study was not powered for these analyses.\u003c/p\u003e \u003cp\u003eIn summary, our study demonstrates the utility of 18-F FES PET when used along with 18F- FDG PET in ER receptor positive breast cancer patients. 18-F FDG PET maintains significant overall sensitivity in detection of lesions. However the value of 18F-FES PET lies in its ability to characterize FDG indeterminate lesions and also to detect exclusive lesions in certain scenarios which might change course of clinical management. Especially when 18-F FDG PET fails to detect metabolically active lesions in the background of high clinical suspicion, 18F-FES PET can be used as a problem solving tool. Also, in case of an FDG avid but a FES non-avid lesion in an otherwise non-suspicious scenario, biopsy should be done to rule out non-neoplastic inflammatory lesions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e18-F FES PET CT can be a valuable investigation in strongly ER positive breast cancer patients along with 18-F FDG PET. Considering the findings of our study and existing current evidence, it can be used for better characterization of FDG indeterminate lesions for providing better specificity. Its additional value in detecting skeletal metastases and in lobular histology needs to be investigated with further studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIHC - Immunohistochemistry\u003c/p\u003e\n\u003cp\u003eER - Estrogen Receptor\u003c/p\u003e\n\u003cp\u003ePR - Progesterone Receptor\u003c/p\u003e\n\u003cp\u003eHER2 - Human Epidermal Growth Factor Receptor 2\u003c/p\u003e\n\u003cp\u003ePET - Positron Emission Tomography\u003c/p\u003e\n\u003cp\u003e18-F FDG - 2-[\u003csup\u003e18\u003c/sup\u003eF]-fluoro-2-deoxy-D-glucose\u003c/p\u003e\n\u003cp\u003e18-F FES - 16a-[\u003csup\u003e18\u003c/sup\u003eF]fluoro-17b-estradiol\u003c/p\u003e\n\u003cp\u003eNCCN - National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003eSUVmax - Maximum Standardized Uptake Value\u003c/p\u003e\n\u003cp\u003eILC - Invasive Lobular carcinoma\u003c/p\u003e\n\u003cp\u003eMSKCC- Memeorial Sloan Kettering Cancer Center\u003c/p\u003e\n\u003cp\u003eECOG- Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eMBq- Megabecquerels\u003c/p\u003e\n\u003cp\u003emAs- Milliampereseconds\u003c/p\u003e\n\u003cp\u003ekVp- Kilovoltage peak\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors state that this work has not received any funding.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conception: Dr P S Choudhury, Dr Rajeev Kumar\u003c/p\u003e\n\u003cp\u003eData collection: Dr Suchita Chowdhury\u003c/p\u003e\n\u003cp\u003eData analysis: Dr Suchita Chowdhury, Dr P S Choudhury\u003c/p\u003e\n\u003cp\u003eManuscript preparation: Dr Suchita Chowdhury\u003c/p\u003e\n\u003cp\u003eManuscript review and editing: Dr Rajeev Kumar, Dr A K Dewan, Dr P S Choudhury, Dr Manoj Gupta, Dr Garima Daga\u003c/p\u003e\n\u003cp\u003eProject administration: Dr A K Dewan, Dr Vaishali Zamre, Dr D C Doval, Dr Pankaj Goyal, Dr Sumit Goyal, Dr Ullas Batra\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData will be available on request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis study was performed in line with the principles of the Declaration of Helsinki.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInstitutional Review Board approval was obtained\u0026nbsp;(RGCIRC/IRB-BHR/112/2022, issued 06.10.2022)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for participation:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all subjects (patients) in this study.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe authors affirm that all participants provided informed consent for publication of the data from research in this study\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, Adamoli L, Munzone E, Sciandivasci A, De Vita F, Goldhirsch A, Nol\u0026egrave; F. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014 Jan;50(2):277-89. doi: 10.1016/j.ejca.2013.10.004. Epub 2013 Nov 21. PMID: 24269135.\u003c/li\u003e\n \u003cli\u003eHilton JF, Amir E, Hopkins S, Nabavi M, DiPrimio G, Sheikh A, Done SJ, Gianfelice D, Kanji F, Dent S, Barth D, Bouganim N, Al-Najjar A, Clemons M. Acquisition of metastatic tissue from patients with bone metastases from breast cancer. Breast Cancer Res Treat. 2011 Oct;129(3):761-5. doi: 10.1007/s10549-010-1264-6. Epub 2010 Nov 27. PMID: 21113656.\u003c/li\u003e\n \u003cli\u003eHarris JR, Lippman ME, Osborne CK, Morrow M. Diseases of the Breast. Lippincott Williams \u0026amp; Wilkins; 2012 Mar 28.\u003c/li\u003e\n \u003cli\u003eRavdin PM, Green S, Dorr TM, McGuire WL, Fabian C, Pugh RP, Carter RD, Rivkin SE, Borst JR, Belt RJ. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. Journal of clinical oncology. 1992 Aug;10(8):1284-91.\u003c/li\u003e\n \u003cli\u003eKiesewetter DO, Kilbourn MR, Landvatter SW, et al; Radiochemistry and radiopharmaceuticals. J Nucl Med 25:1212-1221, 1984984\u003c/li\u003e\n \u003cli\u003eMathias CJ, Welch MJ, Katzenellenbogen JA, Brodack JW, Kilbourn MR, Carlson KE, Kiesewetter DO. Characterization of the uptake of 16\u0026alpha;-([18F] fluoro)-17\u0026beta;-estradiol in DMBA-induced mammary tumors. International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology. 1987 Jan 1;14(1):15-25.\u003c/li\u003e\n \u003cli\u003eMintun MA, Welch MJ, Siegel BA, Mathias CJ, Brodack JW, McGuire AH, Katzenellenbogen JA. Breast cancer: PET imaging of estrogen receptors. Radiology. 1988 Oct;169(1):45-8.\u003c/li\u003e\n \u003cli\u003eDehdashti F, Mortimer JE, Siegel BA, Griffeth LK, Bonasera TJ, Fusselman MJ, Detert DD, Cutler PD, Katzenellenbogen JA, Welch MJ. Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays. Journal of Nuclear Medicine. 1995 Oct 1;36(10):1766-74.\u003c/li\u003e\n \u003cli\u003eUlaner GA, Mankoff DA, Clark AS, Fowler AM, Linden HM, Peterson LM, Dehdashti F, Kurland BF, Mortimer J, Mouabbi J, Moon DH. Summary: appropriate use criteria for estrogen receptor\u0026ndash;targeted PET imaging with 16\u0026alpha;-18F-fluoro-17\u0026beta;-fluoroestradiol. Journal of Nuclear Medicine. 2023 Mar 1;64(3):351-4.\u003c/li\u003e\n \u003cli\u003e Gupta M, Datta A, Choudhury P, Dsouza M, Batra U, Mishra A. Can 18F-fluoroestradiol positron emission tomography become a new imaging standard in the estrogen receptor-positive breast cancer patient: a prospective comparative study with 18F-fluorodeoxyglucose positron emission tomography?. World Journal of Nuclear Medicine. 2017 Apr;16(02):133-9\u003c/li\u003e\n \u003cli\u003e Liu C, Gong C, Liu S, Zhang Y, Zhang Y, Xu X, Yuan H, Wang B, Yang Z. 18F‐FES PET/CT Influences the Staging and Management of Patients with Newly Diagnosed Estrogen Receptor‐Positive Breast Cancer: A Retrospective Comparative Study with 18F‐FDG PET/CT. The oncologist. 2019 Dec 1;24(12):e1277-85.\u003c/li\u003e\n \u003cli\u003e Liu C, Ma G, Xu X, Song S, Yang Z. Can 18F-FES PET Improve the Evaluation of 18F-FDG PET in Patients With Metastatic Invasive Lobular Carcinoma?. Clinical Nuclear Medicine. 2024 Apr 1;49(4):301-7.\u003c/li\u003e\n \u003cli\u003e Ulaner GA, Jhaveri K, Chandarlapaty S, Hatzoglou V, Riedl CC, Lewis JS, Mauguen A. Head-to-head evaluation of 18F-FES and 18F-FDG PET/CT in metastatic invasive lobular breast cancer. Journal of Nuclear Medicine. 2021 Mar 1;62(3):326-31.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"FDG PET, FES PET, Estrogen receptor, Breast cancer","lastPublishedDoi":"10.21203/rs.3.rs-6446808/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6446808/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose:\u003c/h2\u003e \u003cp\u003e16a-[\u003csup\u003e18\u003c/sup\u003eF]fluoro-17b-estradiol (FES) is a promising synthetic estrogen analogue which when used as tracer for PET scan, provides an in vivo estimate of tumor estrogen receptor (ER) status in breast cancer. This study aims to investigate the diagnostic accuracy of FES PET scan in diagnosing ER positive lesions in breast cancer patients.\u003c/p\u003e\u003ch2\u003eMethod:\u003c/h2\u003e \u003cp\u003eIn this single centre prospective study, 57 ER positive breast cancer patients underwent both FDG PET and FES PET during the study period of two years. The number of lesions suspected for disease by either modality were calculated and their sensitivities were compared.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e251 lesions were identified using FDG PET/CT and FES PET/CT; eight were proven to be true negatives by biopsy and were excluded. FDG PET had better sensitivity for detecting lesions, both overall (80.25% vs 61.32%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) as well as non hepatic (80.08% vs 63.14%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, FES PET exclusively identified 48 lesions and also helped characterize 18 FDG-PET positive lesions. Hence 18F-FES had an incremental value in 66 out of the 236 non-hepatic lesions (27.9%) either by characterizing 18-F FDG positive lesions or by exclusive detection of lesions not identified by 18-F FDG PET and resulted in change of management of 21.05% of patients.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e18-F FDG PET displays overall better sensitivity for detecting lesions. However, the value of 18-F FES PET lies in the exclusive lesions it identified and the number of FDG avid lesions it helped characterize, both by its negative as well as positive findings.\u003c/p\u003e","manuscriptTitle":"Comparative study between 18-F FDG PET/CT and 18-F FES PET/CT in estrogen receptor positive breast cancer patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-08 20:38:15","doi":"10.21203/rs.3.rs-6446808/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f05ac764-b12c-4bac-bcd9-93a4912ee456","owner":[],"postedDate":"May 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-09T03:53:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-08 20:38:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6446808","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6446808","identity":"rs-6446808","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}