Risk of Maculopathy in Tamoxifen Users: Drug Exposure and Risk Factors

Risk of Maculopathy in Tamoxifen Users: Drug Exposure and Risk Factors | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Article Risk of Maculopathy in Tamoxifen Users: Drug Exposure and Risk Factors Hyeon Yoon Kwon, Jiyeong Kim, Seong Joon Ahn This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3915748/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract Tamoxifen, a pivotal therapy for hormone receptor-positive breast cancer, is known for its efficacy in reducing breast cancer recurrence and mortality. However, concerns about potential ocular complications, particularly maculopathy, have emerged. This study aims to investigate the risk and associated factors of diverse macular conditions in tamoxifen users, considering drug exposure, demographics, and systemic diseases. A nationwide cohort of tamoxifen users, comprised of 14,267 tamoxifen users, was analyzed using the Health Insurance Review and Assessment (HIRA) database in South Korea. Demographic and clinical characteristics were examined, and the cumulative incidence of macular diseases was stratified by age and cumulative tamoxifen dosage. Hazard ratios were calculated for risk factors, including age, sex, and systemic diseases affecting drug metabolism. Cumulative incidences of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema were 26.4%, 11.4%, and 6.5%, respectively. The risk increased with age and cumulative tamoxifen dosage. Significant risk factors included age, sex, diabetes, hypertension, and kidney disease whereas dyslipidemia and liver disease showed no significant association with the macular conditions. Tamoxifen-induced maculopathy poses a concern for prescribing physicians and ophthalmologists, and this study provides valuable insights into its risk and risk factors. The complex interplay between age, cumulative tamoxifen dosage, and systemic diseases highlights the need for vigilant monitoring and screening strategies. This study may contribute to evidence-based guidelines for tamoxifen maculopathy screening, emphasizing the importance of considering multiple factors for recommendation on screening timing and frequency. Health sciences/Diseases/Eye diseases Health sciences/Risk factors Figures Figure 1 Figure 2 INTRODUCTION Tamoxifen, a selective estrogen receptor modulator, has long been a cornerstone in the treatment of hormone receptor-positive breast cancer. 1 , 2 Its efficacy in reducing the risk of recurrence and mortality in breast cancer patients is well established. 3 However, the therapeutic benefits of tamoxifen are not without potential ocular complications, particularly those affecting the macula. 1 , 2 , 4 – 7 Recent studies have focused on the risk and associated factors of maculopathy, prompting the need for comprehensive investigations into the risk factors and incidence rates of ocular complications associated with this widely prescribed drug. 1 , 8 The ocular side effects of tamoxifen, specifically tamoxifen-related retinopathy (maculopathy), have raised concerns among prescribing physicians and ophthalmologists. Alterations in the retina are reported to manifest in approximately 12% of individuals who have been using a daily dose of 20 mg of tamoxifen for a period exceeding two years, 8 corresponding to a cumulative dose of approximately 15 g. These alterations include the presence of crystalline deposits, telangiectasia, hyperreflective deposits in the inner retinal layers, pseudocystic foveal cavitation, and cystoid macular edema. 1 , 2 Understanding the demographic and clinical characteristics of individuals at a higher risk of developing maculopathy is crucial for identifying preventive measures and optimizing patient care. In the present study, we investigated the risk of diverse macular conditions potentially associated with tamoxifen use in a nationwide cohort of tamoxifen users. By examining clinical characteristics such as age, sex, and underlying diseases that potentially affect drug metabolism or macular diseases, we explored the risk factors for macular conditions by focusing on drug exposure and other systemic diseases. This study aimed to delineate the correlation between these factors and the occurrence of several types of maculopathies, providing valuable insights into the dose-response relationship between macular diseases and drug exposure and aiding in the formulation of evidence-based guidelines for tamoxifen maculopathy screening. METHODS Study population This study used the Health Insurance Review and Assessment (HIRA) database, a comprehensive repository encompassing health claims data of approximately 50 million individuals in South Korea. 9 , 10 This database, previously employed in a similar cohort study, contains information on diagnoses, procedures, prescriptions, visit dates, and demographic characteristics, utilizing codes from the Korean Standard Classification of Diseases, 8th Revision, with modifications from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Tamoxifen users were identified within the database, focusing on individuals who initiated tamoxifen therapy between January 1, 2013, and December 31, 2021. To ensure accurate assessment of treatment duration, patients using tamoxifen before January 1, 2015, were excluded. Individuals with macular diseases before initiating tamoxifen treatment were also excluded aiming to include only patients with macular conditions occurring after tamoxifen initiation. The detailed inclusion/exclusion criteria and the number of subjects included/excluded are presented in Fig. 1 . The Institutional Review Board of Hanyang University Hospital approved the study (IRB File no. 2023-01-003), which was conducted in accordance with the Declaration of Helsinki. The need for informed consent was waived by the Institutional Review Board of Hanyang University Hospital because of the retrospective nature of the study and the use of deidentified data. The reporting adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Definitions and evaluations The identification and classification of macular conditions were based on specific KCD-8 codes within the dataset. Overall, macular diseases were defined as the presence of H31.0 (macular scar), H35.3 (degeneration of the macula and posterior pole; including from H35.30 [nonexudative age-related macular degeneration] to H35.39 [unspecified macular degeneration]), or H35.80 (macular edema). Other maculopathy excluding common macular diseases was delineated by the code H35.37 (toxic maculopathy) and H35.39 (unspecified macular degeneration; category for the macular diseases after exclusion of common macular diseases such as age-related macular degeneration and epiretinal membrane), while macular edema was specifically identified by the code H35.80 (macular edema). The cumulative incidence of and risk factors for maculopathies among tamoxifen users were investigated. Among the patients receiving sufficient cumulative tamoxifen exposure, specifically 15 g in total (conventional daily dose of 20 mg for two years), the cumulative incidences of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema during the study period were evaluated. These were stratified by cumulative dose and age categories into three cumulative dose groups (15 – < 30 g, 30 –< 45 g, and ≥ 45 g) and six age groups (below 40, 40–49, 50–59, 60–69, and ≥ 70). To identify the risk factors, hazard ratios (HR) were obtained for demographic factors and systemic diseases, including common systemic diseases and those affecting drug metabolism (liver and kidney) and presented with 95% confidence intervals (CI). Associations between sex, age, diabetes, hypertension, dyslipidemia, renal disease, liver disease, and risk of maculopathies were evaluated in tamoxifen users. Using the health claims data from the HIRA database, we assessed the tests performed for macular evaluation, including fundoscopy/fundus photography, OCT, and fluorescein angiography. The percentage of patients undergoing each test was assessed and presented as demographic and clinical characteristics. Data analysis Descriptive statistics summarized the findings, presenting categorical variables as frequencies and percentages and continuous variables as mean (standard deviation) or median (interquartile range). Chi-square or Fisher’s exact tests were used to compare categorical variables between the groups. In our study, we used the Cochran–Mantel–Haenszel test, a statistical method for analyzing stratified or matched categorical data, to assess the association between a characteristic and a binary outcome, such as maculopathy status, while accounting for the effects of stratification and potential confounding factors. Statistical significance was set at P < 0.05. SAS Enterprise Guide version 7.1 conducted all analyses. RESULTS Demographic and Clinical Characteristics of Study Population Table 1 provides a comprehensive overview of the demographic and clinical characteristics of the tamoxifen users enrolled in this study, revealing the diverse profiles of individuals undergoing tamoxifen therapy. The cohort, consisting of 14,267 users, exhibited a notable sex distribution, with 79.9% female and 20.1% male. The mean age of the population was 54.0 years, with a range from 20 to ≥ 70 years. Underlying diseases including diabetes (30.8%), hypertension (37.7%), dyslipidemia (61.1%), kidney disease (16.1%), and liver disease (41.1%) were prevalent in the cohort. The primary indications for tamoxifen use varied, with breast cancer being the dominant indication, accounting for 58.7% of the cases. Additionally, the table presents the mean duration of tamoxifen use (33.1 ± 23.4 months) and the distribution across different duration categories. The cumulative daily dose of tamoxifen, an indicator of drug exposure, was delineated, with 40.5% of the users falling within the 45 g, 2.0% (n = 284). Approximately 59.5% of those at risk of maculopathy had a substantial cumulative tamoxifen exposure (equal to or greater than 15 g) for retinal toxicity, represent a significant proportion of the overall tamoxifen users. Table 1 Demographic and clinical information of the tamoxifen users included in this study Characteristics Overall users (n = 14,267) Sex Male:female 2,874(20.1%):11,393(79.9%) Mean age ( ± SD), years 54.0 ± 12.5 < 20 27 (0.2%) 20–29 129 (0.9%) 30–39 961 (6.7%) 40–49 5,358 (37.6%) 50–59 3,272 (22.9%) 60–69 2,410 (16.9%) ≥ 70 2,110 (14.8%) Underlying disease Diabetes 4,394 (30.8%) Hypertension 5,374 (37.7%) Dyslipidemia 8,711 (61.1%) Kidney disease 2,302 (16.1%) Liver disease 5,865 (41.1%) Indication for tamoxifen use Breast cancer 8,373 (58.7%) Ductal carcinoma in situ 1,849 (13.0%) Gynecomastia 2,484 (17.4%) Others 1,561 (10.9%) Mean duration of tamoxifen use ( ± SD), months 33.1 ± 23.4 Less than 1 year 1–2 years 3,972 (27.8%) 1,645 (11.5%) 2–3 years 3–4 years 4–5 years 5 years or longer 1,981 (13.9%) 1,890 (13.3%) 2,800 (19.6%) 1,979 (13.9%) Mean cumulative daily dose of tamoxifen ( ± SD), mg/day Less than 15 g 15–30 g 30–45 g 45 g or greater 19.8 ± 14.2 5,783 (40.5%) 3,931 (27.6%) 4,269 (29.9%) 284 (2.0%) Macular evaluation Fundus examination (funduscopy or fundus photography) Optical coherence tomography Fluorescein angiography 13,931 (97.6%) 14,267 (100%) 751 (5.3%) SD, standard deviation. Cumulative Incidences of Diverse Macular Conditions in Overall Patients and Subgroups According to Drug Exposure Level or Age Groups Figure 2 shows the overall cumulative incidence of macular diseases (26.4%; n = 3,764), maculopathy excluding common macular diseases (11.4%; n = 1,632), and macular edema (6.5%; n = 925) in the entire patient cohort during the study period. However, common macular diseases like age-related macular degeneration, epiretinal membrane, and macular hole were observed in 8.5% of the included patients over the study period. Table 2 presents the cumulative incidence of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema among the different risk groups of tamoxifen users during the study period, stratified by cumulative dose and age categories. For overall macular diseases, the cumulative incidence showed variations across both age and cumulative dose groups. Notably, a trend of increasing cumulative incidence was observed with higher age groups and cumulative tamoxifen doses (P < 0.001 by the Cochran–Mantel–Haenszel test), which was statistically significant. This pattern is consistent with other maculopathy excluding common macular diseases and macular edema, highlighting the potential influence of age and cumulative tamoxifen dosage on the development of these macular conditions. The presented P-values (< 0.001 for both other maculopathy excluding common macular diseases and macular edema) indicated statistically significant differences among the risk groups. These findings suggest the importance of considering both age and cumulative tamoxifen dosage when assessing the overall risk of macular diseases, other maculopathy excluding common macular diseases, and macular edema in tamoxifen users. Table 2 Cumulative incidences of overall macular diseases, unspecified maculopathy excluding common macular diseases, and macular edema in different risk groups of patients with tamoxifen exposure ≥ 15 g Cumulative dose group Age P value* < 40 (n = 695) 40–49 (n = 4,018) 50–59 (n = 2,090) 60–69 (n = 1,052) ≥ 70 (n = 629) Overall macular diseases 15-30g 41 (12.9%) 353 (20.1%) 233 (23.8%) 193 (36.6%) 136 (39.0%) < 0.001 30-45g 55 (16.3%) 447 (21.4%) 293 (27.4%) 211 (42.0%) 132 (48.4%) 45g or greater 4 (9.8%) 42 (24.3%) 11 (26.8%) 13 (59.1%) 4 (57.1%) Maculopathy excluding common macular diseases 15-30g 14 (4.4%) 160 (9.1%) 96 (9.8%) 86 (16.3%) 56 (16.1%) < 0.001 30-45g 19 (5.6%) 184 (8.8%) 132 (12.4%) 106 (21.1%) 64 (23.4%) 45g or greater 1 (2.4%) 16 (9.3%) 8 (19.5%) 4 (18.2%) 1 (14.3%) Macular edema 15-30g 18 (5.7%) 93 (5.3%) 60 (6.1%) 37 (7.0%) 29 (8.3%) < 0.001 30-45g 20 (5.9%) 131 (6.3%) 54 (5.1%) 45 (9.0%) 29 (10.6%) 45g or greater - 6 (3.5%) 1 (2.4%) 4 (18.2%) - *Cochran-Mantel-Haenszel test Risk Factors for Maculopathy in Tamoxifen Users Table 3 presents the HR with 95% CI and corresponding P-values for several demographic and systemic factors that may impact drug metabolism and contribute to the development of macular conditions in tamoxifen users. For all the three distinct outcomes including overall macular diseases, other maculopathy excluding common macular diseases, and macular edema, significant associations between sex and the risk of macular conditions were noted. (P < 0.001) Age was also identified as a substantial risk factor for all three macular conditions, emphasizing the heightened vulnerability of older individuals to the development of macular diseases, other maculopathy excluding common macular diseases, and macular edema (all P < 0.001). Table 3 Risk factors for macular diseases in tamoxifen users: demographic and systemic disease factors Factors Overall macular diseases Maculopathy other than common macular diseases Macular edema HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Sex* 0.649 (0.603–0.698) < 0.001 0.695 (0.622–0.778) < 0.001 0.661 (0.571–0.765) < 0.001 Age 1.029 (1.027–1.032) < 0.001 1.032 (1.028–1.036) < 0.001 1.014 (1.009–1.019) < 0.001 Diabetes 1.116 (1.044–1.193) 0.001 1.030 (0.930–1.141) 0.568 1.195 (1.046–1.365) 0.009 Hypertension 1.359 (1.274–1.449) < 0.001 1.336 (1.212–1.473) < 0.001 1.233 (1.083–1.404) 0.002 Dyslipidemia 1.044 (0.976–1.117) 0.209 1.051 (0.948–1.166) 0.341 0.981 (0.857–1.123) 0.782 Kidney disease 1.081 (0.996–1.172) 0.061 0.972 (0.858–1.102) 0.662 1.045 (0.887–1.232) 0.596 Liver disease 0.982 (0.921–1.047) 0.583 0.949 (0.861–1.047) 0.297 0.941 (0.827–1.071) 0.359 *Male as reference Among the systemic diseases, diabetes and hypertension emerged as significant contributors to the overall risk of macular diseases and macular edema, with hypertension being additionally associated with maculopathy other than common macular diseases (all P < 0.05), whereas dyslipidemia was not associated with any of the three conditions. Kidney and liver diseases, potentially affecting tamoxifen metabolism, did not exhibit a statistically significant association with any of the studied macular conditions (all P > 0.05). DISCUSSION Tamoxifen, a vital component in the treatment of hormone receptor-positive breast cancer, has long been recognized for its efficacy in reducing cancer recurrence and mortality. 3 However, because the ocular side effects of tamoxifen, particularly tamoxifen maculopathy, present a critical concern in clinical practice for tamoxifen users, 1 , 2 our study investigated the risk of macular conditions potentially associated with tamoxifen toxicity among users. From a comprehensive analysis of the demographic and clinical characteristics of the tamoxifen user cohort, our findings on the factors influencing the risk of maculopathy may contribute to the growing body of knowledge concerning the risk and risk factors of maculopathy in tamoxifen users, a topic not extensively studied. Tamoxifen retinopathy can present in several forms 4–8,11−14 and similarities with macular telangiectasia, type 2 have been noted in previous studies 1 , 15 Therefore, the macular abnormalities observed on OCT in tamoxifen users may be recognized as a different condition, rather than tamoxifen maculopathy. Furthermore, this maculopathy has not been adequately recognized by ophthalmologists due to limited awareness; thus, it is likely that it has been misdiagnosed as other macular conditions such as macular degeneration and macular edema than toxic maculopathy. To maximize capturing potential macular conditions associated with tamoxifen toxicity, we included several macular conditions for the outcomes while excluding patients with such conditions prior to tamoxifen use. This might have led to an underestimation of the incidence of tamoxifen maculopathy if the analysis was limited to the code for toxic maculopathy in our cohort, which was found to be less than 1%. The cumulative incidence in previous studies varied from 0.9–12%, largely depending on the cumulative dose in the study population. 1 , 8 Furthermore, macular diseases generally occur in elderly individuals, indicating the susceptibility of older patients to macular diseases. Recent studies have reported higher incidence rates than previous studies, which might be partly explained by advances in retinal imaging and its increased sensitivity in detecting microscopic retinal changes in tamoxifen users. Our study, including the patients undergoing OCT imaging, showed maculopathy excluding common macular diseases, the most specific category for tamoxifen maculopathy among our outcomes, in 11% of overall tamoxifen users. This was comparable to the recent figure of 12% among patients receiving tamoxifen. 8 The cumulative incidences of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema, stratified by cumulative dose and age categories, provide valuable insights into the dose-response relationship between drug exposure and maculopathy incidence and age-related susceptibility. The statistical significance of these trends further strengthens the evidence of the impact of these factors on maculopathy risk. The increasing cumulative incidence observed in older age groups and with higher cumulative tamoxifen doses highlights the relevance of age and cumulative tamoxifen dosage in the development of macular conditions. This underscores the need to simultaneously consider both factors in maculopathy screening, suggesting that future guidelines should incorporate these aspects when formulating screening recommendations. Assessment of risk factors for macular diseases in tamoxifen users also revealed significant associations with demographic and systemic disease factors. Sex, age, diabetes mellitus, hypertension, and kidney disease are substantial contributors to the risk of maculopathy. Notably, dyslipidemia did not exhibit a significant association with macular conditions, although a recent study identified hypercholesterolemia as a risk factor for tamoxifen maculopathy. 8 These findings emphasize the relationship between a few systemic diseases potentially affecting retinal diseases such as diabetes and hypertension and development of tamoxifen-induced maculopathy. The heightened vulnerability of older individuals, as indicated by the increasing HR with age, underscores the need for vigilant monitoring of this demographic subgroup. Interestingly, despite the potential impact on drug metabolism and excretion, liver diseases showed no significant association with the incidence of macular diseases. This observation is notable considering that tamoxifen is primarily excreted by the liver and biliary tract, implying that liver disease may influence the systemic concentration of tamoxifen. However, liver function could not be assessed in this study, which limits drawing conclusion on the association between liver diseases or function and tamoxifen maculopathy incidences. While our study provides valuable insights into the risk factors and cumulative incidence of tamoxifen-induced maculopathy, certain limitations must be acknowledged to ensure a nuanced interpretation of the findings. The retrospective nature of our study, which relied on the HIRA database, introduced some inherent limitations. The identification and classification of macular conditions were based on specific KCD-8 codes within the dataset, potentially leading to misclassification or under-reporting. The operational definitions used for the inclusion and exclusion criteria may not have captured all relevant cases, thus contributing to selection bias. The absence of direct clinical assessments and the reliance on diagnostic codes may result in an incomplete representation of tamoxifen maculopathy status. Moreover, we acknowledge the possibility of unmeasured confounding factors that were not accounted for in our analysis. Lifestyle factors, genetic predisposition, and other medications that could influence the development of maculopathy were not comprehensively considered in our study. Furthermore, the generalizability of our findings may be limited because this study focused exclusively on the South Korean population. Healthcare systems and patient demographics vary across regions, and caution should be exercised when extending our results to other populations with different characteristics. Despite these limitations, our study provides a robust exploration of the risk factors and cumulative incidence of diverse macular conditions among tamoxifen users at the national level. The insights gained from this study have implications for clinical practice by guiding the formulation of evidence-based guidelines for tamoxifen-induced maculopathy screening. The intricate interplay between age, cumulative tamoxifen dosage, and systemic diseases highlighted in this study serves as a foundation for future research and enhances our understanding of the ocular complications associated with this widely prescribed breast cancer therapy. Future research may further address tamoxifen maculopathy in diverse ethnic groups by incorporating more detailed clinical assessments to identify tamoxifen-induced maculopathy and by considering a broader range of potential confounding factors to enhance the generalizability of our findings. Declarations Competing interests The authors declare no competing interests. Author Contribution All authors planned and designed the study. H.Y.K. and S.J.A. wrote the main manuscript text, and prepared the figures. J.K. and H.Y.K. provided the data mining and statistical assistance. All authors acquired, analyzed and interpreted the data. S.J.A. and H.Y.K. did critical revision of the manuscript for important intellectual content. S.J.A. obtained funding. S.J.A. supervised the study. All authors reviewed the manuscript. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgements This work was supported by National Research Foundation of Korea grants (NRF-2021R1G1A1013360) funded by the Korean Government MSIT. Neither the sponsor nor the funding organization had any role in the design or conduct of this research. 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Ophthalmol Retina 3, 681–689, doi: 10.1016/j.oret.2019.03.014 (2019). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 22 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 27 Mar, 2024 Reviews received at journal 08 Mar, 2024 Reviews received at journal 03 Mar, 2024 Reviewers agreed at journal 25 Feb, 2024 Reviewers invited by journal 22 Feb, 2024 Editor assigned by journal 22 Feb, 2024 Editor invited by journal 10 Feb, 2024 Submission checks completed at journal 10 Feb, 2024 First submitted to journal 31 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiyeong","middleName":"","lastName":"Kim","suffix":""},{"id":272315471,"identity":"83543a12-4a68-4dbb-8f1f-8d7c8d6b05ea","order_by":2,"name":"Seong Joon Ahn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYDACCRCukJADsQ88IF7LGQtjsJYEorUwtlUkNoA4RGnhn917+IPFGYn0+WGHHwJtsZPTbSBkyZ1zaRJAv+RuvJ1mANSSbGx2gJA1N3LMgH4BapmdANJyIHEbIS3yN3KMP0i2SaQbzk7/QJwWgxs5BhJALQny0jlE2mIIdJgE0GGGG6RzCg4kGBDhFzmgwz5LVNTJy89O3/zhQ4WdHGHvAwEzKG4MwCoNiFAOAowfgIR8A5GqR8EoGAWjYOQBAC7QRXVpIxfeAAAAAElFTkSuQmCC","orcid":"","institution":"Hanyang University Hospital, Hanyang University College of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Seong","middleName":"Joon","lastName":"Ahn","suffix":""}],"badges":[],"createdAt":"2024-02-01 02:44:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3915748/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3915748/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-67670-x","type":"published","date":"2024-07-22T16:15:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51041716,"identity":"9dd3a93c-ee36-425c-bb0f-12a641a4587f","added_by":"auto","created_at":"2024-02-13 07:11:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":527948,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart illustrating the inclusion and exclusion criteria employed in this study, along with the populations after applying these criteria.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3915748/v1/db41aa9cfe4b6b8fcd0ec444.png"},{"id":51041715,"identity":"8bf387cd-3e57-43ac-a8a2-2bc04bf14441","added_by":"auto","created_at":"2024-02-13 07:11:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100925,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidences of macular conditions potentially affected by tamoxifen in the users\u003c/p\u003e","description":"","filename":"Figure2REVISED.png","url":"https://assets-eu.researchsquare.com/files/rs-3915748/v1/0aad1b2d58a97771e2fcdb96.png"},{"id":61596899,"identity":"d3002cd5-9fc0-4b1d-81e9-0d04667cc10a","added_by":"auto","created_at":"2024-08-01 17:30:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1227187,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3915748/v1/b38f5151-a6e4-42fd-bd0b-a6b8dd04b0c5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk of Maculopathy in Tamoxifen Users: Drug Exposure and Risk Factors","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTamoxifen, a selective estrogen receptor modulator, has long been a cornerstone in the treatment of hormone receptor-positive breast cancer.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Its efficacy in reducing the risk of recurrence and mortality in breast cancer patients is well established.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, the therapeutic benefits of tamoxifen are not without potential ocular complications, particularly those affecting the macula.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Recent studies have focused on the risk and associated factors of maculopathy, prompting the need for comprehensive investigations into the risk factors and incidence rates of ocular complications associated with this widely prescribed drug.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe ocular side effects of tamoxifen, specifically tamoxifen-related retinopathy (maculopathy), have raised concerns among prescribing physicians and ophthalmologists. Alterations in the retina are reported to manifest in approximately 12% of individuals who have been using a daily dose of 20 mg of tamoxifen for a period exceeding two years,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e corresponding to a cumulative dose of approximately 15 g. These alterations include the presence of crystalline deposits, telangiectasia, hyperreflective deposits in the inner retinal layers, pseudocystic foveal cavitation, and cystoid macular edema.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Understanding the demographic and clinical characteristics of individuals at a higher risk of developing maculopathy is crucial for identifying preventive measures and optimizing patient care.\u003c/p\u003e \u003cp\u003eIn the present study, we investigated the risk of diverse macular conditions potentially associated with tamoxifen use in a nationwide cohort of tamoxifen users. By examining clinical characteristics such as age, sex, and underlying diseases that potentially affect drug metabolism or macular diseases, we explored the risk factors for macular conditions by focusing on drug exposure and other systemic diseases. This study aimed to delineate the correlation between these factors and the occurrence of several types of maculopathies, providing valuable insights into the dose-response relationship between macular diseases and drug exposure and aiding in the formulation of evidence-based guidelines for tamoxifen maculopathy screening.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis study used the Health Insurance Review and Assessment (HIRA) database, a comprehensive repository encompassing health claims data of approximately 50\u0026nbsp;million individuals in South Korea.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e This database, previously employed in a similar cohort study, contains information on diagnoses, procedures, prescriptions, visit dates, and demographic characteristics, utilizing codes from the Korean Standard Classification of Diseases, 8th Revision, with modifications from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).\u003c/p\u003e \u003cp\u003eTamoxifen users were identified within the database, focusing on individuals who initiated tamoxifen therapy between January 1, 2013, and December 31, 2021. To ensure accurate assessment of treatment duration, patients using tamoxifen before January 1, 2015, were excluded. Individuals with macular diseases before initiating tamoxifen treatment were also excluded aiming to include only patients with macular conditions occurring after tamoxifen initiation. The detailed inclusion/exclusion criteria and the number of subjects included/excluded are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The Institutional Review Board of Hanyang University Hospital approved the study (IRB File no. 2023-01-003), which was conducted in accordance with the Declaration of Helsinki. The need for informed consent was waived by the Institutional Review Board of Hanyang University Hospital because of the retrospective nature of the study and the use of deidentified data. The reporting adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions and evaluations\u003c/h2\u003e \u003cp\u003eThe identification and classification of macular conditions were based on specific KCD-8 codes within the dataset. Overall, macular diseases were defined as the presence of H31.0 (macular scar), H35.3 (degeneration of the macula and posterior pole; including from H35.30 [nonexudative age-related macular degeneration] to H35.39 [unspecified macular degeneration]), or H35.80 (macular edema). Other maculopathy excluding common macular diseases was delineated by the code H35.37 (toxic maculopathy) and H35.39 (unspecified macular degeneration; category for the macular diseases after exclusion of common macular diseases such as age-related macular degeneration and epiretinal membrane), while macular edema was specifically identified by the code H35.80 (macular edema).\u003c/p\u003e \u003cp\u003eThe cumulative incidence of and risk factors for maculopathies among tamoxifen users were investigated. Among the patients receiving sufficient cumulative tamoxifen exposure, specifically 15 g in total (conventional daily dose of 20 mg for two years), the cumulative incidences of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema during the study period were evaluated. These were stratified by cumulative dose and age categories into three cumulative dose groups (15 \u0026ndash; \u0026lt; 30 g, 30 \u0026ndash;\u0026lt; 45 g, and \u0026ge;\u0026thinsp;45 g) and six age groups (below 40, 40\u0026ndash;49, 50\u0026ndash;59, 60\u0026ndash;69, and \u0026ge;\u0026thinsp;70). To identify the risk factors, hazard ratios (HR) were obtained for demographic factors and systemic diseases, including common systemic diseases and those affecting drug metabolism (liver and kidney) and presented with 95% confidence intervals (CI). Associations between sex, age, diabetes, hypertension, dyslipidemia, renal disease, liver disease, and risk of maculopathies were evaluated in tamoxifen users.\u003c/p\u003e \u003cp\u003eUsing the health claims data from the HIRA database, we assessed the tests performed for macular evaluation, including fundoscopy/fundus photography, OCT, and fluorescein angiography. The percentage of patients undergoing each test was assessed and presented as demographic and clinical characteristics.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics summarized the findings, presenting categorical variables as frequencies and percentages and continuous variables as mean (standard deviation) or median (interquartile range). Chi-square or Fisher\u0026rsquo;s exact tests were used to compare categorical variables between the groups. In our study, we used the Cochran\u0026ndash;Mantel\u0026ndash;Haenszel test, a statistical method for analyzing stratified or matched categorical data, to assess the association between a characteristic and a binary outcome, such as maculopathy status, while accounting for the effects of stratification and potential confounding factors. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. SAS Enterprise Guide version 7.1 conducted all analyses.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and Clinical Characteristics of Study Population\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides a comprehensive overview of the demographic and clinical characteristics of the tamoxifen users enrolled in this study, revealing the diverse profiles of individuals undergoing tamoxifen therapy. The cohort, consisting of 14,267 users, exhibited a notable sex distribution, with 79.9% female and 20.1% male. The mean age of the population was 54.0 years, with a range from 20 to \u0026ge;\u0026thinsp;70 years. Underlying diseases including diabetes (30.8%), hypertension (37.7%), dyslipidemia (61.1%), kidney disease (16.1%), and liver disease (41.1%) were prevalent in the cohort. The primary indications for tamoxifen use varied, with breast cancer being the dominant indication, accounting for 58.7% of the cases. Additionally, the table presents the mean duration of tamoxifen use (33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;23.4 months) and the distribution across different duration categories. The cumulative daily dose of tamoxifen, an indicator of drug exposure, was delineated, with 40.5% of the users falling within the \u0026lt;\u0026thinsp;15 g category. The cumulative doses for the other patients ranged as follows; 15 to 30 g, 27.6% (n\u0026thinsp;=\u0026thinsp;3931); 30 to 45 g, 29.9% (n\u0026thinsp;=\u0026thinsp;4269); and \u0026gt;\u0026thinsp;45 g, 2.0% (n\u0026thinsp;=\u0026thinsp;284). Approximately 59.5% of those at risk of maculopathy had a substantial cumulative tamoxifen exposure (equal to or greater than 15 g) for retinal toxicity, represent a significant proportion of the overall tamoxifen users.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical information of the tamoxifen users included in this study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall users (n\u0026thinsp;=\u0026thinsp;14,267)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale:female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,874(20.1%):11,393(79.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean age (\u003c/b\u003e\u0026plusmn;\u0026thinsp;\u003cb\u003eSD), years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e54.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e961 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5,358 (37.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3,272 (22.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,410 (16.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,110 (14.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnderlying disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4,394 (30.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5,374 (37.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyslipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8,711 (61.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,302 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5,865 (41.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIndication for tamoxifen use\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8,373 (58.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuctal carcinoma in situ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,849 (13.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGynecomastia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,484 (17.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,561 (10.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean duration of tamoxifen use (\u003c/b\u003e\u0026plusmn;\u0026thinsp;\u003cb\u003eSD), months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;23.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than 1 year\u003c/p\u003e \u003cp\u003e1\u0026ndash;2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3,972 (27.8%)\u003c/p\u003e \u003cp\u003e1,645 (11.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;3 years\u003c/p\u003e \u003cp\u003e3\u0026ndash;4 years\u003c/p\u003e \u003cp\u003e4\u0026ndash;5 years\u003c/p\u003e \u003cp\u003e5 years or longer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,981 (13.9%)\u003c/p\u003e \u003cp\u003e1,890 (13.3%)\u003c/p\u003e \u003cp\u003e2,800 (19.6%)\u003c/p\u003e \u003cp\u003e1,979 (13.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean cumulative daily dose of tamoxifen (\u003c/b\u003e\u0026plusmn;\u0026thinsp;\u003cb\u003eSD), mg/day\u003c/b\u003e\u003c/p\u003e \u003cp\u003eLess than 15 g\u003c/p\u003e \u003cp\u003e15\u0026ndash;30 g\u003c/p\u003e \u003cp\u003e30\u0026ndash;45 g\u003c/p\u003e \u003cp\u003e45 g or greater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2\u003c/p\u003e \u003cp\u003e5,783 (40.5%)\u003c/p\u003e \u003cp\u003e3,931 (27.6%)\u003c/p\u003e \u003cp\u003e4,269 (29.9%)\u003c/p\u003e \u003cp\u003e284 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMacular evaluation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFundus examination (funduscopy or fundus photography)\u003c/p\u003e \u003cp\u003eOptical coherence tomography\u003c/p\u003e \u003cp\u003eFluorescein angiography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003e13,931 (97.6%)\u003c/p\u003e \u003cp\u003e14,267 (100%)\u003c/p\u003e \u003cp\u003e751 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eSD, standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eCumulative Incidences of Diverse Macular Conditions in Overall Patients and Subgroups According to Drug Exposure Level or Age Groups\u003c/em\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the overall cumulative incidence of macular diseases (26.4%; n\u0026thinsp;=\u0026thinsp;3,764), maculopathy excluding common macular diseases (11.4%; n\u0026thinsp;=\u0026thinsp;1,632), and macular edema (6.5%; n\u0026thinsp;=\u0026thinsp;925) in the entire patient cohort during the study period. However, common macular diseases like age-related macular degeneration, epiretinal membrane, and macular hole were observed in 8.5% of the included patients over the study period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the cumulative incidence of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema among the different risk groups of tamoxifen users during the study period, stratified by cumulative dose and age categories. For overall macular diseases, the cumulative incidence showed variations across both age and cumulative dose groups. Notably, a trend of increasing cumulative incidence was observed with higher age groups and cumulative tamoxifen doses (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 by the Cochran\u0026ndash;Mantel\u0026ndash;Haenszel test), which was statistically significant. This pattern is consistent with other maculopathy excluding common macular diseases and macular edema, highlighting the potential influence of age and cumulative tamoxifen dosage on the development of these macular conditions. The presented P-values (\u0026lt;\u0026thinsp;0.001 for both other maculopathy excluding common macular diseases and macular edema) indicated statistically significant differences among the risk groups. These findings suggest the importance of considering both age and cumulative tamoxifen dosage when assessing the overall risk of macular diseases, other maculopathy excluding common macular diseases, and macular edema in tamoxifen users.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCumulative incidences of overall macular diseases, unspecified maculopathy excluding common macular diseases, and macular edema in different risk groups of patients with tamoxifen exposure\u0026thinsp;\u0026ge;\u0026thinsp;15 g\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCumulative dose group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;40\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;695)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u0026ndash;49\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;4,018)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2,090)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60\u0026ndash;69\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,052)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;629)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eOverall macular diseases\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15-30g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (12.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e353 (20.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e233 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e193 (36.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e136 (39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30-45g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (16.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e447 (21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e293 (27.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e211 (42.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e132 (48.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e45g or greater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (24.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (26.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (59.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (57.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaculopathy excluding common macular diseases\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15-30g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (4.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86 (16.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30-45g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132 (12.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e106 (21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64 (23.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e45g or greater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (19.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMacular edema\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15-30g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37 (7.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30-45g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e131 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45 (9.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e45g or greater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*Cochran-Mantel-Haenszel test\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRisk Factors for Maculopathy in Tamoxifen Users\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the HR with 95% CI and corresponding P-values for several demographic and systemic factors that may impact drug metabolism and contribute to the development of macular conditions in tamoxifen users. For all the three distinct outcomes including overall macular diseases, other maculopathy excluding common macular diseases, and macular edema, significant associations between sex and the risk of macular conditions were noted. (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) Age was also identified as a substantial risk factor for all three macular conditions, emphasizing the heightened vulnerability of older individuals to the development of macular diseases, other maculopathy excluding common macular diseases, and macular edema (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors for macular diseases in tamoxifen users: demographic and systemic disease factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eOverall macular diseases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMaculopathy other than common macular diseases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eMacular edema\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.649\u003c/p\u003e \u003cp\u003e(0.603\u0026ndash;0.698)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.695\u003c/p\u003e \u003cp\u003e(0.622\u0026ndash;0.778)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.661\u003c/p\u003e \u003cp\u003e(0.571\u0026ndash;0.765)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.029\u003c/p\u003e \u003cp\u003e(1.027\u0026ndash;1.032)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.032\u003c/p\u003e \u003cp\u003e(1.028\u0026ndash;1.036)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.014\u003c/p\u003e \u003cp\u003e(1.009\u0026ndash;1.019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.116\u003c/p\u003e \u003cp\u003e(1.044\u0026ndash;1.193)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.030\u003c/p\u003e \u003cp\u003e(0.930\u0026ndash;1.141)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.195\u003c/p\u003e \u003cp\u003e(1.046\u0026ndash;1.365)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.359\u003c/p\u003e \u003cp\u003e(1.274\u0026ndash;1.449)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.336\u003c/p\u003e \u003cp\u003e(1.212\u0026ndash;1.473)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.233\u003c/p\u003e \u003cp\u003e(1.083\u0026ndash;1.404)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDyslipidemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.044\u003c/p\u003e \u003cp\u003e(0.976\u0026ndash;1.117)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.051\u003c/p\u003e \u003cp\u003e(0.948\u0026ndash;1.166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.981\u003c/p\u003e \u003cp\u003e(0.857\u0026ndash;1.123)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.782\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKidney disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.081\u003c/p\u003e \u003cp\u003e(0.996\u0026ndash;1.172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.972\u003c/p\u003e \u003cp\u003e(0.858\u0026ndash;1.102)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.662\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.045\u003c/p\u003e \u003cp\u003e(0.887\u0026ndash;1.232)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.982\u003c/p\u003e \u003cp\u003e(0.921\u0026ndash;1.047)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.949\u003c/p\u003e \u003cp\u003e(0.861\u0026ndash;1.047)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.941\u003c/p\u003e \u003cp\u003e(0.827\u0026ndash;1.071)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*Male as reference\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the systemic diseases, diabetes and hypertension emerged as significant contributors to the overall risk of macular diseases and macular edema, with hypertension being additionally associated with maculopathy other than common macular diseases (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), whereas dyslipidemia was not associated with any of the three conditions. Kidney and liver diseases, potentially affecting tamoxifen metabolism, did not exhibit a statistically significant association with any of the studied macular conditions (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTamoxifen, a vital component in the treatment of hormone receptor-positive breast cancer, has long been recognized for its efficacy in reducing cancer recurrence and mortality.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, because the ocular side effects of tamoxifen, particularly tamoxifen maculopathy, present a critical concern in clinical practice for tamoxifen users, \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e our study investigated the risk of macular conditions potentially associated with tamoxifen toxicity among users. From a comprehensive analysis of the demographic and clinical characteristics of the tamoxifen user cohort, our findings on the factors influencing the risk of maculopathy may contribute to the growing body of knowledge concerning the risk and risk factors of maculopathy in tamoxifen users, a topic not extensively studied.\u003c/p\u003e \u003cp\u003eTamoxifen retinopathy can present in several forms\u003csup\u003e4\u0026ndash;8,11\u0026minus;14\u003c/sup\u003e and similarities with macular telangiectasia, type 2 have been noted in previous studies\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Therefore, the macular abnormalities observed on OCT in tamoxifen users may be recognized as a different condition, rather than tamoxifen maculopathy. Furthermore, this maculopathy has not been adequately recognized by ophthalmologists due to limited awareness; thus, it is likely that it has been misdiagnosed as other macular conditions such as macular degeneration and macular edema than toxic maculopathy. To maximize capturing potential macular conditions associated with tamoxifen toxicity, we included several macular conditions for the outcomes while excluding patients with such conditions prior to tamoxifen use. This might have led to an underestimation of the incidence of tamoxifen maculopathy if the analysis was limited to the code for toxic maculopathy in our cohort, which was found to be less than 1%.\u003c/p\u003e \u003cp\u003eThe cumulative incidence in previous studies varied from 0.9\u0026ndash;12%, largely depending on the cumulative dose in the study population.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Furthermore, macular diseases generally occur in elderly individuals, indicating the susceptibility of older patients to macular diseases. Recent studies have reported higher incidence rates than previous studies, which might be partly explained by advances in retinal imaging and its increased sensitivity in detecting microscopic retinal changes in tamoxifen users. Our study, including the patients undergoing OCT imaging, showed maculopathy excluding common macular diseases, the most specific category for tamoxifen maculopathy among our outcomes, in 11% of overall tamoxifen users. This was comparable to the recent figure of 12% among patients receiving tamoxifen.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe cumulative incidences of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema, stratified by cumulative dose and age categories, provide valuable insights into the dose-response relationship between drug exposure and maculopathy incidence and age-related susceptibility. The statistical significance of these trends further strengthens the evidence of the impact of these factors on maculopathy risk. The increasing cumulative incidence observed in older age groups and with higher cumulative tamoxifen doses highlights the relevance of age and cumulative tamoxifen dosage in the development of macular conditions. This underscores the need to simultaneously consider both factors in maculopathy screening, suggesting that future guidelines should incorporate these aspects when formulating screening recommendations.\u003c/p\u003e \u003cp\u003eAssessment of risk factors for macular diseases in tamoxifen users also revealed significant associations with demographic and systemic disease factors. Sex, age, diabetes mellitus, hypertension, and kidney disease are substantial contributors to the risk of maculopathy. Notably, dyslipidemia did not exhibit a significant association with macular conditions, although a recent study identified hypercholesterolemia as a risk factor for tamoxifen maculopathy.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e These findings emphasize the relationship between a few systemic diseases potentially affecting retinal diseases such as diabetes and hypertension and development of tamoxifen-induced maculopathy. The heightened vulnerability of older individuals, as indicated by the increasing HR with age, underscores the need for vigilant monitoring of this demographic subgroup. Interestingly, despite the potential impact on drug metabolism and excretion, liver diseases showed no significant association with the incidence of macular diseases. This observation is notable considering that tamoxifen is primarily excreted by the liver and biliary tract, implying that liver disease may influence the systemic concentration of tamoxifen. However, liver function could not be assessed in this study, which limits drawing conclusion on the association between liver diseases or function and tamoxifen maculopathy incidences.\u003c/p\u003e \u003cp\u003eWhile our study provides valuable insights into the risk factors and cumulative incidence of tamoxifen-induced maculopathy, certain limitations must be acknowledged to ensure a nuanced interpretation of the findings. The retrospective nature of our study, which relied on the HIRA database, introduced some inherent limitations. The identification and classification of macular conditions were based on specific KCD-8 codes within the dataset, potentially leading to misclassification or under-reporting. The operational definitions used for the inclusion and exclusion criteria may not have captured all relevant cases, thus contributing to selection bias. The absence of direct clinical assessments and the reliance on diagnostic codes may result in an incomplete representation of tamoxifen maculopathy status.\u003c/p\u003e \u003cp\u003eMoreover, we acknowledge the possibility of unmeasured confounding factors that were not accounted for in our analysis. Lifestyle factors, genetic predisposition, and other medications that could influence the development of maculopathy were not comprehensively considered in our study. Furthermore, the generalizability of our findings may be limited because this study focused exclusively on the South Korean population. Healthcare systems and patient demographics vary across regions, and caution should be exercised when extending our results to other populations with different characteristics.\u003c/p\u003e \u003cp\u003eDespite these limitations, our study provides a robust exploration of the risk factors and cumulative incidence of diverse macular conditions among tamoxifen users at the national level. The insights gained from this study have implications for clinical practice by guiding the formulation of evidence-based guidelines for tamoxifen-induced maculopathy screening. The intricate interplay between age, cumulative tamoxifen dosage, and systemic diseases highlighted in this study serves as a foundation for future research and enhances our understanding of the ocular complications associated with this widely prescribed breast cancer therapy. Future research may further address tamoxifen maculopathy in diverse ethnic groups by incorporating more detailed clinical assessments to identify tamoxifen-induced maculopathy and by considering a broader range of potential confounding factors to enhance the generalizability of our findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors planned and designed the study. H.Y.K. and S.J.A. wrote the main manuscript text, and prepared the figures. J.K. and H.Y.K. provided the data mining and statistical assistance. All authors acquired, analyzed and interpreted the data. S.J.A. and H.Y.K. did critical revision of the manuscript for important intellectual content. S.J.A. obtained funding. S.J.A. supervised the study. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Research Foundation of Korea grants (NRF-2021R1G1A1013360) funded by the Korean Government MSIT. Neither the sponsor nor the funding organization had any role in the design or conduct of this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTenney, S., Oboh-Weilke, A., Wagner, D. \u0026amp; Chen, M. Y. Tamoxifen retinopathy: A comprehensive review. 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Cancer Treat Rep 62, 315\u0026ndash;320 (1978).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee, S., Kim, H. A. \u0026amp; Yoon, Y. H. OCT Angiography Findings of Tamoxifen Retinopathy: Similarity with Macular Telangiectasia Type 2. Ophthalmol Retina 3, 681\u0026ndash;689, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.oret.2019.03.014\u003c/span\u003e\u003cspan address=\"10.1016/j.oret.2019.03.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3915748/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3915748/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTamoxifen, a pivotal therapy for hormone receptor-positive breast cancer, is known for its efficacy in reducing breast cancer recurrence and mortality. However, concerns about potential ocular complications, particularly maculopathy, have emerged. This study aims to investigate the risk and associated factors of diverse macular conditions in tamoxifen users, considering drug exposure, demographics, and systemic diseases. A nationwide cohort of tamoxifen users, comprised of 14,267 tamoxifen users, was analyzed using the Health Insurance Review and Assessment (HIRA) database in South Korea. Demographic and clinical characteristics were examined, and the cumulative incidence of macular diseases was stratified by age and cumulative tamoxifen dosage. Hazard ratios were calculated for risk factors, including age, sex, and systemic diseases affecting drug metabolism. Cumulative incidences of overall macular diseases, other maculopathy excluding common macular diseases, and macular edema were 26.4%, 11.4%, and 6.5%, respectively. The risk increased with age and cumulative tamoxifen dosage. Significant risk factors included age, sex, diabetes, hypertension, and kidney disease whereas dyslipidemia and liver disease showed no significant association with the macular conditions. Tamoxifen-induced maculopathy poses a concern for prescribing physicians and ophthalmologists, and this study provides valuable insights into its risk and risk factors. The complex interplay between age, cumulative tamoxifen dosage, and systemic diseases highlights the need for vigilant monitoring and screening strategies. This study may contribute to evidence-based guidelines for tamoxifen maculopathy screening, emphasizing the importance of considering multiple factors for recommendation on screening timing and frequency.\u003c/p\u003e","manuscriptTitle":"Risk of Maculopathy in Tamoxifen Users: Drug Exposure and Risk Factors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-13 07:10:56","doi":"10.21203/rs.3.rs-3915748/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-27T05:32:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-08T07:55:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-03T12:58:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"0a1b7bd4-e5d9-4ece-9e06-7c29088630f8","date":"2024-02-26T01:53:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-22T15:35:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-22T15:32:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-10T17:07:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-10T17:01:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-02-01T02:38:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4b4aa683-53aa-4ca3-a432-7a95d7bd15d2","owner":[],"postedDate":"February 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28702221,"name":"Health sciences/Diseases/Eye diseases"},{"id":28702222,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-08-01T17:16:51+00:00","versionOfRecord":{"articleIdentity":"rs-3915748","link":"https://doi.org/10.1038/s41598-024-67670-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-07-22 16:15:02","publishedOnDateReadable":"July 22nd, 2024"},"versionCreatedAt":"2024-02-13 07:10:56","video":"","vorDoi":"10.1038/s41598-024-67670-x","vorDoiUrl":"https://doi.org/10.1038/s41598-024-67670-x","workflowStages":[]},"version":"v1","identity":"rs-3915748","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3915748","identity":"rs-3915748","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}