Relationship between the Incidence of Metabolic Syndrome and Breast Cancer

Relationship between the Incidence of Metabolic Syndrome and Breast Cancer | 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 Relationship between the Incidence of Metabolic Syndrome and Breast Cancer Naoki Kimoto, Yohei Miyashita, Yutaka Yata, Takeshi Aketa, Masami Yabumoto, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6788404/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Oct, 2025 Read the published version in Cardiovascular Drugs and Therapy → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose Breast cancer affects females from puberty onward, with incidence rates increasing with age. Although metabolic syndrome (MetS) has reportedly increased the incidence of almost all cancers, no clear consensus on the role of MetS in breast cancer development exists. We aimed to clarify the effects of MetS on breast cancer incidence. Methods To investigate this relationship, we analyzed Japanese healthcare data of females from 2005 to 2020 and examined the incidence of breast cancer. MetS was evaluated based on the Japanese criteria or the NCEP ATP III guidelines at enrollment. Of 1,144,791 participants without missing data in our general public cohort, 32,775 with breast cancer at the beginning of the observation period were excluded; 54,330 participants with breast cancer were identified during the observation period. Results Both pre-stage MetS and MetS, defined using the Japanese criteria, decreased the incidence of breast cancer (hazard ratios [HRs], 0.90 and 0.83; p < 0.005). Furthermore, MetS using NCEP ATP III decreased the HR (0.87, p < 0.005), and the number of the factors from 1 to 5 gradually decreased the HRs. Analysis according to age group revealed that this observation was the most prominent in the < 50-year-old group. Conclusion MetS is associated with decreased breast cancer incidence in females, especially aged < 50 years. breast cancer metabolic syndrome big data early stage of metabolic syndrome age Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Cancer poses substantial economic and healthcare burdens worldwide[ 1 ]. Although early detection, prompt diagnosis, and innovative medical and surgical treatments have gradually mitigated various cancer types, cancer-related mortality has been high even in developed countries. In particular, breast cancer is the most frequently diagnosed cancer type among females worldwide, especially affecting those in their 30s–50s[ 2 ]. Cancers, including breast cancer, are reportedly primed by family history[ 3 ], genetic background[ 4 ], smoking[ 5 – 7 ], and type II diabetes mellitus (T2DM)[ 8 ]. We and several investigators have reported that metabolic syndrome (MetS) increases the risk of pancreatic cancer[ 9 , 10 ], and we have shown that MetS increases the risk of almost all cancer types[ 11 ]. The overall incidence of cancers may be influenced by the molecular mechanisms of MetS, including (1) insulin, (2) adipokine, and (3) reactive oxygen species (ROS)[ 12 ]. Among almost all cancer types, breast cancer is special owing to its estrogen sensitivity. Estrogen is known to initiate or proliferate breast cancer[ 13 , 14 ], and MetS or obesity increases estrogen production in adipose tissues[ 15 ] along with the basal secretion of estrogen from the ovary. Furthermore, MetS increases insulin resistance, leading to a high risk of breast cancer[ 16 ]. Several investigators have examined the relationship between the incidences of MetS and breast cancer, and a meta-analysis of nine articles encompassing 6,417 cases of cancer revealed that MetS is associated with a moderately increased risk of postmenopausal breast cancer[ 17 ]. Furthermore, MetS reportedly increased the risk of breast cancer in females aged > 60 years, which is not confirmed in younger females in 4,862 cases of breast cancer[ 18 ]. Conversely, MetS is a risk factor for breast cancer in females aged 40–80[ 19 ] and ≥ 18 years[ 20 ]. Taken together, MetS, especially obesity, may increase breast cancer incidence, and age may serve as a critical threshold that determines whether MetS exacerbates or mitigates breast cancer risk; however, no clear evidence exists regarding the relationship between MetS and breast cancer, as the sample size of each study is relatively small, with < 50,000 participants, 2,000 of whom have breast cancer. Such an investigation is valid; however, we needed a single and large cohort of one million females by age group. Therefore, we planned to form a cohort of more than one million individuals from the general population and followed them for more than 10 years, and we decided to investigate the relationship between the occurrence of MetS or the early phase of MetS and the incidence of breast cancer. Methods Study design This retrospective observational study adhered to the principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research. Participants Our analyses were based on data from healthcare insurance claims provided by JMDC (Japan Medical Data Center), Inc. (Tokyo, Japan). The database comprised standardized eligibility and claims data provided by health insurance societies for insured individuals from 2005 to 2020. It included the data of general corporation employees, their family members, and all medical treatments received by insured individuals at treatment facilities. Moreover, it included a comprehensive record of all the treatments administered to a patient. For this study, we disposed of the decoding indexes stored in JMDC, Inc. and analyzed personal data using unsinkable anonymization. Definition of MetS The Japanese criteria defined MetS as abdominal central obesity with an abdominal circumference at the umbilical levels of ≥ 85 and ≥ 90 cm for males and females, respectively, with two or more of the following factors: (1) elevated triglyceride and/or reduced high-density lipoprotein levels, (2) elevated blood pressure, and (3) elevated fasting glucose levels[ 21 ]. Premetabolic syndrome (preMetS) was defined as the presence of abdominal central obesity combined with one of the abovementioned factors. Furthermore, the nonMetS group comprised participants not classified as having either MetS or preMetS. Additionally, MetS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria[ 22 ]. Study protocol Of the 1,144,791 females with complete dataset, 32,775 with breast cancer at the beginning of the observation period were excluded, and breast cancer occurrence was evaluated. Our results showed that 54,330 participants had breast cancer during the observation period according to the International Classification of Diseases 10th Revision (coded as I10–I15). After acquiring each dataset, we used the Kaplan–Meier analysis to compare breast cancer occurrence with and without MetS or preMetS. Furthermore, we calculated the hazard ratios (HRs) using Cox proportional hazard models between two and three groups. Moreover, we examined breast cancer incidence in the subgroups of females aged < 50 or ≥ 60 years and aged ≥ 50- and 3 years to investigate the effects of metabolic dynamics on breast cancer occurrence. We classified these enrolled participants into the following four groups according to the presence or absence of MetS upon entry: two groups with MetS with and without MetS for 3 years and two groups with nonMetS at with and without MetS for 3 years. Participants with MetS were categorized into either the MetS-recovered (19,598 participants) or MetS-persistent (29,051 participants) groups on the basis of the conditions that MetS improved/disappeared or persisted for 3 years. These participants were followed until the end of the observation period or breast cancer onset. Participants with nonMetS were categorized into the either MetS-developed (26,830 participants) or MetS-free (620,663 participants) groups on the basis of either MetS appeared or not-appeared. We followed these participants until the end of the observation period or breast cancer onset. Statistics Time-to-event data were evaluated using Kaplan–Meier estimates and compared using the log-rank test for primary analyses. The entry time, that is, time = 0 for the Kaplan–Meier plots, varied. Censoring occurred when the patient died or was lost to follow up. We employed a complete case analysis (listwise deletion) for missing data, and a sensitivity analysis was not performed. Cox proportional hazard models were employed for estimating HRs with the MetS or preMetS group assignment or combinations of the components with the MetS, preMetS, and nonMetS groups for calculating the p -values regarding the hypothesis testing between the groups. The models were adjusted for smoking, age, and sex because the incidence of cancer is believed to be affected by these factors. After checking the interactions between the variables age, sex, and smoking through likelihood ratio tests on regression coefficients of interaction terms, the interaction between sex and age was noted to be significant. Therefore, the model that included the sex–age interaction term was used. All statistical analyses were performed using Python v310 and packages, including lifelines v0278 ( https://github.com/nkimoto/PKMetS ). Results The clinical characteristics of patients with and without preMetS or MetS are presented in Table 1. The results of the Kaplan–Meier analysis of the participants with and without MetS defined using the Japanese MetS criteria for breast cancer incidence are depicted in Fig. 1 . As shown in Fig. 1 -A, along with progression from the nonMetS to MetS via preMetS, the incidence of breast cancer decreases in a stepwise manner; as shown in Fig. 1 -B, MetS with two or three factors decreases the incidence of breast cancer compared with preMetS/nonMetS. Both preMetS and MetS decreased the incidence of breast cancer (HR, 0.90; 95% CI, 0.86–0.94; p < 0.005: HR, 0.83; 95% CI, 0.80–0.87; p < 0.005), and MetS with one, two, and three factors, as well as preMetS, decreased the incidence of breast cancer (HR, 0.90; 95% CI, 0.86–0.94; p < 0.005: HR, 0.83; 95% CI, 0.87–0.87; p < 0.005: HR, 0.85; 95% CI, 0.78–0.94; p < 0.005). The results of the subanalysis for investigating the relationship between the presence of MetS or preMetS and breast cancer incidence by age group are shown in Fig. 2 . In the < 50-year-old age group, the relationship between the presence of MetS (HR, 0.71: CI, 0.62–0.82; p < 0.005) and preMetS (HR, 0.69: CI, 0.61–0.79; p < 0.005) decreased the incidence of breast cancer to the same extent. In the ≥ 50- and < 60-year-old age group, breast cancer incidence was significantly decreased by either MetS or preMetS (MetS: HR, 0.73: CI, 0.67–0.78; p < 0.005; preMetS: HR, 0.83: CI, 0.77–0.88; p < 0.005). In the ≥ 60-year-old age group, nonMetS significantly decreased the incidence of breast cancer compared with preMetS and MetS; preMetS increased the incidence of breast cancer (HR, 1.07: CI, 1.00–1.15; p < 0.05), whereas MetS did not affect it (HR, 1.01: CI, 0.95–1.07; p = 0.75). The results of the Kaplan–Meier analysis indicated that participants with and without MetS, defined using the NCEP/ATP III criteria, had decreased breast cancer incidence (HR, 0.87: CI, 0.84–0.90; p < 0.005) (Fig. 3 -A). The negative relationship between the number of the factors of MetS and the incidence of breast cancer is shown in Fig. 3 -B. The HR for the incidence of breast cancer monotonically decreases as the number of MetS factors increases (Fig. 4 -A and B). Particularly, for one factor, the HR was 0.95 (95% CI, 0.93–0.97; p < 0.005); for two factors, the HR was 0.90 (95% CI, 0.87–0.92; p < 0.005); for three factors, the HR was 0.84 (95% CI, 0.81–0.88; p < 0.005); for four factors, the HR was 0.83 (95% CI, 0.77–0.88; p < 0.005); and for five factors, the HR was 0.82 (95% CI, 0.71–0.94; p < 0.005) (Fig. 4 -B). Regarding the effects of changes in the status of MetS during the observation period, Kaplan–Meier analyses (Fig. 5 -A) and log-rank test (Fig. 5 -B) among the nonMetS, MetS-recovered, and MetS-persistent groups revealed that even the temporal MetS status decreased the risk of breast cancer. Compared with the nonMetS groups, the incidences of breast cancer were significantly decreased in the MetS-developed ( p < 0.05), MetS-recovered ( p < 0.05), and MetS-persistent ( p < 0.005) groups. No differences in breast cancer incidences were observed among the MetS-developed, MetS-recovered, and MetS-persistent groups. These findings suggest that the temporary occurrence of MetS decreases the breast cancer incidence rate. Discussion This study revealed that MetS reduces the incidence of breast cancer in females with an average age of 53 years. Interestingly, in females aged < 50 years, MetS and preMetS significantly decreased the incidence of breast cancer compared with nonMetS, with preMetS exhibiting a protective effect comparable to that of MetS. In females aged 50–60 years, although either MetS or preMetS decreased the incidence of breast cancer compared with nonMetS, preMetS seemed to exhibit a weaker protective effect than MetS. In contrast, in females aged ≥ 60 years, the effects of MetS on breast cancer were attenuated, and the breast cancer incidence in participants with either MetS or preMetS was high compared with that of participants with nonMetS, with no significant difference. Considering that females aged < 50 years may not yet have entered menopause, whereas most of those aged ≥ 60 years have already reached menopause, the observed significant age-dependent relationship between MetS (or preMetS) and breast cancer appears to be strongly mediated by menopausal status. Differences and similarities between previous and present results In the cohort investigated in this study, MetS, including preMetS, was associated with a decreased breast cancer incidence overall. This finding contrasts with previous results from a meta-analysis of 97,277 females, which showed that MetS increased breast cancer incidence[ 20 ], suggesting that our findings differ from those of previous studies. However, a larger cohort study encompassing 287,320 females reported that although MetS increased breast cancer incidence in females aged > 60 years, this trend was not observed in younger females[ 18 ]. This hypothesis was also proved in a Japanese cohort[ 23 ]. The present study, with a cohort of 1,112,016 females, including 54,330 participants with breast cancer who can provide potential and definite power to analyze the relationship among MetS, breast cancer, and age, revealed a reversal in the relationship between MetS and breast cancer risk, especially in the < 60-year-old age group. Furthermore, this inverse association between breast cancer incidence and MetS occurrence became stronger as the number of MetS-related factors, including hypertension and dyslipidemia, beyond obesity alone, increased. Additionally, of note, this study showed that preMetS, considered an early stage of MetS, exhibited similar effects to those observed with MetS. This finding suggests that excessive dieting in premenopausal females can increase the risk of breast cancer, whereas obesity in postmenopausal females also mitigates the relationship between MetS and breast cancer. This interesting phenomenon is observed in patients with T2DM. A more recent meta-analysis of 20 studies encompassing 30,407 cases of cancer revealed that females with diabetes (vs. females without diabetes) had a statistically significant 20% increased risk of breast cancer (1.20; 95% CI, 1.12–1.28). However, in the stratified analysis by menopausal status, diabetes was associated with a 16% increased breast cancer risk in postmenopausal females and a 9% reduced risk in premenopausal females[ 24 ]. These findings have profound clinical implications. However, understanding why such a discontinuous relationship between age and breast cancer incidence occurs with age is a major challenge in the present observation. Age-related relationship between MetS and breast cancer Understanding the impact of MetS on breast cancer necessitates investigating its molecular mechanisms, which culminate in the effects of (1) insulin, (2) adipokine, (3) ROS, and (4) estrogen[ 12 ]. Insulin is a major anabolic hormone that stimulates cell proliferation. An indirect mechanism, including insulin-like growth factor (IGF)-1 stimulation, is believed to mediate the effects of insulin on cancer cell proliferation in vivo . IGF-1 receptor activation stimulates the p21 ras/MAPK pathway for cell proliferation and the PI3K/AKT cell survival pathway[ 25 ]. Furthermore, IGF-1 stimulates angiogenesis by increasing vascular endothelial growth factor production[ 26 ]. These findings may be related to breast cancer incidence. However, insulin, adipokine or ROS may not explain the discontinuous relationship between age and breast cancer incidence that occurs with age. Conversely, the levels of estrogen, which increases the incidence of breast cancer[ 13 ], may be changed throughout a female’s life. Breast cancer is mainly influenced by estrogen, and estrogen levels remain high until 50 years old during the premenopausal period; however, they are known to significantly decrease once menopause is reached. In contrast, obesity, frequently observed in MetS, leads to estrogen production in the adipose tissue. After menopause, the primary source of estrogen production shifts from the ovaries to fat cells. Why, then, does MetS appear to reduce the risk of breast cancer before menopause, whereas following menopause, the relationship between MetS and breast cancer risk seems to have disappeared or reversed? MetS, during the premenopausal period, is associated with increased anovulatory cycles[ 27 , 28 ]. More frequent anovulatory cycles cause reduced estrogen production from the ovaries, which is hypothesized to lower the risk of breast cancer. This phenomenon is consistent with findings that breast cancer incidence decreases not only in the MetS-persistent group but also in those who recover from MetS or develop it temporarily. In other words, even a transient premenopausal MetS occurrence may increase anovulatory cycles, thereby decreasing estrogen levels and potentially reducing breast cancer risk. Study limitations and features The relationship between MetS and cancers overall should be carefully concluded. Big data analyses may reveal subtle changes in the cohort. However, we observed that each factor responsible for MetS is independently associated with breast cancer, suggesting that MetS exhibits a stepwise effect on cancer risk modulation. Racial differences may exist whether MetS regulates breast cancer incidence. In Japan, as the lifestyle has recently been westernized, cancers with high prevalence are becoming similar to those of Western countries, and the population with MetS has increased. As we employed a diagnostic method using the NCEP ATP III and Japanese criteria, our conclusion remains unchanged, suggesting that the present conclusion can be applicable worldwide. As the study cohort was obtained from employees of general corporations and their family members, the average age of the participants may be younger than the average of the population in Japan. In 2020, the average age of the Japanese population was 48.9 years, which was similar to the average of the cohort of this study. The present cohort may lack older adult participants aged > 80 years; therefore, the relationship between MetS and breast cancer for females aged > 80 years may not be comparable with the present results. Declarations Funding: Grants-in-Aid form Japan Heart Foundation. Sponsor played no role in the study design, data collection, data analysis, and data interpretation or in the writing of the manuscript. The corresponding author assumed full data access and made the final decision to submit for publication. Conflict of Interest/Competing Interest: Relationships to industry do not exist for N.K, Y.M., Y.Y., T.A., M.Y., T.W., and S.T. Y.S. reports personal fees from AstraZeneca, personal fees from Otsuka Pharmaceutical, personal fees from Nippon Boehringer Ingelheim, personal fees from Novartis Pharma, from Bayer, grants from Nippon Boehringer Ingelheim, grants from Abbott Medical Japan, grants from Otsuka Pharmaceutical outside the submitted work. M.K. reports personal fees from Daiichi-sankyo, personal fees from Viatris, grants and personal fees from Ono, grants from Novartis, grants and personal fees from Tanabe-mitubishi, grants from Takeda, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer-ingelheim, grants from Kowa, personal fees from Otsuka, personal fees from Eli Lilly outside the submitted work. Availability of Data and Material: The data analyzed in this study are available from the corresponding author upon reasonable request, depending on the nature of the request. Code Availability : Not applicable Author Contributions: The followings are the role of each author to this study; Study conceptualization and design: MK, NK, YM, ST; Data curation, NK; Data Formal analysis: NK, YS, TW; Project administration: YY, MY, YS, TW, ST; Visualization: TA, YY, YS; Figures and Tables: NK, YM, TA, ST; Writing and editing: MK. All authors have read and approved the manuscript and the agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Naoki Kimoto, Yohei Miyashita and Masafumi Kitakaze have verified the underlying data of this study. Ethical Approval: This retrospective observational study was approved by the external Ethics Committee of the Kinshukai Medical Group (approval number: 2024–3). Consent to Participate: The Study Committee decided that based on the Japanese Clinical Research Guidelines, obtaining informed consent from patients selected for inclusion was not necessary as this was a retrospective observational study. Instead, we made a public announcement following the Ethics Committee’s request and the Japanese Clinical Research Guidelines. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent to Publish: The authors affirm no use of any individual person’s data in any form. References Hricak H, Abdel-Wahab M, Atun R, et al. Medical imaging and nuclear medicine: a Lancet Oncology Commission. Lancet Oncol. 2021;22(4):e136–72. 10.1016/s1470-2045(20)30751-8 . Łukasiewicz S, Czeczelewski M, Forma A, et al. 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Supplementary Files Table1.xlsx Cite Share Download PDF Status: Published Journal Publication published 07 Oct, 2025 Read the published version in Cardiovascular Drugs and Therapy → Version 1 posted Editorial decision: Major Changes Required 05 Jul, 2025 Reviewers agreed at journal 25 Jun, 2025 Reviewers invited by journal 04 Jun, 2025 Editor assigned by journal 01 Jun, 2025 First submitted to journal 31 May, 2025 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. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6788404","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":466301068,"identity":"129b3e52-6c74-46be-a160-f17f72807b13","order_by":0,"name":"Naoki Kimoto","email":"","orcid":"","institution":"Osaka University: Osaka Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Kimoto","suffix":""},{"id":466301069,"identity":"f9e7177d-ba29-41c8-a35d-fe600babffa0","order_by":1,"name":"Yohei Miyashita","email":"","orcid":"","institution":"Osaka University: Osaka Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Miyashita","suffix":""},{"id":466301070,"identity":"c8b8b538-0143-4ebc-aff2-15eb62a3a65f","order_by":2,"name":"Yutaka Yata","email":"","orcid":"","institution":"Hanwa Kinen Hospital: Hanwa Kinen Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yutaka","middleName":"","lastName":"Yata","suffix":""},{"id":466301071,"identity":"627c9418-ae0d-49b8-881b-3114db768ac2","order_by":3,"name":"Takeshi Aketa","email":"","orcid":"","institution":"ASCLEPIUS, INC.","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Aketa","suffix":""},{"id":466301072,"identity":"cb8f9551-b556-43b0-8a1d-b2b74004124a","order_by":4,"name":"Masami Yabumoto","email":"","orcid":"","institution":"Hanwa Kinen Hospital: Hanwa Kinen 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Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Seiji","middleName":"","lastName":"Takashima","suffix":""},{"id":466301076,"identity":"2e92b0f8-37c9-4bc3-9627-1c3fc5561482","order_by":8,"name":"Masafumi Kitakaze","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIie3QMUvDQBTA8RceXJdIHO8Q6ld4EkgJFD9LSsDZ0aG0B4W4FLPGb1ERnBMO2iXQtU5eyRfQRRBK8aQdInjUbiL3Xy5w9wv3DsDl+oNxBPCk+QjAW+v2DtoJ7oiQGFL7sJ3AnlCJ0emB/+8St0H1VgxH3XCpGMCmD71OXuL1DXR6FnKGiGI2Z2FUKqa97AriqQIsasBY/ky6ZhahmT94qvIFeVKNZ6sU8CQDpNJK8ENv+fhxgozDRgG9NIZs7cRcjImHjBJiX4QZskJDpJ2ICUbx/V1yUdSINDCzUJ2S8ufcOgtfVs3z9H10HuTK06/mxWhRrRt/2E9tL/a9ZL+aK/GUfkXaXR5PXC6X65/2CVORTZbwEA8lAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5157-4213","institution":"Hanwa Memorial Hospital: Hanwa Kinen Byoin","correspondingAuthor":true,"prefix":"","firstName":"Masafumi","middleName":"","lastName":"Kitakaze","suffix":""}],"badges":[],"createdAt":"2025-05-31 03:27:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6788404/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6788404/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10557-025-07780-4","type":"published","date":"2025-10-07T15:58:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84216015,"identity":"2e9f6e76-e5c9-4336-8e11-683b4de02737","added_by":"auto","created_at":"2025-06-09 10:39:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":109345,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of breast cancer incidence in the preMetS or MetS group (A), and Kaplan–Meier curves of breast cancer incidence in the MetS groups with two and three factors (B) based on the Japanese MetS criteria\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/49b389044fc3bb990d55bf40.png"},{"id":84216020,"identity":"66991a32-fe0b-4685-8489-6494a5cd6ad3","added_by":"auto","created_at":"2025-06-09 10:39:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":108472,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of breast cancer incidence according to \u0026lt;50-, 50–60-, and \u0026gt;60-year-old age groups\u003c/p\u003e","description":"","filename":"renamed9fc16.png","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/8c9e6c8a50bffe2682eeb5d0.png"},{"id":84216017,"identity":"e7f2a673-bb3f-44d9-b826-a0e3f8228058","added_by":"auto","created_at":"2025-06-09 10:39:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":113727,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of the incidence of breast cancer with and without MetS (A) and pancreatic cancer incidence among the six groups with 0–5 components of MetS (B) based on the modified NCEP/ATP III criteria\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/c4b40af440be636187e179ce.png"},{"id":84216687,"identity":"5aa8bb4f-26db-4803-9615-eedc84bfc2ca","added_by":"auto","created_at":"2025-06-09 10:47:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":27182,"visible":true,"origin":"","legend":"\u003cp\u003eHRs of the incidence of pancreatic cancer with and without MetS (A) and pancreatic cancer incidence among the six groups with 0–5 components of MetS (B) based on the modified NCEP/ATP III criteria\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/686531447c9ae5d1a5984507.png"},{"id":84217437,"identity":"a096bd70-6ef8-42c1-9249-73d16f49db8c","added_by":"auto","created_at":"2025-06-09 10:55:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":88747,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of the MetS-free and MetS-developed groups and the MetS-recovered and MetS-persistent groups for pancreatic cancer incidence\u003c/p\u003e\n\u003cp\u003eCompared with the nonMetS groups, breast cancer incidences are significantly decreased in the MetS-developed (p \u0026lt; 0.05), MetS-recovered (p \u0026lt; 0.05), and MetS-persistent (p \u0026lt; 0.005) groups. No differences in breast cancer incidences are observed among the MetS-developed, MetS-recovered, and MetS-persistent groups\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/5e47ab242d54789870d58bdc.png"},{"id":93597509,"identity":"8432b659-48d2-4549-b478-c6acb8556fd7","added_by":"auto","created_at":"2025-10-15 14:15:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1058147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/ff41be33-643b-4b1d-be6b-efcbc1ee28d1.pdf"},{"id":84216016,"identity":"47467e60-be41-4278-bf14-edbd926dae41","added_by":"auto","created_at":"2025-06-09 10:39:48","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13124,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6788404/v1/10a3dc84defb2dac7ce34f49.xlsx"}],"financialInterests":"","formattedTitle":"Relationship between the Incidence of Metabolic Syndrome and Breast Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer poses substantial economic and healthcare burdens worldwide[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although early detection, prompt diagnosis, and innovative medical and surgical treatments have gradually mitigated various cancer types, cancer-related mortality has been high even in developed countries. In particular, breast cancer is the most frequently diagnosed cancer type among females worldwide, especially affecting those in their 30s\u0026ndash;50s[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cancers, including breast cancer, are reportedly primed by family history[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], genetic background[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], smoking[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and type II diabetes mellitus (T2DM)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We and several investigators have reported that metabolic syndrome (MetS) increases the risk of pancreatic cancer[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and we have shown that MetS increases the risk of almost all cancer types[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The overall incidence of cancers may be influenced by the molecular mechanisms of MetS, including (1) insulin, (2) adipokine, and (3) reactive oxygen species (ROS)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Among almost all cancer types, breast cancer is special owing to its estrogen sensitivity. Estrogen is known to initiate or proliferate breast cancer[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and MetS or obesity increases estrogen production in adipose tissues[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] along with the basal secretion of estrogen from the ovary. Furthermore, MetS increases insulin resistance, leading to a high risk of breast cancer[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Several investigators have examined the relationship between the incidences of MetS and breast cancer, and a meta-analysis of nine articles encompassing 6,417 cases of cancer revealed that MetS is associated with a moderately increased risk of postmenopausal breast cancer[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, MetS reportedly increased the risk of breast cancer in females aged\u0026thinsp;\u0026gt;\u0026thinsp;60 years, which is not confirmed in younger females in 4,862 cases of breast cancer[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Conversely, MetS is a risk factor for breast cancer in females aged 40\u0026ndash;80[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and \u0026ge;\u0026thinsp;18 years[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Taken together, MetS, especially obesity, may increase breast cancer incidence, and age may serve as a critical threshold that determines whether MetS exacerbates or mitigates breast cancer risk; however, no clear evidence exists regarding the relationship between MetS and breast cancer, as the sample size of each study is relatively small, with \u0026lt;\u0026thinsp;50,000 participants, 2,000 of whom have breast cancer. Such an investigation is valid; however, we needed a single and large cohort of one million females by age group.\u003c/p\u003e \u003cp\u003eTherefore, we planned to form a cohort of more than one million individuals from the general population and followed them for more than 10 years, and we decided to investigate the relationship between the occurrence of MetS or the early phase of MetS and the incidence of breast cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e This retrospective observational study adhered to the principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eOur analyses were based on data from healthcare insurance claims provided by JMDC (Japan Medical Data Center), Inc. (Tokyo, Japan). The database comprised standardized eligibility and claims data provided by health insurance societies for insured individuals from 2005 to 2020. It included the data of general corporation employees, their family members, and all medical treatments received by insured individuals at treatment facilities. Moreover, it included a comprehensive record of all the treatments administered to a patient. For this study, we disposed of the decoding indexes stored in JMDC, Inc. and analyzed personal data using unsinkable anonymization.\u003c/p\u003e\n\u003ch3\u003eDefinition of MetS\u003c/h3\u003e\n\u003cp\u003eThe Japanese criteria defined MetS as abdominal central obesity with an abdominal circumference at the umbilical levels of \u0026ge;\u0026thinsp;85 and \u0026ge;\u0026thinsp;90 cm for males and females, respectively, with two or more of the following factors: (1) elevated triglyceride and/or reduced high-density lipoprotein levels, (2) elevated blood pressure, and (3) elevated fasting glucose levels[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Premetabolic syndrome (preMetS) was defined as the presence of abdominal central obesity combined with one of the abovementioned factors. Furthermore, the nonMetS group comprised participants not classified as having either MetS or preMetS.\u003c/p\u003e \u003cp\u003eAdditionally, MetS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eStudy protocol\u003c/h3\u003e\n\u003cp\u003eOf the 1,144,791 females with complete dataset, 32,775 with breast cancer at the beginning of the observation period were excluded, and breast cancer occurrence was evaluated. Our results showed that 54,330 participants had breast cancer during the observation period according to the International Classification of Diseases 10th Revision (coded as I10\u0026ndash;I15).\u003c/p\u003e \u003cp\u003eAfter acquiring each dataset, we used the Kaplan\u0026ndash;Meier analysis to compare breast cancer occurrence with and without MetS or preMetS. Furthermore, we calculated the hazard ratios (HRs) using Cox proportional hazard models between two and three groups. Moreover, we examined breast cancer incidence in the subgroups of females aged\u0026thinsp;\u0026lt;\u0026thinsp;50 or \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;60 years and aged\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;50- and \u0026lt;\u0026thinsp;60- years old.\u003c/p\u003e \u003cp\u003eFor another subanalysis, we enrolled 206,847 participants with well-followed metabolic states for \u0026gt;\u0026thinsp;3 years to investigate the effects of metabolic dynamics on breast cancer occurrence. We classified these enrolled participants into the following four groups according to the presence or absence of MetS upon entry: two groups with MetS with and without MetS for 3 years and two groups with nonMetS at with and without MetS for 3 years. Participants with MetS were categorized into either the MetS-recovered (19,598 participants) or MetS-persistent (29,051 participants) groups on the basis of the conditions that MetS improved/disappeared or persisted for 3 years. These participants were followed until the end of the observation period or breast cancer onset. Participants with nonMetS were categorized into the either MetS-developed (26,830 participants) or MetS-free (620,663 participants) groups on the basis of either MetS appeared or not-appeared. We followed these participants until the end of the observation period or breast cancer onset.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eTime-to-event data were evaluated using Kaplan\u0026ndash;Meier estimates and compared using the log-rank test for primary analyses. The entry time, that is, time\u0026thinsp;=\u0026thinsp;0 for the Kaplan\u0026ndash;Meier plots, varied. Censoring occurred when the patient died or was lost to follow up. We employed a complete case analysis (listwise deletion) for missing data, and a sensitivity analysis was not performed.\u003c/p\u003e \u003cp\u003eCox proportional hazard models were employed for estimating HRs with the MetS or preMetS group assignment or combinations of the components with the MetS, preMetS, and nonMetS groups for calculating the \u003cem\u003ep\u003c/em\u003e-values regarding the hypothesis testing between the groups. The models were adjusted for smoking, age, and sex because the incidence of cancer is believed to be affected by these factors.\u003c/p\u003e \u003cp\u003eAfter checking the interactions between the variables age, sex, and smoking through likelihood ratio tests on regression coefficients of interaction terms, the interaction between sex and age was noted to be significant. Therefore, the model that included the sex\u0026ndash;age interaction term was used.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using Python v310 and packages, including lifelines v0278 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://github.com/nkimoto/PKMetS\u003c/span\u003e\u003cspan address=\"https://github.com/nkimoto/PKMetS\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe clinical characteristics of patients with and without preMetS or MetS are presented in Table\u0026nbsp;1. The results of the Kaplan\u0026ndash;Meier analysis of the participants with and without MetS defined using the Japanese MetS criteria for breast cancer incidence are depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e-A, along with progression from the nonMetS to MetS via preMetS, the incidence of breast cancer decreases in a stepwise manner; as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e-B, MetS with two or three factors decreases the incidence of breast cancer compared with preMetS/nonMetS. Both preMetS and MetS decreased the incidence of breast cancer (HR, 0.90; 95% CI, 0.86\u0026ndash;0.94; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005: HR, 0.83; 95% CI, 0.80\u0026ndash;0.87; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005), and MetS with one, two, and three factors, as well as preMetS, decreased the incidence of breast cancer (HR, 0.90; 95% CI, 0.86\u0026ndash;0.94; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005: HR, 0.83; 95% CI, 0.87\u0026ndash;0.87; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005: HR, 0.85; 95% CI, 0.78\u0026ndash;0.94; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005). The results of the subanalysis for investigating the relationship between the presence of MetS or preMetS and breast cancer incidence by age group are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In the \u0026lt;\u0026thinsp;50-year-old age group, the relationship between the presence of MetS (HR, 0.71: CI, 0.62\u0026ndash;0.82; p\u0026thinsp;\u0026lt;\u0026thinsp;0.005) and preMetS (HR, 0.69: CI, 0.61\u0026ndash;0.79; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005) decreased the incidence of breast cancer to the same extent. In the \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;50- and \u0026lt;\u0026thinsp;60-year-old age group, breast cancer incidence was significantly decreased by either MetS or preMetS (MetS: HR, 0.73: CI, 0.67\u0026ndash;0.78; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005; preMetS: HR, 0.83: CI, 0.77\u0026ndash;0.88; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005). In the \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;60-year-old age group, nonMetS significantly decreased the incidence of breast cancer compared with preMetS and MetS; preMetS increased the incidence of breast cancer (HR, 1.07: CI, 1.00\u0026ndash;1.15; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), whereas MetS did not affect it (HR, 1.01: CI, 0.95\u0026ndash;1.07; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75).\u003c/p\u003e \u003cp\u003eThe results of the Kaplan\u0026ndash;Meier analysis indicated that participants with and without MetS, defined using the NCEP/ATP III criteria, had decreased breast cancer incidence (HR, 0.87: CI, 0.84\u0026ndash;0.90; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-A). The negative relationship between the number of the factors of MetS and the incidence of breast cancer is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-B. The HR for the incidence of breast cancer monotonically decreases as the number of MetS factors increases (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e-A and B). Particularly, for one factor, the HR was 0.95 (95% CI, 0.93\u0026ndash;0.97; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005); for two factors, the HR was 0.90 (95% CI, 0.87\u0026ndash;0.92; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005); for three factors, the HR was 0.84 (95% CI, 0.81\u0026ndash;0.88; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005); for four factors, the HR was 0.83 (95% CI, 0.77\u0026ndash;0.88; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005); and for five factors, the HR was 0.82 (95% CI, 0.71\u0026ndash;0.94; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e-B).\u003c/p\u003e\u003cp\u003eRegarding the effects of changes in the status of MetS during the observation period, Kaplan\u0026ndash;Meier analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e-A) and log-rank test (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e-B) among the nonMetS, MetS-recovered, and MetS-persistent groups revealed that even the temporal MetS status decreased the risk of breast cancer. Compared with the nonMetS groups, the incidences of breast cancer were significantly decreased in the MetS-developed (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), MetS-recovered (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and MetS-persistent (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005) groups. No differences in breast cancer incidences were observed among the MetS-developed, MetS-recovered, and MetS-persistent groups. These findings suggest that the temporary occurrence of MetS decreases the breast cancer incidence rate.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study revealed that MetS reduces the incidence of breast cancer in females with an average age of 53 years. Interestingly, in females aged\u0026thinsp;\u0026lt;\u0026thinsp;50 years, MetS and preMetS significantly decreased the incidence of breast cancer compared with nonMetS, with preMetS exhibiting a protective effect comparable to that of MetS. In females aged 50\u0026ndash;60 years, although either MetS or preMetS decreased the incidence of breast cancer compared with nonMetS, preMetS seemed to exhibit a weaker protective effect than MetS. In contrast, in females aged\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;60 years, the effects of MetS on breast cancer were attenuated, and the breast cancer incidence in participants with either MetS or preMetS was high compared with that of participants with nonMetS, with no significant difference. Considering that females aged\u0026thinsp;\u0026lt;\u0026thinsp;50 years may not yet have entered menopause, whereas most of those aged\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;60 years have already reached menopause, the observed significant age-dependent relationship between MetS (or preMetS) and breast cancer appears to be strongly mediated by menopausal status.\u003c/p\u003e\n\u003ch3\u003eDifferences and similarities between previous and present results\u003c/h3\u003e\n\u003cp\u003eIn the cohort investigated in this study, MetS, including preMetS, was associated with a decreased breast cancer incidence overall. This finding contrasts with previous results from a meta-analysis of 97,277 females, which showed that MetS increased breast cancer incidence[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], suggesting that our findings differ from those of previous studies. However, a larger cohort study encompassing 287,320 females reported that although MetS increased breast cancer incidence in females aged\u0026thinsp;\u0026gt;\u0026thinsp;60 years, this trend was not observed in younger females[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This hypothesis was also proved in a Japanese cohort[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The present study, with a cohort of 1,112,016 females, including 54,330 participants with breast cancer who can provide potential and definite power to analyze the relationship among MetS, breast cancer, and age, revealed a reversal in the relationship between MetS and breast cancer risk, especially in the \u0026lt;\u0026thinsp;60-year-old age group. Furthermore, this inverse association between breast cancer incidence and MetS occurrence became stronger as the number of MetS-related factors, including hypertension and dyslipidemia, beyond obesity alone, increased. Additionally, of note, this study showed that preMetS, considered an early stage of MetS, exhibited similar effects to those observed with MetS. This finding suggests that excessive dieting in premenopausal females can increase the risk of breast cancer, whereas obesity in postmenopausal females also mitigates the relationship between MetS and breast cancer. This interesting phenomenon is observed in patients with T2DM. A more recent meta-analysis of 20 studies encompassing 30,407 cases of cancer revealed that females with diabetes (vs. females without diabetes) had a statistically significant 20% increased risk of breast cancer (1.20; 95% CI, 1.12\u0026ndash;1.28). However, in the stratified analysis by menopausal status, diabetes was associated with a 16% increased breast cancer risk in postmenopausal females and a 9% reduced risk in premenopausal females[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings have profound clinical implications. However, understanding why such a discontinuous relationship between age and breast cancer incidence occurs with age is a major challenge in the present observation.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAge-related relationship between MetS and breast cancer\u003c/h2\u003e \u003cp\u003eUnderstanding the impact of MetS on breast cancer necessitates investigating its molecular mechanisms, which culminate in the effects of (1) insulin, (2) adipokine, (3) ROS, and (4) estrogen[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Insulin is a major anabolic hormone that stimulates cell proliferation. An indirect mechanism, including insulin-like growth factor (IGF)-1 stimulation, is believed to mediate the effects of insulin on cancer cell proliferation \u003cem\u003ein vivo\u003c/em\u003e. IGF-1 receptor activation stimulates the p21 ras/MAPK pathway for cell proliferation and the PI3K/AKT cell survival pathway[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Furthermore, IGF-1 stimulates angiogenesis by increasing vascular endothelial growth factor production[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These findings may be related to breast cancer incidence. However, insulin, adipokine or ROS may not explain the discontinuous relationship between age and breast cancer incidence that occurs with age.\u003c/p\u003e \u003cp\u003eConversely, the levels of estrogen, which increases the incidence of breast cancer[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], may be changed throughout a female\u0026rsquo;s life. Breast cancer is mainly influenced by estrogen, and estrogen levels remain high until 50 years old during the premenopausal period; however, they are known to significantly decrease once menopause is reached. In contrast, obesity, frequently observed in MetS, leads to estrogen production in the adipose tissue. After menopause, the primary source of estrogen production shifts from the ovaries to fat cells. Why, then, does MetS appear to reduce the risk of breast cancer before menopause, whereas following menopause, the relationship between MetS and breast cancer risk seems to have disappeared or reversed?\u003c/p\u003e \u003cp\u003eMetS, during the premenopausal period, is associated with increased anovulatory cycles[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. More frequent anovulatory cycles cause reduced estrogen production from the ovaries, which is hypothesized to lower the risk of breast cancer. This phenomenon is consistent with findings that breast cancer incidence decreases not only in the MetS-persistent group but also in those who recover from MetS or develop it temporarily. In other words, even a transient premenopausal MetS occurrence may increase anovulatory cycles, thereby decreasing estrogen levels and potentially reducing breast cancer risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations and features\u003c/h2\u003e \u003cp\u003eThe relationship between MetS and cancers overall should be carefully concluded. Big data analyses may reveal subtle changes in the cohort. However, we observed that each factor responsible for MetS is independently associated with breast cancer, suggesting that MetS exhibits a stepwise effect on cancer risk modulation.\u003c/p\u003e \u003cp\u003eRacial differences may exist whether MetS regulates breast cancer incidence. In Japan, as the lifestyle has recently been westernized, cancers with high prevalence are becoming similar to those of Western countries, and the population with MetS has increased. As we employed a diagnostic method using the NCEP ATP III and Japanese criteria, our conclusion remains unchanged, suggesting that the present conclusion can be applicable worldwide.\u003c/p\u003e \u003cp\u003eAs the study cohort was obtained from employees of general corporations and their family members, the average age of the participants may be younger than the average of the population in Japan. In 2020, the average age of the Japanese population was 48.9 years, which was similar to the average of the cohort of this study. The present cohort may lack older adult participants aged\u0026thinsp;\u0026gt;\u0026thinsp;80 years; therefore, the relationship between MetS and breast cancer for females aged\u0026thinsp;\u0026gt;\u0026thinsp;80 years may not be comparable with the present results.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGrants-in-Aid form Japan Heart Foundation. Sponsor played no role in the study design, data collection, data analysis, and data interpretation or in the writing of the manuscript. The corresponding author assumed full data access and made the final decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest/Competing Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRelationships to industry do not exist for N.K, Y.M., Y.Y., T.A., M.Y., T.W., and S.T. Y.S. reports personal fees from AstraZeneca, personal fees from Otsuka Pharmaceutical, personal fees from Nippon Boehringer Ingelheim, personal fees from Novartis Pharma, from Bayer, grants from Nippon Boehringer Ingelheim, grants from Abbott Medical Japan, grants from Otsuka Pharmaceutical outside the submitted work. M.K. reports personal fees from Daiichi-sankyo, personal fees from Viatris, grants and personal fees from Ono, grants from Novartis, grants and personal fees from Tanabe-mitubishi, grants from Takeda, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer-ingelheim, grants from Kowa, personal fees from Otsuka, personal fees from Eli Lilly outside the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Material:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data analyzed in this study are available from the corresponding author upon reasonable request, depending on the nature of the request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode Availability\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions: \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe followings are the role of each author to this study; Study conceptualization and design: MK, NK, YM, ST; Data curation, NK; Data Formal analysis: NK, YS, TW; Project administration: YY, MY, YS, TW, ST; Visualization: TA, YY, YS; Figures and Tables: NK, YM, TA, ST; Writing and editing: MK. All authors have read and approved the manuscript and the agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Naoki Kimoto, Yohei Miyashita and Masafumi Kitakaze have verified the underlying data of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study was approved by the external Ethics Committee of the Kinshukai Medical Group (approval number: 2024–3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Study Committee decided that based on the Japanese Clinical Research Guidelines, obtaining informed consent from patients selected for inclusion was not necessary as this was a retrospective observational study. Instead, we made a public announcement following the Ethics Committee’s request and the Japanese Clinical Research Guidelines. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm no use of any individual person’s data in any form.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHricak H, Abdel-Wahab M, Atun R, et al. Medical imaging and nuclear medicine: a Lancet Oncology Commission. 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Cancer. 1985;56(5):1206\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/1097-0142(19850901)56:5\u0026lt;1206::aid-cncr2820560541\u0026gt;3.0.co;2-9\u003c/span\u003e\u003cspan address=\"10.1002/1097-0142(19850901)56:5%3C1206::aid-cncr2820560541%3E3.0.co;2-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-drugs-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cdty","sideBox":"Learn more about [Cardiovascular Drugs and Therapy](https://www.springer.com/journal/10557)","snPcode":"10557","submissionUrl":"https://submission.nature.com/new-submission/10557/3","title":"Cardiovascular Drugs and Therapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"breast cancer, metabolic syndrome, big data, early stage of metabolic syndrome, age","lastPublishedDoi":"10.21203/rs.3.rs-6788404/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6788404/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eBreast cancer affects females from puberty onward, with incidence rates increasing with age. Although metabolic syndrome (MetS) has reportedly increased the incidence of almost all cancers, no clear consensus on the role of MetS in breast cancer development exists. We aimed to clarify the effects of MetS on breast cancer incidence.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTo investigate this relationship, we analyzed Japanese healthcare data of females from 2005 to 2020 and examined the incidence of breast cancer. MetS was evaluated based on the Japanese criteria or the NCEP ATP III guidelines at enrollment. Of 1,144,791 participants without missing data in our general public cohort, 32,775 with breast cancer at the beginning of the observation period were excluded; 54,330 participants with breast cancer were identified during the observation period.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBoth pre-stage MetS and MetS, defined using the Japanese criteria, decreased the incidence of breast cancer (hazard ratios [HRs], 0.90 and 0.83; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005). Furthermore, MetS using NCEP ATP III decreased the HR (0.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005), and the number of the factors from 1 to 5 gradually decreased the HRs. Analysis according to age group revealed that this observation was the most prominent in the \u0026lt;\u0026thinsp;50-year-old group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eMetS is associated with decreased breast cancer incidence in females, especially aged\u0026thinsp;\u0026lt;\u0026thinsp;50 years.\u003c/p\u003e","manuscriptTitle":"Relationship between the Incidence of Metabolic Syndrome and Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 10:39:43","doi":"10.21203/rs.3.rs-6788404/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Changes Required","date":"2025-07-05T07:14:54+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-25T11:58:05+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-04T08:23:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-01T23:19:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Drugs and Therapy","date":"2025-05-31T09:08:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-drugs-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cdty","sideBox":"Learn more about [Cardiovascular Drugs and Therapy](https://www.springer.com/journal/10557)","snPcode":"10557","submissionUrl":"https://submission.nature.com/new-submission/10557/3","title":"Cardiovascular Drugs and Therapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"565986a1-ca4b-430a-8bce-a09e4d0ab085","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T16:03:16+00:00","versionOfRecord":{"articleIdentity":"rs-6788404","link":"https://doi.org/10.1007/s10557-025-07780-4","journal":{"identity":"cardiovascular-drugs-and-therapy","isVorOnly":false,"title":"Cardiovascular Drugs and Therapy"},"publishedOn":"2025-10-07 15:58:26","publishedOnDateReadable":"October 7th, 2025"},"versionCreatedAt":"2025-06-09 10:39:43","video":"","vorDoi":"10.1007/s10557-025-07780-4","vorDoiUrl":"https://doi.org/10.1007/s10557-025-07780-4","workflowStages":[]},"version":"v1","identity":"rs-6788404","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6788404","identity":"rs-6788404","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}