Metabolic syndrome (MS) is the simultaneous occurrence of a cluster of predefined cardiovascular risk factors. Although individual MS components are associated with increased risk of cancer, it is still unclear whether the association between MS and cancer differs from the association between individual MS components and cancer. The aim of this matched case-control study was to estimate the association of 13 types of cancer with (1) MS and (2) the diagnosis of 0, 1 or 2 individual MS components.Cases included 183,248 patients ≥40 years from the SIDIAP database with incident cancer diagnosed between January 2008-December 2017. Each case was matched to four controls by inclusion date, sex and age. Adjusted conditional logistic regression models were used to evaluate the association between MS and cancer risk, comparing the effect of global MS versus having one or two individual components of MS.MS was associated with an increased risk of the following cancers: colorectal , liver , pancreas , post-menopausal breast , pre-menopausal endometrial , post-menopausal endometrial , bladder , kidney , non-Hodgkin lymphoma , leukaemia , lung  and thyroid . Except for prostate, pre-menopause breast cancer and Hodgkin and non-Hodgkin lymphoma, MS is associated with a higher risk of cancer than 1 or 2 individual MS components. Estimates were significantly higher in men than in women for colorectal and lung cancer, and in smokers than in non-smokers for lung cancer.MS is associated with a higher risk of developing 11 types of common cancer, with a positive correlation between number of MS components and risk of cancer. Metabolic Syndrome (MS) is the cluster of cardiovascular risk factors such as obesity , hypertension, dyslipidaemia and insulin resistance . MS is aMS was initially considered a risk factor just for cardiovascular disease . HoweverSome studies show that 1 or 2 components of MS are individually associated with colorectal, breast, endometrial, bladder, kidney, lung and thyroid cancer , 12–15. The main aim of this study was to investigate the association between MS and 13 types of cancer in Catalonia, using data collected from 2006–2017 in a large electronic health records validated database , 19. We www.sidiap.org)  2016/679), the data contained in SIDIAP are always pseudonymised. Thus, it is not necessary to ask for informed consent from the participants and so was waived by the Clinical Ethics Committee at IDIAPJGol.http://www.boe.es/boe/dias/1999/12/14/pdfs/A43088-43099.pdf).For the link with the CMBD database, SIDIAP uses a third party to ensure confidentiality. The study protocol was approved by the Clinical Research Ethics Committee of IDIAPJGol (P17/212) on November 29, 2017. Anonymity and confidentiality of data and medical records were guaranteed at all times in accordance with the Organic Law 15/1999 on the Protection of Personal Data ; 5,386 endometrial ; 20,799 bladder; 6,833 kidney; 30,888 prostate; 682 Hodgkin lymphoma; 3,621 non-Hodgkin lymphoma; 6,957 leukaemia; 20,387 lung and 2,709 thyroid . Four coBaseline characteristics of cases and controls are summarized in Hypertension was the most frequent component of MS among the patients included in the study with exposure to only one component . In patients exposed to two components, the most frequent combination was hypertension + high glycemia . Lastly, in patients exposed to ≥3 components, the most frequent combination was hypertension + high glycemia + obesity  .Regarding controls, more MS components (gradient from 0 to ≥ 3) were observed in women, older patients, participants living in deprived areas, smokers and patients with a lower registered consumption of paracetamol, ASA and ibuprofen .The cancer types associated with MS in the adjusted models were post-menopausal endometrial , pre-menopausal endometrial , liver , kidney , pancreas , thyroid , leukaemia , bladder , colorectal , non-Hodgkin lymphoma , lung  and post-menopausal breast . No association was found between MS and Hodgkin lymphoma . The ORs in gynaecological cancers were higher in post-menopausal  than pre-menopausal women  .The increasing number of MS components positively correlates with cancer risk in adjusted models, except for prostate, lung, pre-menopausal breast cancer and non-Hodgkin lymphoma. With the increasing number of MS components, the protective power on pre-menopausal breast cancer increase. Interestingly, while MS was not associated with increased risk of prostate cancer, there was a correlation between the presence of 1 or 2 components of MS and the risk of this cancer . In contrast, the risk of lung cancer was similar for participants with 1, 2 and ≥ 3 (MS) components . Participants with 1 or 2 components presented a higher risk of pre-menopausal breast cancer than participants with MS . Participants with 2 components presented a similar risk of non-Hodgkin lymphoma than participants with MS .We stratified all MS-cancer associations by sex . For colThe association between MS and lung cancer changed when the analysis was stratified according to smoking status ; the risk in smokers and ex-smokers was higher than in non-smokers . .We performed two sensitivity analyses in which we altered the main definition of MS.In the first analysis, two abnormal measures were used to ensure that the patient was exposed to that component. In a second analysis, we used WC instead of BMI to report obesity. The results in sensitive analyses using two measures to define MS components were similar for almost all cancers. However, for liver, kidney and Hodgkin lymphoma the ORs in the models with two measures were slightly higher than the ORs of the main models. The largest difference was found for kidney cancer . The ORs were similar when WC was used instead of BMI, except for prostate and lung cancer, although the sample was small due to the high number of missing values. In the main analysis, MS was not associated with prostate cancer. However, when using WC instead of BMI, MS was inversely associated with prostate cancer . In contrast, in the main analysis MS was a risk factor for lung cancer and when using WC, MS was not associated with lung cancer . The KaIn this large population-based study, MS was associated with an increased risk of 11 out of 13 cancers, namely endometrial, liver, kidney, pancreas, leukaemia, bladder, colorectal, non–Hodgkin lymphoma, lung and post-menopausal breast, although the effects differed substantially by cancer type. An increasing number of MS components positively correlated with a significant increase in cancer risk in adjusted models, except for non-Hodgkin lymphoma and prostate, lung and pre-menopausal breast cancer. The observed effect sizes for the cancers associated with MS in our data were broadly consistent with previous studies , 28–34. The risk of most cancers was higher in individuals with MS than in patients with one or two components of MS. In agreement with the literature , 31, 34,Mechanisms that link metabolic syndrome and cancer risk are not fully understood. Metabolic syndrome may be a surrogate marker for other cancer risk factors, such as decreased physical activity, consumption of high–calorie dense foods, high dietary fat intake, low fiber intake, and oxidative stress .In accordance with previous studies, when stratifying by gender, the risk of colorectal, lung and bladder cancer was higher in men , 15, 30.While MS has multiple definitions, the most widely recognised criteria to construct MS belong to the NCEP ATP III and the IDF . A studyWe also conducted a sensitivity analysis, in which we required two abnormal measurements of each component for diagnosis, and found that it did not significantly affect the results. When using WC in the analysis instead of BMI, the ORs obtained were similar except for lung and prostate cancer. However, the Kappa index between both measurement methods was low. Since we only had WC measurements for 15% of the population and the number of missing values of this variable was too high, we used BMI criteria for obesity in agreement with other publications , 34. FurOur study has several strengths. Firstly, we used a large data source with sufficient statistical power to investigate associations of less frequent cancers (i.e. Hodgkin and non-Hodgkin lymphoma and thyroid). Consequently, we have been able to present the first results on the association between MS and haematological malignancies. SIDIAP patients broadly represent the wider population, suggesting good generalizability to the Catalonian and similar populations. In 2019, Recalde et al. –45.Our study also has limitations. Firstly, we assumed that once a person had an abnormal result, this person was constantly exposed to this component even if later results showed improvement. Some evidence points at the concept of metabolic memory, i.e., even when an individual stops meeting MS criteria, they are still at higher risk of specific cancers (i.e. kidney cancer) . Also, tThe increasing prevalence of MS worldwide and the high incidence of some cancers suggests that a large number of cancer cases diagnosed every year are related to the metabolic syndrome. There is a compelling need for evidence on whether effective interventions to reduce the prevalence of metabolic syndrome in adult populations could reduce cancer risk. The formulation of public health strategies based on lifestyle changes could obtain significant results in the fight against cancer. Investigating the role of MS as a risk factor of specific cancers is crucial to diagnose and treat cancer in earlier stages.In summary, MS is associated with a higher risk of developing at least 11 cancer types. The risk of most cancers increased with the number of MS components present in an individual. Our results indicate that prevention strategies targeting individual components of MS could reduce the risk of several cancer types.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableaConsider two measures of parameters separated at least by 2 weeks (maximum 1 year) to ensure that the patient has that pathological component of MS. bUsing Waist circumference instead of one measure of BMI. There were 157,872 (86.1%) missing values in the case group and 636,984 (86.9%) missing values in the control group. cAlso adjusted by hepatitis and others liver disease. dThe model does not converge when using Waist circumference instead of one measure od BMI, because the number of observations in this model are very low. 1Wald test. 2P-Trend. OR, odds ratio; CI, confidence interval.Adjusted ORs and 95% CI. Multiple imputation by chained equations with 20 imputed datasets were applied to outcomes and covariates. Models adjusted by age, medea, tobacco, alcohol, nationality. (DOCX)Click here for additional data file. 7 Dec 2021
 PONE-D-21-30858

 Association between Metabolic Syndrome and 13 types of Cancer in Catalonia: a matched case-control study

 PLOS ONEDear Dr. Puente,

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Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********  2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #2: Yes**********  3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This article reported results MS is statistically associated with a higher risk of developing at 11 cancer types after the evaluation of 13. Moreover, they demonstrated in this manuscript that the risk of most cancers increased with the number of MS components present in an individual. Hence, the authors finally suggest that prevention strategies targeting individual components of MS could reduce the risk of several cancer types. Although the manuscript is potentially interesting, it is mostly descriptive and most of the conclusions have been published previously (see comments below).Thus, there are major aspects that could be revised to improve the results:- The authors should take care in the use of “recent” when they are referring to other published works since I cannot consider a recent work that has been published more than 5 years ago. An example is given, “MS was initially considered a risk factor just for cardiovascular disease. However, recent studies associate MS with a higher risk of liver, colorectal, and bladder cancer in men; and endometrial, pancreatic, colorectal, ovarian, and postmenopausal breast cancer in women”. However, the original manuscript was published in 2012(doi: 10.2337/dc12-0336).- The authors did not give too many reasons for the selection of these 13 cancer types. The authors only said, “However, no evidence has been yet provided for the impact of MS components in other less common cancers”. Conversely, for example, lung cancer has related to some metabolic factors of metabolic syndrome. Please, I am really encouraged to provide more reasons for the selection of these cancer types.- The author must justify the fact of comparing every case with four controls since a major number of control cases could imply a major statistical power being really important for the final results and conclusions of this study.-In general, the manuscript needs to get a significant improvement in the discussion section. For instance, the sentence is too descriptive: “In gynecological cancers, the menopausal status was a determinant factor, especially in breast cancer. In agreement with previous studies, we observed that MS increased breast cancer risk in postmenopausal women and decreased it in premenopausal women”.- Concerning the important limitation of not following up with the patients, the authors should clearly explain this limitation and how it could affect the results of the paper. Furthermore, the authors should provide information about when the MS component was identified such as previous to tumor diagnose (1 year or 2 years), during tumor treatment…Minor comments:- A sentence in the abstract is not very clear. “Adjusted conditional logistic regression models were used to estimate OR and 95% CI for the association between individual components of MS and cancer, and MS and cancer.” It seems to be confusing.- The use of “approximately” when you are talking about the patients available in the study is not accurate for scientific work.- The authors described in methodology “All individuals ≥ 40-99 years of age with information in the SIDIAP database between 01/01/2006 and 31/12/2017 were included. Final participants included patients with any of the 13 types of incident cancers of interest, together with their paired controls.” Please, the authors should provide the number of patients after the application of each inclusion criteria in the methodology section.- Typing errors like “MS component..” should be corrected in the new manuscript.Reviewer #2: In this study, Diana Puente et al studied the potential association between Metabolic syndrome (and number of components met) and the risk of 13 types of cancer. The authors included 183,248 patients from the Information System for Research in Primary Care. The data derived from this study showed that Metabolic Syndrome is associated to 11 cancer types . These results are interesting for the field and shed light on the relation between Metabolic Syndrome and cancer risk. Therefore, the Reviewer consider that this article is well written, adds to the field valuable information and is suitable to be published in PLOS One. However, the following minor comments should be addressed:- The manuscript is well-written. However, some typos can be found in the text and should be corrected:o Remove intro in line 130.o Remove intro in line 131.o Two period symbols in line 133.- In the introduction there is no information about the inconclusive relation between prostate cancer and metabolic syndrome. Authors should include some information about that in the introduction.- In addition to the presence of Metabolic Syndrome, the authors also analysed the impact of the number of criteria met on cancer risk. However, no information was shared with regards to the potential association of specific MS criteria and cancer risk. As an example, Gomez-Gomez et al showed that high-blood pressure was associated with clinically significant prostate cancer in their cohort of patients (1). Authors should analyse this or add some information about this in the limitations paragraph.- The authors performed two sensitivity analyses in which they altered the main definition of Metabolyc Sindrome. The data obtained when using WC instead of BMI are especially interested as WC is a better criterion to ‘measure’ obesity. Although the authors appreciated that the sample is smaller when classifying the patients using WC due to the high number of missing values, this information  is not showed in Supplemental Table 3. Therefore, authors should include this information in the final version of the manuscript.- The fact that patients with 1 or 2 MS components presented a higher risk of pre-menopausal breast cancer and prostate cancer than participants with MS has not been discussed in the manuscript. Could the authors explain this rare phenomenon? The authors should address this question in the discussion section of the final manuscript.References1. Gomez-Gomez E, Carrasco-Valiente J, Campos-Hernandez JP, Blanca-Pedregosa AM, Jimenez-Vacas JM, Ruiz-Garcia J, Valero-Rosa J, Luque RM, Requena-Tapia MJ. Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer. J Cell Mol Med. 2019;23(2):934-942.**********  6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Yes: Fuentes-Fayos, Antonio CReviewer #1: Reviewer #2: Nohttps://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, AttachmentPONE-D-21-30858_reviewer.docxSubmitted filename: Click here for additional data file. 31 Jan 2022Dear editor,Many thanks for allowing us the opportunity to revise and resubmit this manuscript. The reviewers have provided us with many constructive suggestions. We have addressed each reviewer’s point below. Two versions of the revised manuscript have been uploaded .Editorial and formatting comments1. Please amend your current ethics statement to address the following concerns:a) Did participants provide their written or verbal informed consent to participate in this study?b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure.RESPONSE: The database is comprised of electronic health records from 286 primary healthcare centres. According to the European and Spanish legislation, it is not necessary to ask for informed consent from the participants to use their data for research after anonymization. Thus, the participants did not provide written or verbal informed consent to participate in this study. The study protocol was approved by the Clinical Research Ethics Committee of the IDIAPJGol (P17/212).We have changed the “Ethics approval and consent to participate” section . The revised statement is: “This study follows all national and international regulations: Declaration of Helsinki and Principles of Good Research Practice.In accordance with European and Spanish legislation on confidentiality and data protection ([EU] 2016/679), the data contained in SIDIAP are always pseudonymised. Thus, it is not necessary to ask for informed consent from the participants and so was waived by the Clinical Ethics Committee at IDIAPJGol. http://www.boe.es/boe/dias/1999/12/14/pdfs/A43088-43099.pdf)”.For the link with the CMBD database, SIDIAP uses a third party to ensure confidentiality. The study protocol was approved by the Clinical Research Ethics Committee of IDIAPJGol (P17/212) on November 29, 2017. Anonymity and confidentiality of data and medical records were guaranteed at all times in accordance with the Organic Law 15/1999 on the Protection of Personal Data . The revised statement is:www.sidiap.org). SIDIAP database and the corresponding research projects were developed thanks to an agreement with the Catalan Health Institute (the owner of the data). Thus, we are not allowed to distribute or make publicly available the data to other parties. However, researchers from public institutions can request data from the SIDIAP and other sources  if they comply with certain requirements. Further information is available online (https://www.sidiap.org/index.php/menu-solicitudes-en/application-proccedure) or by contacting the SIDIAP Team (sidiap@idiapjgol.org)’‘In accordance with current European and national law, the data used in this study is only available for the researchers participating in this project. The data and variables of this study are obtained from the electronic registries of medical records, which are components of the Information System for Research in Primary Care (SIDIAP) .http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. 5. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: RESPONSE: In the new ‘Data Availability Statement’ we explain in detail the ethical or legal restrictions that apply to publicly sharing our data.Reviewer #1:1. This article reported results MS is statistically associated with a higher risk of developing at 11 cancer types after the evaluation of 13. Moreover, they demonstrated in this manuscript that the risk of most cancers increased with the number of MS components present in an individual. Hence, the authors finally suggest that prevention strategies targeting individual components of MS could reduce the risk of several cancer types. Although the manuscript is potentially interesting, it is mostly descriptive and most of the conclusions have been published previously (see comments below).RESPONSE: Thank you for the positive comments. We believe our manuscript provides novel contributions to the scientific community and we show this in our specific responses below.2. Thus, there are major aspects that could be revised to improve the results:- The authors should take care in the use of “recent” when they are referring to other published works since I cannot consider a recent work that has been published more than 5 years ago. An example is given, “MS was initially considered a risk factor just for cardiovascular disease. However, recent studies associate MS with a higher risk of liver, colorectal, and bladder cancer in men; and endometrial, pancreatic, colorectal, ovarian, and postmenopausal breast cancer in women”. However, the original manuscript was published in 2012(doi: 10.2337/dc12-0336).RESPONSE: We agree with the reviewer. We have modified the sentence to exclude the word “recent” .3. The authors did not give too many reasons for the selection of these 13 cancer types. The authors only said, “However, no evidence has been yet provided for the impact of MS components in other less common cancers”. Conversely, for example, lung cancer has related to some metabolic factors of metabolic syndrome. Please, I am really encouraged to provide more reasons for the selection of these cancer types.RESPONSE: We agree with the reviewer and have modified the paragraph accordingly. The new paragraph is: “We decided to include the most frequent cancer types (ICD-10 codes) in Spain as outcomes. Even though there is evidence of the association between MS and some of these cancer types such as colorectal (C18+20), prostate (C61), liver (C22), bladder (C67), endometrium (C54), pancreas (C25) and breast (C50). Prior studies have not investigated the MS-cancer association for several cancer types using a systematic analysis approach like lung cancer (C34) and kidney cancer (C64) but were included due to their high prevalence in the general population. In addition, we included some less frequently occurring cancer types such as thyroid (C73), Hodgkin lymphoma (C81), non- Hodgkin lymphoma (C82-85) and leukemia (C91-95), for which the current literature is limited. An association between MS and more cancer types than currently recognized in the literature is possible given that the components of MS can trigger biological  processes involved in tumor development” .4. The author must justify the fact of comparing every case with four controls since a major number of control cases could imply a major statistical power being really important for the final results and conclusions of this study.RESPONSE: In case-control studies, the inclusion of more than four or five controls per case provides very little gain in statistical power . Thus, we decided to include only four controls per case given that the dataset is already very large and requires a lot of computing power to run the analyses. We included this reference to justify the number of controls. In the ‘Control definition’ section, we add the phrase ‘No more controls were obtained as it has been previously shown that little statistical power is gained by further increasing this ratio (ref)’ Reference included: Hennessy S, Bilker WB, Berlin JA et al. Factors influencing the optimal control-to-case ratio in matched case-control studies. Am J Epidemiol. 1999 15;149(2):195-7. 5. In general, the manuscript needs to get a significant improvement in the discussion section. For instance, the sentence is too descriptive: “In gynecological cancers, the menopausal status was a determinant factor, especially in breast cancer. In agreement with previous studies, we observed that MS increased breast cancer risk in postmenopausal women and decreased it in premenopausal women”.RESPONSE: This is an epidemiological observational study and we tried to be cautious in making any conclusions that could refer to causality. One of our objectives was to provide evidence on the association between MS and cancer, but we need to be careful when making interpretations of such associations. However, considering the reviewer's comment, we tried to include further details in this specific sentence. Specifically, we added information in the paragraph: “In the case of gynaecological cancers, menopausal status was a determinant factor, especially in breast cancer. In agreement with previous studies, we observed that MS increased breast cancer risk in postmenopausal women and decreased it in premenopausal women. Previous investigations proposed that each component of the metabolic syndrome is connected with systemic alterations. Concerning breast cancer, it has been proposed that components of MS, especially obesity, play different roles in cancer risk according to menopausal status and estrogen receptor status. Obesity is associated with decreased risk of estrogen receptor–positive breast cancer in premenopausal women, but it is closely related with increased risk of estrogen receptor–positive breast cancer in postmenopausal women (ref)”. References included: Esposito K, Chiodini P, Colao A, et al: Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care 2012, 35: 2402-2411. 2012;35:2402-2411. Esposito K, Chiodini P, Capuano A, et al. :Metabolic syndrome and postmenopausal breast cancer: systematic review and meta-analysis. Menopause. 2013 Dec;20(12):1301-9. Hwang KT, Han KD, Oh S, et al. :Influence of Metabolic Syndrome on Risk of Breast Cancer: A Study Analyzing Nationwide Data from Korean National Health Insurance Service. Cancer Epidemiol Biomarkers Prev 2020, 29: 2038-2047. We have also included the following paragraph in the discussion section: “Mechanisms that link metabolic syndrome and cancer risk are not fully understood. Metabolic syndrome may be a surrogate marker for other cancer risk factors, such as decreased physical activity, consumption of high–calorie dense foods, high dietary fat intake, low fiber intake, and oxidative stress (ref).” .Reference included: Esposito K, Chiodini P, Colao A, et al: Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care 2012, 35: 2402-2411. 2012;35:2402-2411. 6. Concerning the important limitation of not following up with the patients, the authors should clearly explain this limitation and how it could affect the results of the paper. RESPONSE: There is no follow-up for patients after cancer onset (or index date for controls) in this study. However, data has been treated longitudinally using electronic health records data from healthcare use, which allowed us to determine the timing of exposure in relation to the outcome date. The only limitation in that regard is that we were not able to estimate absolute risks, but only relative risks. We have added a sentence in the paper explaining this limitation “This is a case-control study, when estimating the association between MS and cancer; however, we were not able to estimate cumulative incidences or other types of absolute risks, which would have been useful to put the relative increase in absolute terms”. 7. Furthermore, the authors should provide information about when the MS component was identified such as previous to tumor diagnose (1 year or 2 years), during tumor treatment…RESPONSE: Exposure to MS before the event must be at least 2 years prior to cancer diagnosis to avoid reverse causality as it is written in methodological section. We added a phrase in the last paragraph of the “MS definition” section: “Both cases and controls had to be exposed either to MS or to 1 or 2 MS components for at least 2 years before the index date (cancer diagnosis or control identification) to avoid reverse causality” . We did not have information about previous treatment for other health conditions. This is a limitation of our study that we have mentioned in the limitations section. In the paragraph explaining the lack of data, we have added “Also, the lack of data on other possible confounders influencing the relationship between MS and cancer, such as physical activity and parity, or information related to previous treatment for other health conditions might have biased the results” .Minor comments:8. A sentence in the abstract is not very clear. “Adjusted conditional logistic regression models were used to estimate OR and 95% CI for the association between individual components of MS and cancer, and MS and cancer.” It seems to be confusing.RESPONSE: In agreement with the reviewer, we replaced this sentence by the following one: “Adjusted conditional logistic regression models were used to evaluate the association between MS and cancer risk, comparing the effect of global MS versus having one or two individual components of MS”. 9. The use of “approximately” when you are talking about the patients available in the study is not accurate for scientific work.RESPONSE: We agree with the reviewer and have deleted “approximately” accordingly 10. The authors described in methodology “All individuals ≥ 40-99 years of age with information in the SIDIAP database between 01/01/2006 and 31/12/2017 were included. Final participants included patients with any of the 13 types of incident cancers of interest, together with their paired controls.” Please, the authors should provide the number of patients after the application of each inclusion criteria in the methodology section.RESPONSE: We agree with the reviewer and have replaced this paragraph with the following: “All individuals ≥ 40 years of age with information in the SIDIAP database between 01/01/2006 and 31/12/2017 were suitable to be included. Patients were excluded from participation when they presented with secondary cancers and metastases.A total of 190,505 individuals with incident cancer were initially included. Of these, we later excluded 334 men with breast cancer, 6,826 cases because they were diagnosed with more than one cancer on the same day, and 61 because they were >99 years of age on the index date. Finally, a total of 183,284 cases and 733,136 paired controls, four controls for each case, were included .” This information was explained at the beginning of the results section, so we have removed it from the results section. We have also removed the word "remaining" from first sentence in the result section so that the sentence is consistent. 11. Typing errors like “MS component..” should be corrected in the new manuscript.RESPONSE: The extra period has been removed.Reviewer #2:1. In this study, Diana Puente et al studied the potential association between Metabolic syndrome (and number of components met) and the risk of 13 types of cancer. The authors included 183,248 patients from the Information System for Research in Primary Care. The data derived from this study showed that Metabolic Syndrome is associated to 11 cancer types . These results are interesting for the field and shed light on the relation between Metabolic Syndrome and cancer risk. Therefore, the Reviewer consider that this article is well written, adds to the field valuable information and is suitable to be published in PLOS One. RESPONSE: We thank the reviewer for the positive comments.2. However, the following minor comments should be addressed:The manuscript is well-written. However, some typos can be found in the text and should be corrected:o Remove intro in line 130.o Remove intro in line 131.o Two period symbols in line 133RESPONSE: We thank the Reviewer for spotting these typos, we have corrected these specific typos and reviewed the manuscript to make sure that there were no other similar mistakes 3. In the introduction there is no information about the inconclusive relation between prostate cancer and metabolic syndrome. Authors should include some information about that in the introduction.RESPONSE: We have included the following sentence in the introduction section with its respective reference: “The results from studies on prostate cancer and MS are inconclusive, while some of them show an increase in risk, others show a reduction. References included: Gomez-Gomez E, Carrasco-Valiente J, Campos-Hernandez JP et al. Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer. J Cell Mol Med 2019, 23: 934-942. Blanc-Lapierre A, Spence A, Karakiewicz PI et al.: Metabolic syndrome and prostate cancer risk in a population-based case-control study in Montreal, Canada BMC Public Health 2015, 15: 9134. In addition to the presence of Metabolic Syndrome, the authors also analysed the impact of the number of criteria met on cancer risk. However, no information was shared with regards to the potential association of specific MS criteria and cancer risk. As an example, Gomez-Gomez et al showed that high-blood pressure was associated with clinically significant prostate cancer in their cohort of patients (1). Authors should analyse this or add some information about this in the limitations paragraph.RESPONSE: This is an interesting issue, and we agree with the reviewer it is important to explore the potential effect of specific components. However, exploring the association of specific MS components and cancer risk was not the main objective of the article . Additionally, we are providing a comprehensive study looking at the association between single MS components and MS as whole in relation to the risk of numerous types of cancer. The effect of specific components into the risk is likely to vary by cancer type. In order to keep the analyses reasonable for this study, we would prefer to not include this information in the current manuscript. We added some information about this in the limitation paragraph “In addition, it is necessary to explore the potential association of specific MS criteria and risk of specific cancer types in future studies.” .Published protocol:Puente D, Lopez-Jimenez T, Cos-Claramunt X et al.: Metabolic syndrome and risk of cancer: a study protocol of case-control study using data from the Information System for the Development of Research in Primary Care (SIDIAP) in Catalonia. BMJ Open 2019, 9: e0253655. The authors performed two sensitivity analyses in which they altered the main definition of Metabolyc Sindrome. The data obtained when using WC instead of BMI are especially interested as WC is a better criterion to ‘measure’ obesity. Although the authors appreciated that the sample is smaller when classifying the patients using WC due to the high number of missing values, this information  is not showed in Supplemental Table 3. Therefore, authors should include this information in the final version of the manuscript.RESPONSE: We have now included this information at the end of the table “There were 157,872 (86.1%) missing values in the case group and 636,984 (86.9%) missing values in the control group” .6. The fact that patients with 1 or 2 MS components presented a higher risk of pre-menopausal breast cancer and prostate cancer than participants with MS has not been discussed in the manuscript. Could the authors explain this rare phenomenon? The authors should address this question in the discussion section of the final manuscript.RESPONSE: Unfortunately, with the data available we could not explore biological mechanisms that could be behind this association. Nevertheless, as indicated in the literature, we found that a study by Gomez-Gomez et al., showed that each of the individual criterion of MS, circulating testosterone levels and inflammatory status may have on the risk and aggressiveness of prostate cancer. Regarding breast cancer, it may be that the presence of a single component could be a risk determinant. Although in our study we cannot determine which component is involved, a study by Xiang Y et al, reported that the hypertriglyceridemic-waist phenotype could be regarded as a strong predictor of breast cancer (ref) and we have included the sentence:” Concerning breast cancer, it has been proposed that components of MS, especially obesity, play different roles in cancer risk according to menopausal status and estrogen receptor status (ref).”  (see response 5 to Reviewer #1)However, the differences that we find between the presence of 1 or 2 factor and global MS are few and not all of them are statistically significant.References included: Gomez-Gomez E, Carrasco-Valiente J, Campos-Hernandez JP, et al. Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer. J Cell Mol Med 2019, 23: 934-942.Xiang Y, Zhou W, Duan X, et al. Metabolic Syndrome, and Particularly the Hypertriglyceridemic-Waist Phenotype, Increases Breast Cancer Risk, and Adiponectin Is a Potential Mechanism: A Case-Control Study in Chinese Women. Front Endocrinol (Lausanne) 2019, 10: 905.AttachmentResponse to reviewers PLOS ONE.docxSubmitted filename: Click here for additional data file. 15 Feb 2022Association between Metabolic Syndrome and 13 types of Cancer in Catalonia: a matched case-control studyPONE-D-21-30858R1Dear Dr. Puente,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. 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Only one in five students (21%) ever practiced breast self-examination. The mean score of practice of breast self-examination was significantly higher (p<0.001) among participants who reported having family member of breast cancer. Total knowledge score about breast cancer and practice of breast self-examination were significantly correlated with each other . About 33% participants reported ‘lack of knowledge’ as the main barrier to practicing breast self-examination followed by ‘I do not have the symptoms’ (22%), and ‘shyness/ uncomfortable feelings’ (17%). The study revealed low levels of knowledge about breast cancer and low breast self-examination practices. Our findings highlight the need to develop, implement and promote socially, culturally and demographically appropriate educational interventions programs aimed at breast cancer and breast self-examination awareness and practice in Bangladesh.Early diagnosis of breast cancer is the best approach towards its control that may result in alleviating related mortality and morbidity. This study aimed to evaluate knowledge about breast cancer and both practices and perceived barriers to breast self-examination among female university students in Bangladesh. A cross-sectional study was carried out with 400 female students of Jahangirnagar University, Bangladesh. Participants were sampled from female dormitories at the university from January to April 2020. Proportionate stratified random sampling was conducted to calculate the study sample from each dormitory. A validated semi-structured self-reported questionnaire was employed to collect data from participants during the survey periods. The questionnaire consisted of demographic variables, items about knowledge about breast cancer, breast self-examination practices and its barriers. We applied descriptive and inferential statistics and data were analyzed using the Statistical Package for the Social Sciences (SPSS). Participants were aged between 18–26 years and comprised university students of first year (20%), second year (24%), third year (22%), fourth year (21%) and Master’s (14%). 18% of them reported positive family history  of breast cancer. The overall mean score of total knowledge items was 15 (SD = 3) out of 43, with an overall correct rate of 34%. The mean score of total knowledge items was significantly higher ( Generally, this disease occurs more frequently among older women above 50, but in recent years, the rising population in this age range has led to a surge in the absolute number of younger women diagnosed with breast cancer. According to Ahmadian and Samah (2012), Asian women get breast cancer at a younger age (40 to 49 years old), than their Western counterparts, who develop it at a later age, (between 50 to 59 years old) [Breast cancer is a major global health concern and a prominent reason of mortality among females. It is the most frequent cancer among women globally, impacting 2.1 million women each year, and is predicted to grow to approximately 3.2 million new cases per year by 2050 . Delay iars old) .In Bangladesh, Mammography and MRI screening are available at some tertiary level hospitals. However, mammography is more sensitive at detecting cancer in older women  and MRI The American Cancer Society also recommends that women should be familiar with how their breasts normally feel via breast self-examination (BSE) and report any breast changes promptly to their health care providers. The ‘National Cancer Control Strategy and Plan of Action 2009–15’ in Bangladesh advocates encouraging clinical breast examination (CBE) and BSE as breast cancer’s early detection approach for disease downstage and survival improvement . In addiBSE is an easy, expedient, non-invasive and no-cost way to check out women’s own breasts to find any changes in their breasts. BSE can identify symptoms of breast cancer at early stages of cancer, when the condition can be more successfully treated and thus increasing survival rate from breast cancer. BSE aids women by making them conversant about how their breasts should look and feel thus leading to ‘breast awareness’ and also enable them to identify changes in their breasts in the initial stage . It can In Bangladesh, a previous study reported poor knowledge and awareness of breast cancer and lack of adherence to any recommended screening method of breast cancer, including BSE . HoweverA cross-sectional study was carried out with 400 female students who enrolled in Bachelor and Master’s programs of Jahangirnagar University . The study was solely conducted in the 8 female dormitories and data were collected over four months from January-April 2020. At first, for sample size determination, Yamane’s simplified sampling formula was used, which calculated our sample size required as 386 participants. However, in order to be even more confident, we decided to slightly over-sample, and aim for 400 participants. We then applied proportionate stratified random sampling, based on the population proportion of dormitories in order to calculate the study sample from each dormitory. Using this approach, each stratum sample size is directly proportional to the population size of the entire population of strata.The inclusion criteria included: (ⅰ) being 18 years of above; (ⅱ) being female university students who reside at dormitories; and (ⅲ) being willing to take part in the survey. The exclusion criteria were being below 18 years old and having incomplete responses.S1 File.A pre-tested, self-reported, semi-structured questionnaire including informed consent, socio-demographic information and questions related to knowledge of breast cancer, BSE practices and its barriers, was prepared for the study through extensive literature review –20. In oSocio-demographic information was recorded during the survey including age, study year (first/ second/ third/ fourth/ Master’s), marital status (unmarried/ unmarried), family history of breast cancer (yes/ no), and relationship with breast cancer affected patient (mother/ sister/ cousin/ aunt/ grandmother).S2 File.To assess the participants’ knowledge of breast cancer, a total of 43 questions regarding breast cancer  were asked during the survey. Each question has three possible responses . The distributions (frequencies and percentages) of all questions are presented in Have you ever self-examined your breast for breast cancer?) was used to assess the BSE with binary responses (yes/no). In addition, the barriers of BSE were also recorded.A single construct  was set at 0.05.Data analysis was performed using the SPSS version 25. Descriptive statistics such as frequencies and percentages were computed for categorical variables; whereas, means and standard deviations were for continuous variables. Some first-order analyses (i.e. t-tests and one-way ANOVA) were performed to assess the association between independent and dependent variables. The Pearson correlation test was also carried out to find out the correlations between two continuous variables. The significance level , second year (23.5%), third year (21.8%), fourth year (21.0%) and Master’s (14.2%) . Most ofThe mean score of knowledge about breast cancer symptoms was 2.94 (SD = 1.14) out of 8, with an overall correct rate of 36.8% . The mosThe mean score of knowledge about breast cancer prevention was 3.26 (SD = 1.14) out of 8, with an overall correct rate of 36.2%. The mean score of knowledge about breast cancer prevention was significantly higher among participants who reported being Master’s students. The mean score of knowledge about breast cancer screening was 1.82 (SD = 0.55) out of 5, with an overall correct rate of 36.4%. The mean score of knowledge about breast cancer screening was not significantly different among participants in terms of socio-demographic groups or source of information. The mean score of knowledge about BSE process was 1.57 (SD = 1.86) out of 5, with an overall correct rate of 31.4%. The mean score of knowledge about BSE process was significantly higher among participants who reported having family members of breast cancer and those who have practiced BSE in the past.Overall, the mean score of total knowledge items was 14.74 (SD = 3.15) out of 43, with an overall correct rate of 34.3% . The mear = 0.54; p<0.001).About one-fifth of participants reported they had ever practiced BSE (21.3%). The mean score of practice of BSE was significantly higher among participants who reported having family members of breast cancer. Descriptive statistics and correlations between all outcome variables  are presented in About 33.3% of the participants have addressed ‘lack of knowledge’ as the main barrier to practicing BSE followed by ‘I do not have the symptoms’ (21.8%), ‘shyness/ uncomfortable feelings’ (16.5%), ‘I don’t think it’s important (9.5%), ‘I know I will never have breast cancer’ (6.8%), and ‘fear or being diagnosed of cancer’ (6.3%).The present study explored knowledge of breast cancer and practice of BSE among female university students in Bangladesh. The present findings on the common symptoms are in consensus with a study conducted in Saudi Arabia which also showed a moderate knowledge of ‘presence of lump in the breast’ (48%) and ‘change in the shape of the breast or nipple’ (42.9%), although ‘inverted nipple’ was known as a warning sign of breast cancer by only 29% of the students . In anotOur findings on levels of knowledge about risk factors of breast cancer were also consistent with the Saudi Arabian study, which also showed that only 42.3% of the study sample knew that lack of physical exercise increases the risk of breast cancer . ConsistBSE was known to only 42.0% of the respondents in our study, a finding consistent with a study in Pakistan which found that only 40.3% of students knew about BSE . CBE wasIn our study, there was a significant relationship between the overall knowledge score and practice of BSE, implying that the more knowledgeable participants are also more likely to practice breast self-examination. We are acutely aware that correlation does not equal causation, but it seems plausible that knowledge of breast cancer would impact BSE as opposed to the other way around. This supports the fact that knowledge about breast cancer can play a vital role in the increased breast awareness and the practice of BSE. As Bangladesh is a developing country with low resources, mammography as a screening procedure is not a feasible first-line prevention or detection procedure. Therefore, BSE and CBE should be the main screening procedure for breast cancer in Bangladesh. Television/radio/mass media were identified as the main source of information in our study and this was similar in other studies , 29, 30,p < .001) with breast cancer knowledge about symptoms, risk factors and treatment options, indicating that higher the educational level is associated with higher knowledge about breast cancer. In addition, those who had a family history of breast cancer with close relatives had significantly higher knowledge about BSE procedure (p < .001). A similar association was also found in Saudi Arabia [The number of years that our participants had been studying had a significant association  BSE. Also, the accuracy, timing, frequency and interpretation of BSE practice were not assessed. Moreover, we conducted the study on female students of only one university using cross-sectional methods. Given that our sample are highly educated, we also cannot claim any generalizability to other groups of women in Bangladesh. So, a future study with larger sample sizes including a broader cross-section of the population  and prospective methods is warranted to overcome the potential study limitations.The present study reveals that university female students had limited knowledge on breast cancer, ranging from 30% about treatment options to 37% about symptoms, with overall correct rate of knowledge being 34.3%. Moreover, the present study revealed that the practice of BSE was low in our sample. This study also found a significant association between knowledge of breast cancer and practice of BSE, implying appropriate knowledge and awareness about breast cancer may lead to practice of BSE and thus early diagnosis which in terms can help to reduce the breast cancer morbidity and mortality. More studies need to be conducted to find out the baseline knowledge and practice about breast cancer across the general population and between different socio-demographic groups so that effective preventive policies can be developed and implemented. Also, educational interventions programs that are socially, demographically and culturally appropriate should be promoted and implemented to raise awareness regarding breast cancer and enhance BSE practice among all females in Bangladesh.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(XLSX)Click here for additional data file.


Despite increasing evidence for the association of adherence to the Dietary approaches to stop hypertension (DASH) diet with breast cancer risk, the results remain inconclusive. The purpose of the current systematic review was to summarize the evidence from previous observational studies and explore the potential association between DASH diet and breast cancer risk using meta-analysis.Q test and I-squared (I2) statistic were used to detect the sources of heterogeneity among the included studies.A comprehensive literature search was conducted using the databases of PubMed, Web of Science, CNKI and Wanfang Data to identify the relevant publications from inception up to July 2022. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for the highest versus the lowest categories of DASH score in relation to breast cancer risk, using a random-effects model. The Cochran’s P < 0.0001). Stratified analysis showed a significant association between adherence to the DASH diet and risk of breast cancer in case-control studies , and a marginally significant association in prospective cohort studies , respectively. Besides, a more significant association between DASH score and reduced risk of breast cancer was observed in Asian countries  than in the United States . Similarly, when we conducted analyses separately by menopausal status, we found a significant inverse association between DASH diet and breast cancer risk in postmenopausal women .Overall, eleven studies, involving 23,254 breast cancer cases and 449,273 participants, were included in this systematic review and meta-analysis. Combining 16 effect sizes from 11 studies, a significant inverse association between adherence to the DASH diet and risk of breast cancer was observed (RR = 0.79; 95% CI: 0.70, 0.90, The results of this systematic review and meta-analysis indicate a significant inverse association between adherence to the DASH diet and risk of breast cancer. Further large prospective studies and randomized controlled trials are required to confirm our findings. Breast cancer is the most common malignancy among women worldwide, and the annual incidence rates continue to rise . AccordiThe Dietary Approaches to Stop Hypertension (DASH) diet which emphasizes high intakes of fruits, vegetables, whole grains, nuts and legumes, moderate intakes of low-fat dairy products, and low intakes of sodium, sugar-sweetened beverages and red/processed meats, is initially designed to counteract high blood pressure . In contIn the last decade, the relationship between DASH diet and breast cancer has been a concern for researchers. To date, numerous observational studies have attempted to explore the association between adherence to the DASH diet and breast cancer incidence and mortality –17. HoweWe followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting this study .via four databases, including PubMed, Web of Science, CNKI, and Wanfang Data was conducted to identify relevant articles written in the English or Chinese languages published from their dates of inception up to July 2022, with the following terms: {[“breast adenoma”  OR “breast carcinoma”  OR “breast cancer”  OR “breast tumor”  OR “breast neoplasms”  OR “breast neoplasms” (MeSH)] AND [“DASH score”  OR “DASH diet”  OR “DASH”  OR “Dietary Approaches To Stop Hypertension”  OR “Dietary Approaches To Stop Hypertension” (MeSH)]}. Additionally, we also manually searched all references lists of retrieved articles and previously published reviews to identify potentially eligible studies. All of these steps were accomplished by two independent reviewers (LS and Y-QH), and any disagreements with article selection were resolved through discussion with QZ.An electronic literature search Two reviewers (LS and J-YZ) independently screened the titles and abstracts of articles retrieved in the initial search to identify studies that examined the association between DASH diet and breast cancer risk. Any disagreements were settled by discussion or in consultation with the third reviewer. When all agreed, the full-text versions of articles were reviewed against inclusion and exclusion criteria for this systematic review and meta-analysis. To be eligible for inclusion, studies met the following criteria: (1) evaluated the association between DASH diet and breast cancer risk in an observational study; (2) estimated odds ratios (ORs), hazard ratios (HRs), or relative risk (RRs) along with their corresponding 95% confidence interval (CI) ; (3) If the data in retrieved article lacked sufficient detail, the corresponding author of the original study was contacted by email; and (4) breast cancer diagnoses were confirmed by clinical interviews, or self-report on a previous physician-made diagnosis of breast cancer. If the same dataset had been published more than once, we selected the study with the largest number of participants or the best complete findings. Studies were excluded if they met the following criteria: (1) they were non-English or non-Chinese studies; (2) they were reviews, case reports, conference papers, letters, editorials, cellular and molecular studies, and animal studies (3) for studies based on the same cohort, we selected only the study with the most complete data. In total, eleven articles reported the association between DASH diet and breast cancer risk.From the selected studies, we extracted the following information: the first author’s last name, publication date, country, study design, follow-up period, sample size, mean age/age range for cases and participants, the number of breast cancer cases, reported risk estimates (HR/OR/RR) and their corresponding 95% CI, and the factors that were adjusted for in the analysis. In the case of presenting menopausal status-stratified or effect sizes, we treated them as two separate studies. Besides, for a study that reported several risk estimates, the adjusted model was selected. All aforementioned steps were carried out by two reviewers, independently.The Newcastle-Ottawa Scale  was usedQ test and I2 statistic. A P-value of Q-test > 0.10 or I2 < 50% indicated an absence of heterogeneity between studies, and a fixed-effects model was implemented to calculate the pooled RRs. If a P-value of Q-test ≤ 0.10 or I2 ≥ 50% indicated a high degree of heterogeneity among studies, then a random-effects model (DerSimonian and Laird method) was used  were obtained using risk ratios  which were previously extracted for the association between adherence to the DASH diet and risk of breast cancer. Between-study heterogeneity was measured by Cochran’s was used . If therwas used . SensitiThe initial search yielded 587 potential articles, and after removing 52 duplicates, 535 articles were considered for screening. Reviewing titles and abstracts led to the exclusion of 506 studies because they did not report the association between DASH diet and risk of breast cancer, and the full-text versions of the remaining 29 articles were carefully checked for eligibility. Of the remaining 29 articles, 18 articles were excluded based on the following reasons: 3 did not assess breast cancer risk; 1 reported the same participants; 14 did not mention DASH score. Finally, eleven studies with 449,273 participants and 23,254 cases of breast cancer were selected for the final analysis , 23–28. The characteristics of all included studies assessing the association between adherence to DASH diet and breast cancer risk are shown in P < 0.0001). The heterogeneity among the included studies was high , and hence the effect was assessed using the random-effects model.The association between the highest intake compared with the lowest intake categories of DASH diet with breast cancer risk is shown in P = 0.019). However, the between-study heterogeneity was most apparent . In the prospective cohort studies, there was less evidence of heterogeneity , and a marginally significant association between DASH diet and risk of breast cancer . The stratified association between DASH diet and risk of breast cancer according to country based on the random-effects model is provided in P = 0.005). In United States, there was less evidence of heterogeneity , and a small decrease in the risk of breast cancer was shown . When we conducted analyses separately by menopausal status . However, the heterogeneity was most apparent in postmenopausal women . Similarly, we also performed stratified analysis based on comparison in P < 0.00001, I2 = 90.6%), and a significantly decreased risk of breast cancer was shown . In Q5 vs. Q1 comparison studies, there was no evidence of significant heterogeneity between studies , and a marginally significant association between DASH diet and risk of breast cancer was shown .To further explore the reasons for heterogeneity among included studies, we carried out subgroup analyses according to study design, country, menopausal status, and comparison . When wel status , we founP = 0.065).Funnel plots showed little evidence of asymmetry  and therThe quality of each study in terms of population and sampling methods, description of exposure and outcomes, and statistical adjustment of data, was shown in Appendix 1. When all included studies received a score of seven or higher, they would be deemed to be of relatively higher quality , 28, 29.Sensitivity analyses were performed by excluding each study individually to investigate the influence on overall estimates. Based on the results of sensitivity analysis , no signTo the best of our knowledge, this is the first systematic review and meta-analysis summarizing the published evidence regarding the effect of adherence to the DASH diet on breast cancer. Data from eleven studies involving 23,254 breast cancer cases and 449,273 participants, were included in the present meta-analysis. Our results indicated that high adherence to the DASH diet was associated with a 21% reduction in the risk of breast cancer. Sensitivity analysis revealed that the summary effect of DASH diet on breast cancer was not substantially modified by excluding a certain study. Collectively, our findings augment the evidence for an inverse association between DASH diet and breast cancer risk, and support the adoption of adherence to the DASH diet for the primary prevention of breast cancer.a priori and a posteriori approaches. The a priori methods, namely dietary indices, were hypothesis-driven and were used to quantified dietary quality according to dietary guidelines or certain types of diets (a priori dietary pattern, recommends higher intake of fruits, vegetables whole grains, poultry, fish, and nuts and restricts saturated fat, red meat, sweets beverages, and refined grains (Among women, breast cancer accounts for 1 in 4 cancer cases and for 1 in 6 cancer deaths, ranking first for incidence in many countries . With anof diets . The DASd grains . In addid grains , 12, 39.d grains  reportedd grains . Howeverd grains , 43. Besd grains , is in ad grains , 46. In d grains . Second,d grains . Althougd grains . Besidesd grains , an impod grains . Furtherd grains . Third, d grains  reportedd grains  have repd grains . Besidesd grains  has alsod grains . Also, pd grains . Finallyd grains . In brieThis systematic review and meta-analysis holds its own strengths and limitations. First, this is the first systematic review and meta-analysis so far assessing the relationship between adherence to the DASH diet and breast cancer risk. Our findings underline the importance of supporting the population in adhering to DASH diet for prevention of breast cancer. Second, the cases of breast cancer have been diagnosed through view of cancer registry or medical records or pathological records, avoiding misdiagnosis. Third, no signs of publication bias were evident in the funnel plot, and the statistical test for publication bias was non-significant. Fourth, the quality assessment showed that most studies included in this meta-analysis were of high quality. Lastly, the majority of the selected studies had adjusted for some potential confounders, which can reduce the effects of confounding factors. Despite these strengths, a number of limitations should be taken into account when interpreting our findings. First, 3 out of 11 studies included in this systematic review used the case-control design, which is more susceptible to recall and selection bias, than cohort design. In addition, owing to the observational nature of included studies, the possibility of residual bias from unmeasured, imprecisely measured, or unknown confounders remains. Hence, further prospective cohort studies or randomized controlled trials are needed to confirm the exact association between DASH diet and breast cancer. Second, the participants’ dietary intakes were self-reported through FFQs, which carried an inherent recall bias. At the same time, the levels of the highest and the lowest categories of DASH diet scores were inconsistent in the included studies, which might have attenuated the true association between adherence to the DASH diet and breast cancer risk. Third, only single time-point measurements of dietary patterns were provided in included studies, and these do not explain the changes in diet over time. Meanwhile, there was also an inconsistent adjustment for potential confounders in the included studies. As a result, the data included in our analyses may suffer from differing degrees of completeness and accuracy. Fourth, there was strong evidence for heterogeneity of results across the studies in our analyses. Subgroup analyses revealed that study design, country, menopausal status and comparison were the potential source of heterogeneity. Besides, it should be kept in mind that although the DASH diet was defined based on food groups in all included studies, the macro-nutrient composition of DASH diet was different between them, and this might explain the high heterogeneity found between included studies. Fifth, although DASH diet was associated with decreased risk of breast cancer, the results should be interpreted with caution. Because we could not determine and explain the source of between-study heterogeneity sufficiently. Finally, this study had a geographical restriction, as the majority of included studies came from the United States, where the dietary intakes were markedly different from the Asian countries. This leaded to a reduction in the heterogeneity of this meta-analysis and hence, further large prospective studies and randomized controlled trials are needed to confirm our findings in different regions and populations.In conclusion, the current study revealed a significant inverse association between adherence to the DASH diet and the risk of breast cancer. Our findings add to the current evidence that healthy dietary pattern, like the DASH diet, could offer a practical strategy in the prevention of breast cancer. Further studies, particularly large prospective studies, are required to validate our findings in different geographic regions.The original contributions presented in this study are included in the article/J-YZ designed the research. LS performed the systematic literature search, identified the studies meeting the inclusion criteria, extracted data from the included studies, and wrote the manuscript. Y-QH assessed the risk of bias of the included studies. QZ performed the statistical analysis. J-YZ and P-FZ assisted in the interpretation of the results and the revision of the manuscript. All authors had primary responsibilities for the final content and read and approved the final manuscript.


Breast cancer has become one of the most common cancers affecting women worldwide, and researchers have struggled to explore new avenues for managing it for decades. One of the ways was to analyze the diet and its importance concerning this disease. This review aims to study the effect dietary fat has on the risk of breast cancer incidence as well as its influence on the survival of breast cancer patients. The main population under consideration for this review is women older than the age of 18.A thorough and detailed search was conducted until July 21, 2022, using four databases: PubMed, ScienceDirect, Google Scholar, and The Cochrane Library. After screening, 22 articles were selected for inclusion in this review. Of the 22 articles, 12 were from PubMed, two from ScienceDirect, one from The Cochrane Library, and seven from Google Scholar. The risk of bias was assessed, and the required information was extracted from the articles.A systematic review of all the included articles found a significant correlation between dietary fat and an increased risk of breast cancer development and worsening the prognosis for patients already diagnosed with breast cancer.Although many overlapping factors may be responsible for this development, studies show a trend that suggests that this particular factor can be a contributor. Further studies need to be conducted to highlight the role of fat in the diet and the use of dietary modification to curb breast cancer rates. In 2020, according to statistics by GLOBOCAN , there were over two million cases of breast cancer diagnosed worldwide, which comprised 25% of all cancers among women . More reMultiple modifiable risk factors for breast cancer have been recognized, such as exposure to radiation, alcohol consumption, obesity, hormonal causes, and insufficient physical activity . Among tEvolving evidence suggests that diet, one of the most important components of a healthy lifestyle, plays a crucial part in its development . As anotIn many previously conducted studies regarding causative factors for diet-induced breast cancer, both nutrition, dietary patterns, and individual foods have been considered. For example, elevated levels of consumption of processed meats, alcohol, and animal fats, and decreased levels of dietary fiber, fruits, and vegetables may be associated with a greater risk of developing breast cancer .Among important nutrient groups, fat has garnered increasing attention for having some association with breast cancer . BiochemThis systematic review will pursue the correlation between dietary fat and breast cancer, highlighting the possible causation and effect that a diet that is rich in fat has on the incidence of breast cancer and potential implications for mortality among breast cancer patients.MethodsA systematic literature search was conducted under the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines .A free full-text article search was instituted utilizing databases such as PubMed, Google Scholar, ScienceDirect, and the Cochrane Library between the dates of June 5, 2022, and July 21, 2022. The keywords "dietary fat," "breast cancer," and "mortality" were used in addition to Medical Subject Headings (MeSH) terms, either alone or in combination.Inclusion and Exclusion CriteriaRelevant articles were selected based on keywords and MeSH search terms. Only free full-text articles in English that were published within the last 20 years and that included women beyond the age of 18 have been selected. Articles were excluded from non-English publications and studies involving males and animals.PubMed Search StrategyThe detailed MeSH search strategy in PubMed is given in Table Combined search results after screening by title and abstract on PubMed: 12 results.Date of the last search: July 21, 2022.Search Strategies in Other DatabasesThe databases of Google Scholar, ScienceDirect, and The Cochrane Library were searched using the keywords "dietary fat," "breast cancer," and "mortality." The results are shown in Table Date of the last search: July 21, 2022.ResultsA total of 1282 articles were found within the eligibility criteria by utilizing keywords and MeSH terms. One duplicate was found in the PubMed database, and 1281 articles were then screened for relevance.Of the 1281 articles, 584 were from PubMed, 369 were from Google Scholar, 11 were from the Cochrane Library, and 317 were from ScienceDirect. The screening was then conducted by title and abstract, as well as relevance to the review. This involved screening specifically for articles that show a correlation between dietary fat and breast cancer. The final selection consisted of 22 articles, which were included in this review.The PRISMA flowchart of the literature and search strategy is shown in Figure Study CharacteristicsThe Scale for the Assessment of Narrative Review Articles (SANRA)  was usedThe Assessment of Multiple Systematic Reviews (AMSTAR)  checklisThe characteristics and appraisal of the clinical trials selected for discussion in this review are shown in Table The Cochrane risk-of-bias assessment tool was used to assess the quality of the clinical trials, as shown in Table Table The Newcastle-Ottawa Scale was used to assess the quality of observational studies. The minimum acceptable score was six out of a possible eight to be included in this review. The results are shown in Table DiscussionTo understand the association between dietary fat and breast cancer (BC), let us first look at the pathophysiology of fat intake in our diet and the causation of breast cancer.Multiple hypothesized pathways are associated with fat consumption and cancer onset. One such pathway is the mechanism by which they are both linked: oxidative stress and the production of reactive oxygen species (ROS). ROS are free radicals that are highly reactive and interact with the DNA within our body’s cells. ROS can cause DNA damage and changes in gene expression, potentially leading to cancer-causing genes such as oncogenes.There could then be a change in cell signaling pathways, causing a cascade effect and prompting carcinogenesis  by changFat consumption may also have an indirect connection with breast cancer through another major disease epidemic in the world, obesity. Obesity refers to a condition where individuals have a high amount of adipose tissue. Numerous studies have shown a positive correlation between adiposity and a high-fat diet (relative risk (RR) = 0.57, P-factor (p) = 0.0002) .In a controlled clinical trial, 100 women were split into two equal groups (one being a low-fat diet group and the other a control diet group) and changes in BMI  and waist circumference  were noted. This adds further evidence to the linkage between high-fat diets and obesity. Adipose tissue, through androgen aromatization, becomes a source of estrogen production. The same study also found that the low-fat diet group had a reduced estradiol (an endogenous estrogen) concentration  . Higher There is strong reason to believe that an unhealthy diet rich in fat might lead to obesity, and that has a myriad of implications for breast cancer, including worsening risk and affecting the quality of life and survival ,28. In tThe impact of obesity is so significant that it has been shown to increase the risk of breast cancer-specific mortality by 18%, 14%, and 29% for every 5 kg/m2 BMI increase before, less than 12 months after, and more than 12 months after the diagnosis, respectively [A study in Malaysia  involvinBlücher  explaineIn patients with cachexia, the body is in a state of catabolism, and the body fat quantity is reduced through lipase enzymes (adipose-triglyceride lipase and hormone-sensitive lipase) that break down the triglycerides into FFA. The rising levels of FFA act as a foundation for cancer growth and tumorigenesis  . FurtherFigure As shown by a model created by Nieman and his colleagues , cancer Fat QualityNow that we have explained the possible mechanisms by which dietary fat and breast cancer could be linked, let us delve into the finer aspects of this subject. It is important to remember that the harmful effects of dietary fat are not exclusive to all types of fat. It is critical to consider the quality, subtype, and quantity of fat when discussing potential interactions and potentially pathogenic mechanisms ,10. Let By chemical structure, fats can generally be classified into saturated fats (SF), unsaturated fats (USF), and trans fats. USF is divided into monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids. PUFA are omega-3 fatty acids, which include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-6 fatty acids, which include linoleic acid (LA), arachidonic acid (ARA), gamma linoleic acid (GLA), and conjugated linoleic acid (CLA) . The orgThese various subtypes can have protective or harmful effects depending on which ones we consider and identify as part of our regular diet , 14.Many studies have been conducted that show a positive and negative influence of fatty acids on cancer, whether it is harmful or protective. Elevated SFA, MUFA, and trans fats have been linked to an increased risk of cancer, whereas PUFA (such as omega-3 PUFA) have been shown to protect against it ,10.Comparing two diets that show varying levels of type and quantity of fat can help us resolve this matter. Western diets are known for having higher levels of saturated fat and trans fats than Mediterranean diets . MediterAnother case-control study, which had 10,000 cases of cancer and 17,000 controls, found a higher adherence to this diet decreased the risk of all types of cancer (an odds ratio (OR) of 0.76 for a two-point increment in their Mediterranean Diet Score) . It alsoMany studies have shown that western diets, which have a lower omega-3 to omega-6 ratio, have a higher risk of several cancers . They shMany of these correlations between a western diet and breast cancer risk can also be partly due to red meat consumption. A pooled meta-analysis of case-control and cohort studies found that the RR of breast cancer for red meat consumption was 1.17 (95% CI = 1.06-1.29) .Polyunsaturated FatsWhile describing in detail the effects of PUFA, the dichotomy between the roles of omega-3 and omega-6 PUFA has to be highlighted. Omega-3 PUFA is said to be breast cancer (BC) protective and can reduce the risk by 5% for every 0.1 gram/day incremental increase in consumption of marine sources where they are found .There are many theories regarding the mechanism of its protective effects. Due to the high peroxidizing capabilities of omega-3 PUFA, they are said to enhance chemosensitization. They rapidly integrate into cancer cell membranes (particularly those deficient in PUFA) and alter membrane integrity. They can even cause the generation of ROS and inhibition of anti-oxidation safeguards by cancer cells .Subtypes of fats, such as EPA and DHA, are metabolized into resolvins and protectins and confer anti-inflammatory and immunoregulatory properties. In women with early-stage BC, these compounds could also protect healthy cells from chemotherapeutic agents . A phaseOmega-3 PUFA could also bind to receptors within the nucleus of tumor cells, causing target gene modulation involving metabolism and cell death . For exaIn a cohort of women with early-stage BC, high eicosapentaenoic acid and docosahexaenoic acid intakes (>73 mg/day) from foods (marine sources) for 7.3 years reduced BC events by ∼25% and modulated BC risk biomarkers-both in premenopausal  and postmenopausal  women-suggesting their potential contribution toward BC prevention . SimilarA phase III trial involving 65 BC patients with metastasis and focusing on the role of omega-3 PUFA and chemotherapeutic uses supported the discovery that DHA improves chemosensitivity. Future research into the chemoprotective effects of omega-3 PUFA and their therapeutic value in BC  may yielOn the other side of the spectrum, omega-6 PUFA is said to have pro-inflammatory and pro-tumorigenic inclinations. Higher omega-6 PUFA consumption (seen in western diets) has been associated with an increased risk of multiple different cancers . In partA recent meta-analysis of 19 prospective cohort studies including 1,013,273 participants and 195,515 deaths showed that a 5% increase in energy from PUFA was associated with a 4%  reduction in mortality from cancer [Monounsaturated FatsOleate, an omega-9 MUFA, has shown an increased expression of angiopoietin-like factor-4 (ANGPTL4) in different types of cancer cells, including BC cells. ANGPTL4 has been known to stimulate BC invasion into the lung .The effect of MUFAs has also been varied when discussing the nature of BC in a particular patient. For example, Li et al. (2014)  showed tAlso, regarding MUFAs, there have been mixed results depending on their source in the diet. MUFAs derived from extra-virgin olive oil have been negatively correlated with BC risk. This finding is most likely due to the oxidative stability of MUFA, as well as the reduction of insulin resistance and the polyphenols (hydroxytyrosol and oleuropein aglycone) found in olive oil. These polyphenols showed reduced survivability in BC cells . A populInterestingly, MUFAs that were derived from trans-fatty acids such as margarine were positively correlated with BC risk .Saturated FatsSaturated fat has been considered one of the highest-risk fats for BC incidence and has a plethora of evidence to support it. A recent report by the World Cancer Research Fund/American Institute for Cancer Research has brought forth consistent findings suggesting this idea .Table As supported by many of the studies given in the table, in addition to many others, there is strong reason to believe in the harmful correlation between saturated fat and BC incidence and mortality. But surprising evidence has been found that challenges this theory. In fact, palmitate, the most ubiquitous fatty acid in human circulation, actually inhibited tumor growth in certain in vitro studies .This may also vary depending upon the age demographics and ethnicity of the population. Xia et al.  noted a Trans FatsTrans fats were also found to be incredibly harmful to BC patients, significantly affecting those consuming high levels of them.The Nurses' Health Study II (NHSII)  showed aOne meta-analysis  also shoOverall Fat IntakeLet us analyze the Women's Health Initiative Dietary Modification Trial for information regarding the effect of total dietary fat intake without any discrimination based on its subtypes. It was a randomized, controlled clinical trial  . Deaths specifically attributed to BC had also been reduced  Although this population mainly concerned postmenopausal women, it did show the necessity for a low-fat dietary pattern to improve the survivability of breast cancer.LimitationsAs explained, some of the limitations of this study arise due to the dynamic nature of the subtypes of fat and their effects on BC, making it challenging to analyze due to the contrasting effects of the different types of dietary fat. Additionally, data from the selected articles for review assumes that the dietary fat intake of their participants is uniform as a group and does not account for inaccurate reporting or food waste. This study also mentioned the linkage of dietary fat to obesity, which has increased BC risk and mortality rates and may indicate a confounding effect.Another possible method by which the data can be skewed is that people consuming higher levels of dietary fat may also have a lower likelihood of keeping up with a healthier lifestyle and initiating any form of dietary control. Many diverse factors can also contribute to worsening the risk and prognosis for BC, whether it be physical exercise, other unhealthy habits , or lack of body fat control.Based upon all the evidence provided in this discussion, entailing all the hypotheses and collected data from studies, strongly supports the notion that fat impacts breast cancer negatively by increasing the risk of its incidence and reducing survival in those already diagnosed. However, as we have seen, the question is more complex due to the diverse nature of fats and how they interact with cancer cells. Some have been shown to be protective, whereas others have been shown to be harmful.However, more studies are needed for an in-depth analysis of the role of nutrition in breast cancer and how it can be modulated to improve the prognosis of many cancer patients and avoid the development of cancer itself. As a result, it is possible that dietary control could be a critical intervention point for reducing worldwide incidences of breast cancer and mortality as a result.