The influence of statin therapy on the recurrence of early-stage estrogen receptor-positive breast cancer: A meta-analysis

The influence of statin therapy on the recurrence of early-stage estrogen receptor-positive breast cancer: A meta-analysis | 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 The influence of statin therapy on the recurrence of early-stage estrogen receptor-positive breast cancer: A meta-analysis Xiaowen Ma, Jia Gao, Yiming Sun, Feng Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5084342/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Statins have been recognized for their significant role in mitigating drug resistance to endocrine therapy in breast cancer. A substantial body of research has indicated that statin usage is associated with a marked improvement in both overall survival rates and breast cancer-specific survival (BCSS) among patients. The objective of this research is to determine whether the use of statins influences the local recurrence in early-stage estrogen receptor-positive (ER+) breast cancer patients. This investigation could provide crucial insights into the potential of statins as an adjunct therapy to reduce the risk of recurrence in this patient population. Materials and Methods : Our review encompassed three studies comparing the recurrence rates in stage I-III ER+ breast cancer patients who did and did not use statins. The endpoint focused on recurrence, with the inclusion criterion being studies that reported fully adjusted hazard ratios (HRs). Summary odds ratios (ORs) were derived using random-effects models. Publication bias and heterogeneity were evaluated through sensitivity analyses, Q statistic tests, and I² tests. Results : Three population-based studies, comprising a total of 102,525 patients with ER+ breast cancer, were included in our analysis: 24,598 of whom were on statin therapy, and 77,349 were not. The pooled OR revealed a notably significant 52% reduction in the risk of recurrence for patients who used statins compared to those who did not (Summary OR = 0.48; 95% CI: 0.27–0.86). Our analysis of three population-based studies, which included a total of 102,525 ER+ breast cancer patients 24,598 on statin therapy and 77,349 not on statins demonstrates a significant 52% reduction in recurrence risk for those treated with statins. However, it is crucial to acknowledge the substantial heterogeneity present among the studies, as indicated by an I² of 96% and a highly significant chi-square test (P < 0.00001). In the Leave-One-Out Sensitivity Analysis, the meta-analysis results proved to be relatively stable with the exclusion of studies Sim Y 2022 and Borgquist S 2017. Nevertheless, the study by Ahern TP 2011 exerted a more significant influence on the overall effect size, suggesting a potential contribution to the observed heterogeneity. Regarding publication bias, Egger’s test yielded a P-value of 0.1964, indicating no evidence of small-study effects or publication bias in this meta-analysis. Conclusion : The pooled OR for statin use compared to non-use is 0.48 with a 95% CI of [0.27, 0.86]. Despite the considerable variation in ORs and high heterogeneity, the conclusions drawn from the three studies are relatively consistent, indicating that the use of statins indeed reduces the recurrence rate in early-stage ER+ breast cancer patients. Cancer Biology breast cancer statins recurrence hormone receptor-positive Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Statins, a prevalent class of lipid-lowering medications, have emerged in recent years as potential anti-tumor agents, particularly within the realm of breast cancer therapy. And statins have an important positive effect on reducing drug resistance to endocrine therapy in breast cancer. [ 1 ] In recent years, several studies have reported the association between statin use and the survival rate of patients with breast cancer. Especially for triple-negative breast cancer, a more aggressive subtype, the use of statins has significantly improved the overall survival and breast cancer-specific survival rates of patients. Statin use post-diagnosis was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75–0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57–0.88). [ 2 ] The purpose of this study is to determine whether statin lipid-lowering drugs can reduce the recurrence rate in patients with ER + breast cancer. Methods Literature search This review adhered meticulously to the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) guidelines, aiming to systematically compare the recurrence rates in hormone receptor-positive breast cancer patients between those treated with statins and those untreated. A comprehensive literature search was meticulously conducted by two independent reviewers, XiaoWen Ma and Jia Gao, employing established search strategies across various databases, including PubMed, Medline, Cochrane, and Web of Science. The search criteria were inclusive, spanning from January 1, 2004, to January 1, 2024. The search employed the following medical subject headings (MeSH): ("statin"[All Fields]) AND ("breast neoplasms"[MeSH Terms]) AND ((clinicalconference[Filter] OR clinicalstudy[Filter] OR clinicaltrial[Filter] OR comparativestudy[Filter] OR controlledclinicaltrial[Filter] OR multicenterstudy[Filter] OR observationalstudy[Filter] OR randomizedcontrolledtrial[Filter]) AND (fft[Filter])). All identified citations were independently assessed by the two authors and categorized as relevant or irrelevant. Studies deemed relevant were then selected for full-text review, and their reference lists were meticulously searched for additional significant citations. Ecological studies, case reports, reviews, and editorials were deemed ineligible for inclusion. Eligibility criteria: Inclusion Criteria: 1. Studies published comprehensive adjusted risk estimates (at least accounting for age, tumor size, and lymph node status) comparing statin use versus no statin use in patients with ER + breast cancer, without any prior history of cancer or metastatic disease. 2. They were independent studies that did not duplicate results already published in another article. 3. The studies reported HRs for recurrence rate, along with their corresponding 95% CIs. In this article, "recurrence" refers to local recurrence, regional recurrence, distant recurrence, and contralateral recurrence. The selected recurrence data pertain exclusively to patients who were prescribed statins following a breast cancer diagnosis, encompassing both those who continued statin use after diagnosis and those who initiated statin therapy subsequent to the diagnosis of breast cancer. Exclusion Criteria: 1. Studies lacking a comparative group between statin users and non-users. 2. Studies without comprehensive adjusted risk estimates for the specified factors. 3. Studies that did not report HRs with corresponding 95% CIs for recurrence rates. Data Extraction: Two reviewers, XiaoWen Ma and Jia Gao, independently and precisely extracted data, ensuring consensus on all outcomes. A standardized data-collection protocol was meticulously applied to compile pertinent data from each article selected for inclusion. For each eligible study, the following details were meticulously documented: 1. Lead author's name. 2. Publication year. 3. Comprehensive set of study characteristics, including research objective, patient recruitment timeframe, geographical context, eligibility criteria, median follow-up period, breast cancer stage, types of statistical adjustments made, median age of the patient cohort, and recurrence rate. Additionally, detailed information for each arm of the treatment groups was recorded, including: 1. Total number of patients in the statin use and no statin use cohorts. 2. Distribution of patients across various tumor stages (T1, T2, T3 and Tx), nodal stages (N0, N1, N2 or more). 3. Duration and type of statin use. This rigorous approach to data extraction and documentation ensured the integrity and reliability of the information used in our systematic review and meta-analysis. Data analysis and statistical methods: Each HR, meticulously adjusted for a comprehensive set of confounding variables, along with its corresponding confidence interval, was extracted and converted into an OR. The summary OR was calculated by pooling the study-specific estimates using random-effects models. The I² statistic was used to measure the extent of heterogeneity, representing the proportion of total variation across studies attributable to heterogeneity, with higher I² values indicating greater heterogeneity. Conventionally, an I² threshold below 50% is considered to represent an acceptable level of variability. Forest plots were generated, including both the study-specific estimates and the summary OR. Heterogeneity and sensitivity analyses were carefully evaluated, considering all possible factors that could influence the estimates, including adjustments for confounding factors, types of endpoints, and study design characteristics. Publication bias was assessed graphically using Egger's test. All statistical analyses were meticulously conducted using Stata software version 17 and the Cochrane Review Manager (RevMan) version 5.4. Findings Results of the Search Strategy: A total of 366 articles were identified through the specified MeSH terms. Following an initial screening, 109 records were excluded based on the abstract, resulting in 257 articles selected for full-text review. We retrieved and meticulously examined all 6 eligible studies. Ultimately, 3 articles were excluded from the analysis: 2 for employing an alternative endpoint definition, and 1 for using endocrine therapy as a proxy for the inclusion criterion of hormone receptor positivity. Description of studies The meta-analysis provides a comprehensive description of the included studies, as detailed in Table 1. This table presents a thorough summary, including the total number of cases, publication years, geographical regions, and diagnostic periods, along with study designs, considerations for age and tumor stage, and follow-up durations. The analysis included a total of 102,525 patients with ER+ breast cancer from 3 population-based studies: 24,598 were on statin therapy, and 77,349 were not. The timeframe for diagnosis and treatment across these studies ranged from 1996 to 2015, offering a substantial dataset for analysis. Of these three studies, one was prospective, while the other two were retrospective in nature. First author Public year Country and diagnostic time Study type cases controls BC stage Median follow-up(months/years) Outcomes measured Ahern TP [ 3 ] 2011 Denmark 1996-2003 prospective cohort NA I-III 6.8y HR Sim Y [ 4 ] 2022 Singapore 2005-2015 retrospective cohort NA I-III 8.67y HR Borgquist S [ 5 ] 2017 Sweden 1998-2003 retrospective cohort Early postmenopausal ER+ I-III 8y HR Table 1 Characteristics of ER+ Patients Across the Three Studies Table 2 delineates the distribution of T and N stages among patient groups in the studies. The participants, all diagnosed with stages I-III breast cancer, underwent surgical treatment followed by standard postoperative endocrine therapy. Enrollment in the three studies was not subject to age limitations. Nevertheless, comprehensive TNM staging information was constrained, with detailed T and N stage data available for only one of the studies, as illustrated in Table 2. study group Mean age Total case T N 1 2 3 X 0 1 2 or more Ahern TP2011 [ 3 ] Statins use NA 20255 NA NA NA NA NA NA NA No use NA 67888 NA NA NA NA NA NA NA Sim Y2022 [ 4 ] Statins use NA 3706 NA NA NA NA NA NA NA No use NA 27135 NA NA NA NA NA NA NA Borgquist S [ 5 ] Statins use NA 637 165 385 138 9 413 208 76 No use NA 7326 1092 2880 1146 129 3095 1500 652 Table 2 T and N stages and adjuvant therapies of the BCT group patients and mastectomy group patients Figure 3 presents a comparative analysis of the total patient count, recurrence incidence, recurrence rates, HRs, and P-values between early-stage ER+ breast cancer patients who were on statin therapy and those who were not, across the three studies. In each of these studies, the adjusted HRs are accompanied by confidence intervals that exclude the value of 1, with HRs less than 1. This suggests a consistent trend indicating that the recurrence rate among ER+ breast cancer patients who utilized statins is significantly lower compared to those who did not, highlighting the potential benefits of statin use in this patient population. First author Statins use No use Adjusted HR/OR and CI P Total case(n) Recurrence case Recurrence rate (%) Total case(n) Recurrence case Recurrence rate (%) Ahern TP [ 3 ] 20255 198 0.98 67888 2174 3.20 0.69 (0.55 to 0.88) NA Sim Y [ 4 ] 3706 59 1.60 27135 773 2.85 0.57 (0.43 – 0.76) <0.001 Borgquist S [ 5 ] 637 124 19.47 7326 1881 25.68 0.84(0.68-0.99) 0.04 Table 3 The observed values and statistical results of each study Table 4 presents the Newcastle-Ottawa Scale (NOS) scores for the three studies, each earning a score of 8 points, which is indicative of their high methodological quality. Study selection comparability outcome Representativeness of the exposed cohort Selection of the nonexposed cohort Ascertainment of exposure Demonstration that outcome of interest was not present at start of study Comparability of cohorts on the basis of the design or analysis Assessment of outcome Was follow-up long enough for outcomes to occur Adequacy of follow-up of cohorts Quality score Ahern TP [ 3 ] ★ ★ ★ ★★ ★ ★ ★ 8 Sim Y [ 4 ] ★ ★ ★ ★★ ★ ★ ★ 8 Sakellakis M [ 5 ] ★ ★ ★ ★★ ★ ★ ★ 8 Table 4 Newcastle‒Ottawa Scale (NOS) Meta-analysis Findings: Impact of Statin Use on Recurrence Risk in ER+ Breast Cancer: Our meta-analysis, synthesizing data from three studies as depicted in Figure 2, compiled a total of three risk estimates. The aggregated OR reveals a notably significant 52% reduction in recurrence risk for patients on statin therapy compared to those not on statins (Summary OR = 0.48; 95% CI: 0.27–0.86), as illustrated in Figure 1. This finding suggests that ER+ breast cancer patients who receive statins exhibit a substantial decrease in recurrence rates. However, it is crucial to acknowledge the substantial heterogeneity observed among the studies, with an I² statistic of 96% and a chi-square test P-value significantly less than 0.00001. This high degree of heterogeneity suggests considerable variability in the study outcomes, which could potentially influence the overall interpretation of the results. Figure 2 The forest plot compares the effects of statin use versus no use on the risk of recurrence in estrogen receptor-positive breast cancer. Sensitivity Analysis Overview: The meta-analysis utilized a random-effects model with the Restricted Maximum Likelihood (REML) method to assess heterogeneity, yielding the following key metrics: Tau² (τ²) = 0.1590 represents the estimated variance in the true effect sizes across the studies, signifying the presence of heterogeneity, as a non-zero value indicates variability among the study outcomes. I² = 94.84%: This statistic measures the proportion of total variation across the studies that is attributable to heterogeneity rather than chance, with 94.84% indicating a very high degree of heterogeneity. H² = 19.37: Serving as another indicator of heterogeneity, a value exceeding 1 suggests significant variability among the studies. Z = -3.10, P= 0.0020: The z-score and corresponding p-value confirm that the aggregated effect size is statistically significant at the p < 0.05 level. Test of Homogeneity: Q = 50.05, P= 0.0000: The Q statistic, which tests the null hypothesis of a common effect size across all studies, returns a very low p-value (< 0.0001), denoting substantial heterogeneity among the studies. These results underscore the importance of considering heterogeneity when interpreting the meta-analysis outcomes and highlight the need for further investigation into the sources of this variability. The leave-one-out sensitivity analysis indicates that: The overall meta-analysis result is relatively robust to the exclusion of the studies Sim Y [ 4 ] and Borgquist S [ 6 ] . However, the study Ahern TP [ 3 ] has a more substantial impact on the overall effect size, indicating it may contribute more to the observed heterogeneity. This study should be further examined to understand its influence and why it has a more pronounced effect on the pooled result. Egger’s test for publication bias: The Egger's regression test is used to detect potential publication bias or small-study effects in a meta-analysis. The null hypothesis (H0) is that there is no small-study effect, meaning the intercept (beta1) equals zero. Beta1 = 9.76: This is the estimated intercept from the Egger's test regression model. A significant deviation from zero could suggest the presence of small-study effects or publication bias. SE of Beta1 = 7.557: The standard error of the estimated intercept. Z = 1.29: This is the test statistic for Egger's test. P-value = 0.1964: The P-value indicates the probability that the observed value of the test statistic would occur if the null hypothesis were true. The P-value is greater than the conventional significance level of 0.05. Therefore, we fail to reject the null hypothesis. This suggests that there is no evidence of small-study effects or publication bias in this meta-analysis based on Egger's test. Conclusion A study [ 6 ] published in the journal Cancer pointed out that the overall survival rate of breast cancer patients taking statins could be relatively increased by 30%, while the BCSS rate could be relatively increased by 58%. This finding provides new insights into the treatment of breast cancer. There may be differences in the effects of different statins on improving the prognosis of patients with breast cancer. Hydrophobic statins (such as simvastatin, atorvastatin, etc.) have a statistically significant relationship with the improvement of patients' overall survival. And research on the recurrence rate of breast cancer, statin users displayed longer mean relapse-free survival (16.6 vs 10.2 years, P=0.028). After data had been adjusted for patient and disease characteristics, statin users maintained a lower risk of recurrence. [ 4 , 7 , 8 ] In this meta-analysis the combined OR for statin use versus no use is 0.48 with a 95% CI of [0.27, 0.86]. This result indicates that statin use is associated with a statistically significant reduction in the recurrence risk (OR < 1) compared to no use, with a P-value of 0.01, suggesting that the overall effect is statistically significant. Heterogeneity Statistics: Chi² (Q) = 50.13, P < 0.00001, I²=96% ,The Chi-squared test for heterogeneity shows a highly significant P-value, confirming the presence of significant heterogeneity among the included studies. This statistic quantifies the proportion of total variation in study estimates due to heterogeneity rather than chance. And there is considerable variation in effect sizes across the three studies. Ahern TP [ 3 ] shows a much stronger effect than Borgquist S [ 5 ] and Sim Y [ 4 ] which could suggest differences in study populations, methods, or definitions of outcomes. 1 Discuss the sources of heterogeneity: 1.1 Study-Specific Odds Ratios and Confidence Intervals: Ahern TP [3] : OR = 0.30 [0.26, 0.35], with a weight of 34.1%. This study shows a strong association between statin use and risk reduction, contributing significantly to the overall pooled effect. However, it also has the smallest confidence interval, indicating high precision, likely due to its large sample size. Borgquist S [ 5 ] : OR = 0.70 [0.57, 0.88], with a weight of 33.4%. This study shows a moderate effect size that is smaller than Ahern TP [3] but still statistically significant. Its result is less extreme than Ahern TP [3] and has a wider confidence interval. Sim Y 2022: OR = 0.55 [0.42, 0.72], with a weight of 32.5%. This study also shows a moderate effect size, with its confidence interval overlapping with that of Borgquist S [ 5 ] but not Ahern TP [3] . Despite the considerable variation in ORs, the conclusions drawn from the three studies are relatively consistent, indicating that the use of statins indeed reduces the recurrence rate in early-stage ER+ breast cancer patients. 1.2 Possible Sources of Heterogeneity: 1.2.1 The differences in the study populations are as follows: Sim Y [4] focuses on breast cancer patients from the SingHealth Public Health Cluster in Singapore (2005-2015), including ductal carcinoma in situ (DCIS) and stages I to III invasive cancer. Ahern TP [3] involves all female residents in Denmark diagnosed with stages I-III invasive breast cancer (1996-2003). Borgquist S [ 5 ] includes postmenopausal women with stages I-III invasive breast cancer from the BIG 1-98 trial (1988-2003). Since the recurrence risk for DCIS is lower than that for invasive breast cancer, this may result in a lower recurrence risk in the Sim Y [4] study compared to the other two studies. Additionally, Borgquist S [ 5 ] study population consists of postmenopausal early-stage breast cancer patients, which may lead to a lower recurrence risk compared to the other two studies that include patients of all ages. Sim Y [4] excluded patients who used statins before surgery, while the other two studies included breast cancer patients who used lipid-lowering drugs before diagnosis and after diagnosis. Patients using lipid-lowering drugs may be older than those who have not used such drugs, which could lead to a younger study population in Sim Y [4] with a higher baseline recurrence risk. Sample Size Differences: Ahern TP [3] has a much larger total sample size compared to the other two studies, which could lead to its greater weight and influence on the pooled effect size. The larger sample size may provide more precise estimates, but it can also introduce variability if the study population is significantly different from the others. And the age baseline of the populations included in the three studies is inconsistent, but due to insufficient detailed data, statistical analysis is not possible, and only descriptive analysis can be conducted: In Ahern TP [3] , the age distribution of the statin use group is 50–59 years old (33.7%) and 60–69 years old (40.9%), while for the nonuser group, it is 50–59 years old (33.2%) and 60–69 years old (27.4%). In Borgquist S [ 5 ] , the statin user group represents 6% of those under 65 years old and 11% of those 65 and older. In Sim Y [4] , the statin user group is predominantly aged 50-59 (35.0%) and 60-69 (35.8%), while the nonusers group is mainly 40-49 years old (33.9%) and 50-59 years old (33.2%). 1.2.2 Differences in Research Methods Ahern TP [3] utilizes a nationwide population-based prospective cohort study, registered through the Danish Breast Cancer Cooperative Group (DBCG), employing the Cox proportional hazards model to estimate the association between statin use and breast cancer recurrence. Borgquist S [ 5 ] conducts a retrospective study, employing marginal structural Cox proportional hazards models to address potential biases due to cholesterol levels, specified endocrine treatments, patient-specific risk factors, practice variations, and enrollment locations, comparing patient use of CLM and breast cancer outcomes under different treatment allocations. Sim Y [4] is a retrospective study focusing on patients who used statins post-diagnosis, adjusting for variables such as cardiac events and diabetes through statistical models to eliminate the impact of confounding factors on the results. The three studies include populations of different ethnicities, and the confounding factors excluded to interfere with the trials are not consistent, which may contribute to heterogeneity among the studies. Ahern TP [3] , being a prospective cohort study, can better establish causal relationships compared to the other two retrospective cohort studies, reducing selection and recall biases and providing better control over the data collection process, thus making the results more persuasive. 1.3 Specific Differences in Outcome Evaluation Ahern TP [3] conducted subgroup analyses that established a correlation between the use of lipophilic statins, such as simvastatin, and a reduced risk of breast cancer recurrence, while hydrophilic statins showed no significant association. Borgquist S [ 5 ] observed significant improvements in disease-free survival (DFS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI) for patients using lipid-lowering drugs at the initiation of endocrine therapy; however, these benefits were primarily limited to those undergoing letrozole treatment, with no subgroup analysis conducted on the types of lipid-lowering drugs. Sim Y [4] did not perform subgroup analyses regarding drug types or endocrine therapy. Affects the following: 1.3.1 Increased heterogeneity: The studies by Ahern TP [ 3 ] and Borgquist S [ 5 ] performed different levels of subgroup analyses on the use of lipid-lowering drugs and lipophilic statins, while Sim Y [ 4 ] did not perform subgroup analyses based on drug types or endocrine therapy. This inconsistency in analysis methods may lead to increased heterogeneity in the meta-analysis, meaning greater variability between study results, which could affect the overall effect estimate. 1.3.2 Influence of confounding factors: Studies that do not perform subgroup analyses based on drug types or endocrine therapy (such as Sim Y) may overlook potential confounding factors. For example, different types of statins (lipophilic vs. hydrophilic) or different endocrine therapies (e.g., letrozole vs. other drugs) may have varying impacts on the risk of breast cancer recurrence. Failing to distinguish these differences may lead to biased effect estimates. By considering these factors, the findings suggest that while there is evidence of a beneficial effect of statin use, the differences between studies are substantial and should be explored further to understand the true magnitude and applicability of the observed effects. 2 Mechanisms by Which Statins Improve Prognosis in Breast Cancer ER+ breast cancer patients taking endocrine therapy may experience elevated blood lipid levels due to the reduction of estrogen levels. Statins, which lower blood lipid levels, could potentially improve the postoperative incidence of cardiovascular and cerebrovascular diseases in ER+ patients. On the other hand, statins primarily reduce cholesterol levels by inhibiting HMG-CoA reductase. [ 9 , 10 , 11 ] This action helps to diminish the lipid-rich environment required by breast cancer cells, thereby inhibiting tumor growth and spread. The specific mechanisms include: 2.1 Inhibition of Tumor Cell Proliferation and Migration Statins are capable of inhibiting the proliferation and migration of breast cancer cells, reducing the invasiveness of these cells [ 12 , 13 , 14 ] . This may be related to statins' ability to regulate the cell cycle, induce apoptosis, and inhibit tumor angiogenesis. 2.2 Enhancement of the Immune System's Anti-Tumor Effects Statins may also improve the prognosis of breast cancer patients by enhancing the immune system's anti-tumor effects. [ 15 ] For example, statins can promote the maturation and activation of dendritic cells, enhancing the body's ability to recognize and eliminate tumor cells. [ 16 , 17 , 18 ] 3 Limitations of This Study: 3.1The meta-analysis data were not sufficiently detailed to conduct a thorough subgroup analysis based on endocrine therapy medications or lipid-lowering drugs. Additionally, it did not allow for classification based on tumor size, presence of axillary lymph node metastasis, or other immunohistochemical results (such as Her-2 expression). Some laboratory and epidemiological studies have suggested that statins, a class of drugs commonly used to lower cholesterol levels, may have a positive impact on patients with triple-negative breast cancer. [ 19 , 20 ] Due to the lack of consistent subgroup analysis, the conclusions of the meta-analysis may be limited and unable to clarify the specific relationships between certain drug types or therapy types and disease prognosis. This could result in more generalized findings, making it difficult to provide specific and targeted recommendations for clinical decision-making. 3.2 Study Design and Generalizability: The study relied on retrospective data, which is more susceptible to biases such as selection bias and recall bias compared to prospective studies. And due to the limited number of studies and the specific patient populations they represent, the findings may not be generalizable to all ER+ breast cancer patients. 3.3 Lack of Long-Term Data: The study did not include long-term follow-up data, which is essential for understanding the long-term effects of statin use on recurrence rates and overall survival. 3.4 Dosage and Duration: Information regarding the dosage and duration of statin use was not detailed, which are important factors that could influence the effects of statins on breast cancer outcomes. [ 19 , 22 ] 4 Future Perspectives and Research Directions: 4.1 Large-Scale Prospective Studies: Conducting large-scale, multicenter, prospective cohort studies to confirm the effects of statins on breast cancer recurrence rates, especially among ER+ patients. These studies should aim to collect more detailed data on statin usage, including type, dosage, and duration. 4.2 Subgroup Analysis: Future studies should aim to perform subgroup analyses based on various factors such as the type of endocrine therapy, specific statin medications, tumor characteristics (size, grade, and molecular subtypes), and patient demographics to better understand the nuances of statin effects. 4.3 Mechanistic Studies: Further laboratory and clinical research is needed to elucidate the mechanisms by which statins may influence breast cancer outcomes. This includes exploring the impact of statins on tumor cell proliferation, migration, angiogenesis, and immune response. 4.4 Genetic and Pharmacogenomic Studies: Investigating genetic factors that may influence individual responses to statin therapy could identify patients who are more likely to benefit from statin treatment. 4.5 Randomized Controlled Trials: While observational studies provide preliminary evidence, randomized controlled trials are needed to establish a causal relationship between statin use and breast cancer outcomes. 4.6 Combination Therapy: Exploring the potential synergistic effects of statins in combination with other breast cancer treatments, such as chemotherapy, endocrine therapy, or targeted therapies. 4.7Disease Surveillance: Developing and validating predictive models that incorporate statin use along with other clinical variables to improve risk stratification and personalized treatment strategies for breast cancer patients. 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PMID: 28380313 McKechnie T, Brown Z, Lovrics O, Yang S, Kazi T, Eskicioglu C, Parvez E (2024) Concurrent Use of Statins in Patients Undergoing Curative Intent Treatment for Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis. Clin Breast Cancer 24(3):e103–e115 Epub 2023 Dec 16. PMID: 38296737 Sakellakis M, Akinosoglou K, Kostaki A, Spyropoulou D, Koutras A (2016) Statins and risk of breast cancer recurrence. Breast Cancer (Dove Med Press) 8:199–205. 10.2147/BCTT.S116694 PMID: 27853392; PMCID: PMC5104306 Chae YK, Valsecchi ME, Kim J, Bianchi AL, Khemasuwan D, Desai A, Tester W (2011) Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Invest 29(9):585–593 Epub 2011 Sep 21. PMID: 21936625 Martin TA, Jiang WG (2010) Anti-Cancer agents in medicinal chemistry (Formerly current medicinal chemistry - Anti-cancer agents). Anticancer Agents Med Chem. ;10(1):1. 10.2174/1871520611009010001 . 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Med Oncol 39(10):142. 10.1007/s12032-022-01733-9 PMID: 35834073; PMCID: PMC9283343 McKechnie T, Brown Z, Lovrics O, Yang S, Kazi T, Eskicioglu C, Parvez E (2024) Concurrent Use of Statins in Patients Undergoing Curative Intent Treatment for Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis. Clin Breast Cancer 24(3):e103–e115 Epub 2023 Dec 16. PMID: 38296737 Li L, Wang H, Zhang S, Gao S, Lu X, Pan Y, Tang W, Huang R, Qiao K, Ning S (2024) Statins inhibit paclitaxel-induced PD-L1 expression and increase CD8 + T cytotoxicity for better prognosis in breast cancer. Int J Surg 110(8):4716–4726. 10.1097/JS9.0000000000001582 PMID: 39143707; PMCID: PMC11325938 Lauridsen AR, Skorda A, Winther NI, Bay ML, Kallunki T (2024) Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers. J Exp Clin Cancer Res 43(1):254. 10.1186/s13046-024-03172-y PMID: 39243069; PMCID: PMC11378638 Kobayashi Y, Kashima H, Wu RC, Jung JG, Kuan JC, Gu J, Xuan J, Sokoll L, Visvanathan K, Shih IM, Wang TL (2015) Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models. Clin Cancer Res 21(20):4652–4662. 10.1158/1078-0432.CCR-14-3368 Epub 2015 Jun 24. PMID: 26109099; PMCID: PMC4609247 Wu L, Hong X, Yang C, Yang Y, Li W, Lu L, Cai M, Cao D, Zhuang G, Deng L (2023) Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12. Sci Immunol 8(90):eadf4919. 10.1126/sciimmunol.adf4919 Epub 2023 Dec 1. PMID: 38039379 McKechnie T, Brown Z, Lovrics O, Yang S, Kazi T, Eskicioglu C, Parvez E (2024) Concurrent Use of Statins in Patients Undergoing Curative Intent Treatment for Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis. Clin Breast Cancer 24(3):e103–e115 Epub 2023 Dec 16. PMID: 38296737 Nowakowska MK, Lei X, Thompson MT, Shaitelman SF, Wehner MR, Woodward WA, Giordano SH, Nead KT (2021) Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. ;127(22):4142–4150. 10.1002/cncr.33797 . Epub 2021 Aug 3. PMID: 34342892 Lv H, Shi D, Fei M, Chen Y, Xie F, Wang Z, Wang Y, Hu P (2020) Association Between Statin Use and Prognosis of Breast Cancer: A Meta-Analysis of Cohort Studies. Front Oncol 10:556243. 10.3389/fonc.2020.556243 PMID: 33178584; PMCID: PMC7596255 Mc Menamin ÚC, Murray LJ, Hughes CM, Cardwell CR (2016) Statin use and breast cancer survival: a nationwide cohort study in Scotland. BMC Cancer 16:600. 10.1186/s12885-016-2651-0 PMID: 27491389; PMCID: PMC4973520 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5084342","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":353693583,"identity":"04b48ede-9378-4482-91e2-a596ccacf9aa","order_by":0,"name":"Xiaowen Ma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYDACZuaDDyQMbOrtG85///HBwMaOsBZ2tmQDi4q0BAPGAwaSMwrSkglr4ecxk6g4czjBgPmAgTTPh0OMDYR06DYDbbnZlpZnznYgwdjG4AAzA/vhoxvwaTE7zHzw4cw2m2LLngMHknMM7vAx8KSl3cCvhS3ZWLItjbHhxsGGwzkGz5gZJHjMCGjhMZP+23aYseH+Y8ZmCwMggxgtEhJnDiduOHCMmZmBOC1A70tUpBlLNpxhY+wxSEtmI+iX84fBUSnHz3CGjeHHHxs7fvbDx/BqwQRspCkfBaNgFIyCUYANAABHHVFZ+6jqmQAAAABJRU5ErkJggg==","orcid":"","institution":"Hangzhou Women's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaowen","middleName":"","lastName":"Ma","suffix":""},{"id":353693584,"identity":"32dc184f-c605-4a96-ad66-25617e5a1bdb","order_by":1,"name":"Jia Gao","email":"","orcid":"","institution":"Hangzhou Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Gao","suffix":""},{"id":353693585,"identity":"f09694f1-8c32-412f-bb9d-73147d9c9ef1","order_by":2,"name":"Yiming Sun","email":"","orcid":"","institution":"Tongde Hospital of Zhejiang Province","correspondingAuthor":false,"prefix":"","firstName":"Yiming","middleName":"","lastName":"Sun","suffix":""},{"id":353694026,"identity":"88aefcee-ea54-4f25-9247-523619cc03c2","order_by":3,"name":"Feng Zhang","email":"","orcid":"","institution":"Hangzhou Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2024-09-13 14:04:18","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5084342/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5084342/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64707359,"identity":"258b94e8-0715-43f4-ade2-b84d72e56313","added_by":"auto","created_at":"2024-09-18 01:30:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38996,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the Article Selection Process\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5084342/v1/2868b90e06049b482ae2f7c6.png"},{"id":64707353,"identity":"57f43eda-89b4-4bb2-9ca9-c283e201e5d9","added_by":"auto","created_at":"2024-09-18 01:30:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75666,"visible":true,"origin":"","legend":"\u003cp\u003eThe forest plot compares the effects of statin use versus no use on the risk of recurrence in estrogen receptor-positive breast cancer.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5084342/v1/d2347934a083b264b31a1621.png"},{"id":64707358,"identity":"3cd813bb-8437-48cc-a3ee-c4dc94d4859c","added_by":"auto","created_at":"2024-09-18 01:30:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86410,"visible":true,"origin":"","legend":"\u003cp\u003eThe sensitivity analysis assesses the impact of statin use on recurrence risk in estrogen receptor-positive breast cancer.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5084342/v1/28e9709b719db46de46a9531.png"},{"id":64707356,"identity":"895c5cb4-f857-429c-ad65-f592b4dfff23","added_by":"auto","created_at":"2024-09-18 01:30:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":17422,"visible":true,"origin":"","legend":"\u003cp\u003eThe leave-one-out sensitivity analysis assesses the impact of statin use on recurrence risk in estrogen receptor-positive breast cancer.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5084342/v1/7323657c998ff137f19b91fc.png"},{"id":64707355,"identity":"985758c9-fd7f-433e-8201-d30f21266404","added_by":"auto","created_at":"2024-09-18 01:30:17","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":64327,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 4 Public bias analysis for Statins use VS no use for ER+ breast cancer recurrence risk\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5084342/v1/02c1d4f1d00b4c3c6c7fc5e0.png"},{"id":64708260,"identity":"bf30a3af-58d2-4d0e-b101-33b79e8f490e","added_by":"auto","created_at":"2024-09-18 01:38:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":646486,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5084342/v1/4104d1b5-4a6d-4e35-adad-1aedde40de78.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eThe influence of statin therapy on the recurrence of early-stage estrogen receptor-positive breast cancer: A meta-analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eStatins, a prevalent class of lipid-lowering medications, have emerged in recent years as potential anti-tumor agents, particularly within the realm of breast cancer therapy. And statins have an important positive effect on reducing drug resistance to endocrine therapy in breast cancer.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e In recent years, several studies have reported the association between statin use and the survival rate of patients with breast cancer. Especially for triple-negative breast cancer, a more aggressive subtype, the use of statins has significantly improved the overall survival and breast cancer-specific survival rates of patients. Statin use post-diagnosis was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75–0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57–0.88).\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e The purpose of this study is to determine whether statin lipid-lowering drugs can reduce the recurrence rate in patients with ER + breast cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eLiterature search\u003c/p\u003e\u003cp\u003e This review adhered meticulously to the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) guidelines, aiming to systematically compare the recurrence rates in hormone receptor-positive breast cancer patients between those treated with statins and those untreated. A comprehensive literature search was meticulously conducted by two independent reviewers, XiaoWen Ma and Jia Gao, employing established search strategies across various databases, including PubMed, Medline, Cochrane, and Web of Science. The search criteria were inclusive, spanning from January 1, 2004, to January 1, 2024. The search employed the following medical subject headings (MeSH): (\"statin\"[All Fields]) AND (\"breast neoplasms\"[MeSH Terms]) AND ((clinicalconference[Filter] OR clinicalstudy[Filter] OR clinicaltrial[Filter] OR comparativestudy[Filter] OR controlledclinicaltrial[Filter] OR multicenterstudy[Filter] OR observationalstudy[Filter] OR randomizedcontrolledtrial[Filter]) AND (fft[Filter])). All identified citations were independently assessed by the two authors and categorized as relevant or irrelevant. Studies deemed relevant were then selected for full-text review, and their reference lists were meticulously searched for additional significant citations. Ecological studies, case reports, reviews, and editorials were deemed ineligible for inclusion.\u003c/p\u003e\u003cp\u003eEligibility criteria:\u003c/p\u003e\u003cp\u003eInclusion Criteria: 1. Studies published comprehensive adjusted risk estimates (at least accounting for age, tumor size, and lymph node status) comparing statin use versus no statin use in patients with ER + breast cancer, without any prior history of cancer or metastatic disease. 2. They were independent studies that did not duplicate results already published in another article. 3. The studies reported HRs for recurrence rate, along with their corresponding 95% CIs. In this article, \"recurrence\" refers to local recurrence, regional recurrence, distant recurrence, and contralateral recurrence. The selected recurrence data pertain exclusively to patients who were prescribed statins following a breast cancer diagnosis, encompassing both those who continued statin use after diagnosis and those who initiated statin therapy subsequent to the diagnosis of breast cancer.\u003c/p\u003e\u003cp\u003eExclusion Criteria: 1. Studies lacking a comparative group between statin users and non-users. 2. Studies without comprehensive adjusted risk estimates for the specified factors. 3. Studies that did not report HRs with corresponding 95% CIs for recurrence rates.\u003c/p\u003e\u003cp\u003eData Extraction: Two reviewers, XiaoWen Ma and Jia Gao, independently and precisely extracted data, ensuring consensus on all outcomes. A standardized data-collection protocol was meticulously applied to compile pertinent data from each article selected for inclusion. For each eligible study, the following details were meticulously documented: 1. Lead author's name. 2. Publication year. 3. Comprehensive set of study characteristics, including research objective, patient recruitment timeframe, geographical context, eligibility criteria, median follow-up period, breast cancer stage, types of statistical adjustments made, median age of the patient cohort, and recurrence rate. Additionally, detailed information for each arm of the treatment groups was recorded, including: 1. Total number of patients in the statin use and no statin use cohorts. 2. Distribution of patients across various tumor stages (T1, T2, T3 and Tx), nodal stages (N0, N1, N2 or more). 3. Duration and type of statin use. This rigorous approach to data extraction and documentation ensured the integrity and reliability of the information used in our systematic review and meta-analysis.\u003c/p\u003e\u003cp\u003eData analysis and statistical methods: Each HR, meticulously adjusted for a comprehensive set of confounding variables, along with its corresponding confidence interval, was extracted and converted into an OR. The summary OR was calculated by pooling the study-specific estimates using random-effects models. The I² statistic was used to measure the extent of heterogeneity, representing the proportion of total variation across studies attributable to heterogeneity, with higher I² values indicating greater heterogeneity. Conventionally, an I² threshold below 50% is considered to represent an acceptable level of variability. Forest plots were generated, including both the study-specific estimates and the summary OR. Heterogeneity and sensitivity analyses were carefully evaluated, considering all possible factors that could influence the estimates, including adjustments for confounding factors, types of endpoints, and study design characteristics. Publication bias was assessed graphically using Egger's test. All statistical analyses were meticulously conducted using Stata software version 17 and the Cochrane Review Manager (RevMan) version 5.4.\u003c/p\u003e"},{"header":"Findings","content":"\u003cp\u003eResults of the Search Strategy:\u003c/p\u003e\n\u003cp\u003eA total of 366 articles were identified through the specified MeSH terms. Following an initial screening, 109 records were excluded based on the abstract, resulting in 257 articles selected for full-text review. We retrieved and meticulously examined all 6 eligible studies. Ultimately, 3 articles were excluded from the analysis: 2 for employing an alternative endpoint definition, and 1 for using endocrine therapy as a proxy for the inclusion criterion of hormone receptor positivity.\u003c/p\u003e\n\u003cp\u003eDescription of studies\u003c/p\u003e\n\u003cp\u003eThe meta-analysis provides a comprehensive description of the included studies, as detailed in Table 1. This table presents a thorough summary, including the total number of cases, publication years, geographical regions, and diagnostic periods, along with study designs, considerations for age and tumor stage, and follow-up durations. The analysis included a total of 102,525 patients with ER+ breast cancer from 3 population-based studies: 24,598 were on statin therapy, and 77,349 were not. The timeframe for diagnosis and treatment across these studies ranged from 1996 to 2015, offering a substantial dataset for analysis. Of these three studies, one was prospective, while the other two were retrospective in nature.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.829787234042554%\" style=\"width: 12.3529%;\"\u003e\n \u003cp\u003eFirst author\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 7.0588%;\"\u003e\n \u003cp\u003ePublic year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 11.9118%;\"\u003e\n \u003cp\u003eCountry and diagnostic time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.7647%;\"\u003e\n \u003cp\u003ecases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.51063829787234%\" style=\"width: 15.2941%;\"\u003e\n \u003cp\u003econtrols\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.6176%;\"\u003e\n \u003cp\u003eBC stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.02127659574468%\" style=\"width: 17.0588%;\"\u003e\n \u003cp\u003eMedian follow-up(months/years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" style=\"width: 10.4412%;\"\u003e\n \u003cp\u003eOutcomes measured\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.829787234042554%\" style=\"width: 12.3529%;\"\u003e\n \u003cp\u003eAhern TP\u003csup\u003e\u0026nbsp;[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 7.0588%;\"\u003e\n \u003cp\u003e2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 11.9118%;\"\u003e\n \u003cp\u003eDenmark 1996-2003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eprospective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.7647%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.51063829787234%\" style=\"width: 15.2941%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.6176%;\"\u003e\n \u003cp\u003eI-III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.02127659574468%\" style=\"width: 17.0588%;\"\u003e\n \u003cp\u003e6.8y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" style=\"width: 10.4412%;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.829787234042554%\" style=\"width: 12.3529%;\"\u003e\n \u003cp\u003eSim Y\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 7.0588%;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 11.9118%;\"\u003e\n \u003cp\u003eSingapore 2005-2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eretrospective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.7647%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.51063829787234%\" style=\"width: 15.2941%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.6176%;\"\u003e\n \u003cp\u003eI-III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.02127659574468%\" style=\"width: 17.0588%;\"\u003e\n \u003cp\u003e8.67y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" style=\"width: 10.4412%;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.829787234042554%\" style=\"width: 12.3529%;\"\u003e\n \u003cp\u003eBorgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 7.0588%;\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 11.9118%;\"\u003e\n \u003cp\u003eSweden 1998-2003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" style=\"width: 12.5%;\"\u003e\n \u003cp\u003eretrospective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.7647%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.51063829787234%\" style=\"width: 15.2941%;\"\u003e\n \u003cp\u003eEarly postmenopausal ER+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.446808510638298%\" style=\"width: 6.6176%;\"\u003e\n \u003cp\u003eI-III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.02127659574468%\" style=\"width: 17.0588%;\"\u003e\n \u003cp\u003e8y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" style=\"width: 10.4412%;\"\u003e\n \u003cp\u003eHR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 1 Characteristics of ER+ Patients Across the Three Studies\u003c/p\u003e\n\u003cp\u003eTable 2 delineates the distribution of T and N stages among patient groups in the studies. The participants, all diagnosed with stages I-III breast cancer, underwent surgical treatment followed by standard postoperative endocrine therapy. Enrollment in the three studies was not subject to age limitations. Nevertheless, comprehensive TNM staging information was constrained, with detailed T and N stage data available for only one of the studies, as illustrated in Table 2.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003estudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMean age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eTotal case\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 or more\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAhern TP2011\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStatins use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20255\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e67888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSim Y2022\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStatins use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3706\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBorgquist S\u003csup\u003e\u0026nbsp;[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStatins use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e652\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2 T and N stages and adjuvant therapies of the BCT group patients and mastectomy group patients\u003c/p\u003e\n\u003cp\u003eFigure 3 presents a comparative analysis of the total patient count, recurrence incidence, recurrence rates, HRs, and P-values between early-stage ER+ breast cancer patients who were on statin therapy and those who were not, across the three studies. In each of these studies, the adjusted HRs are accompanied by confidence intervals that exclude the value of 1, with HRs less than 1. This suggests a consistent trend indicating that the recurrence rate among ER+ breast cancer patients who utilized statins is significantly lower compared to those who did not, highlighting the potential benefits of statin use in this patient population.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eFirst author\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003eStatins use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003eNo use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eAdjusted HR/OR and CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal case(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence case\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence rate (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal case(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence case\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence rate (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAhern TP\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20255\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e198\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e67888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2174\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.69 (0.55 to 0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSim Y\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3706\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.57 (0.43\u0026nbsp;\u0026ndash;\u0026nbsp;0.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBorgquist S \u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1881\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.84(0.68-0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3 The observed values and statistical results of each study\u003c/p\u003e\n\u003cp\u003eTable 4 presents the Newcastle-Ottawa Scale (NOS) scores for the three studies, each earning a score of 8 points, which is indicative of their high methodological quality.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.183673469387756%\" rowspan=\"2\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"46.93877551020408%\" colspan=\"4\"\u003e\n \u003cp\u003eselection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.204081632653061%\"\u003e\n \u003cp\u003ecomparability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.673469387755105%\" colspan=\"4\"\u003e\n \u003cp\u003eoutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.27906976744186%\"\u003e\n \u003cp\u003eRepresentativeness of the exposed cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.465116279069768%\"\u003e\n \u003cp\u003eSelection of the nonexposed cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.790697674418604%\"\u003e\n \u003cp\u003eAscertainment of exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.790697674418604%\"\u003e\n \u003cp\u003eDemonstration that outcome of interest was not present at start of study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.627906976744185%\"\u003e\n \u003cp\u003eComparability of cohorts on the basis of the design or analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.465116279069768%\"\u003e\n \u003cp\u003eAssessment of outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.30232558139535%\"\u003e\n \u003cp\u003eWas follow-up long enough for outcomes to occur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.30232558139535%\"\u003e\n \u003cp\u003eAdequacy of follow-up of cohorts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.976744186046512%\"\u003e\n \u003cp\u003eQuality score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003eAhern TP\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.736842105263158%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003eSim Y\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.736842105263158%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003eSakellakis M\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.736842105263158%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 4\u0026nbsp;Newcastle‒Ottawa\u0026nbsp;Scale\u0026nbsp;(NOS)\u003c/p\u003e\n\u003cp\u003eMeta-analysis Findings:\u003c/p\u003e\n\u003cp\u003eImpact of Statin Use on Recurrence Risk in ER+ Breast Cancer:\u003c/p\u003e\n\u003cp\u003eOur meta-analysis, synthesizing data from three studies as depicted in Figure 2, compiled a total of three risk estimates. The aggregated OR reveals a notably significant 52% reduction in recurrence risk for patients on statin therapy compared to those not on statins (Summary OR = 0.48; 95% CI: 0.27\u0026ndash;0.86), as illustrated in Figure 1. This finding suggests that ER+ breast cancer patients who receive statins exhibit a substantial decrease in recurrence rates. However, it is crucial to acknowledge the substantial heterogeneity observed among the studies, with an I\u0026sup2; statistic of 96% and a chi-square test P-value significantly less than 0.00001. This high degree of heterogeneity suggests considerable variability in the study outcomes, which could potentially influence the overall interpretation of the results.\u003c/p\u003e\n\u003cp\u003eFigure 2 The forest plot compares the effects of statin use versus no use on the risk of recurrence in estrogen receptor-positive breast cancer.\u003c/p\u003e\n\u003cp\u003eSensitivity Analysis Overview:\u003c/p\u003e\n\u003cp\u003eThe meta-analysis utilized a random-effects model with the Restricted Maximum Likelihood (REML) method to assess heterogeneity, yielding the following key metrics: Tau\u0026sup2; (\u0026tau;\u0026sup2;) = 0.1590 represents the estimated variance in the true effect sizes across the studies, signifying the presence of heterogeneity, as a non-zero value indicates variability among the study outcomes. I\u0026sup2; = 94.84%: This statistic measures the proportion of total variation across the studies that is attributable to heterogeneity rather than chance, with 94.84% indicating a very high degree of heterogeneity. H\u0026sup2; = 19.37: Serving as another indicator of heterogeneity, a value exceeding 1 suggests significant variability among the studies. Z = -3.10, P= 0.0020: The z-score and corresponding p-value confirm that the aggregated effect size is statistically significant at the p \u0026lt; 0.05 level. Test of Homogeneity: Q = 50.05, P= 0.0000: The Q statistic, which tests the null hypothesis of a common effect size across all studies, returns a very low p-value (\u0026lt; 0.0001), denoting substantial heterogeneity among the studies. These results underscore the importance of considering heterogeneity when interpreting the meta-analysis outcomes and highlight the need for further investigation into the sources of this variability.\u003c/p\u003e\n\u003cp\u003eThe leave-one-out sensitivity analysis indicates that:\u003c/p\u003e\n\u003cp\u003eThe overall meta-analysis result is relatively robust to the exclusion of the studies Sim Y\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003eand Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003e. However, the study Ahern TP\u003csup\u003e\u0026nbsp;[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e has a more substantial impact on the overall effect size, indicating it may contribute more to the observed heterogeneity. This study should be further examined to understand its influence and why it has a more pronounced effect on the pooled result.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEgger\u0026rsquo;s\u0026nbsp;test\u0026nbsp;for\u0026nbsp;publication bias:\u003c/p\u003e\n\u003cp\u003eThe Egger\u0026apos;s regression test is used to detect potential publication bias or small-study effects in a meta-analysis. The null hypothesis (H0) is that there is no small-study effect, meaning the intercept (beta1) equals zero. Beta1 = 9.76: This is the estimated intercept from the Egger\u0026apos;s test regression model. A significant deviation from zero could suggest the presence of small-study effects or publication bias. SE of Beta1 = 7.557: The standard error of the estimated intercept. Z = 1.29: This is the test statistic for Egger\u0026apos;s test. P-value = 0.1964: The P-value indicates the probability that the observed value of the test statistic would occur if the null hypothesis were true. The P-value is greater than the conventional significance level of 0.05. Therefore, we fail to reject the null hypothesis. This suggests that there is no evidence of small-study effects or publication bias in this meta-analysis based on Egger\u0026apos;s test.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eA study\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003epublished in the journal Cancer pointed out that the overall survival rate of breast cancer patients taking statins could be relatively increased by 30%, while the BCSS rate could be relatively increased by 58%. This finding provides new insights into the treatment of breast cancer. There may be differences in the effects of different statins on improving the prognosis of patients with breast cancer. Hydrophobic statins (such as simvastatin, atorvastatin, etc.) have a statistically significant relationship with the improvement of patients\u0026apos; overall survival. And research on the recurrence rate of breast cancer, statin users displayed longer mean relapse-free survival (16.6 vs 10.2 years, P=0.028). After data had been adjusted for patient and disease characteristics, statin users maintained a lower risk of recurrence.\u003csup\u003e\u0026nbsp;[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e8\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn this meta-analysis the combined OR for statin use versus no use is 0.48 with a 95% CI of [0.27, 0.86]. This result indicates that statin use is associated with a statistically significant reduction in the recurrence risk (OR \u0026lt; 1) compared to no use, with a P-value of 0.01, suggesting that the overall effect is statistically significant. Heterogeneity Statistics: Chi\u0026sup2;\u0026nbsp;(Q) = 50.13, P \u0026lt; 0.00001, I\u0026sup2;=96% ,The Chi-squared test for heterogeneity shows a highly significant P-value, confirming the presence of significant heterogeneity among the included studies. This statistic quantifies the proportion of total variation in study estimates due to heterogeneity rather than chance. And there is considerable variation in effect sizes across the three studies. Ahern TP\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e shows a much stronger effect than Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003eand Sim Y\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e which could suggest differences in study populations, methods, or definitions of outcomes.\u003c/p\u003e\n\u003cp\u003e1 Discuss the sources of heterogeneity:\u003c/p\u003e\n\u003cp\u003e1.1 Study-Specific Odds Ratios and Confidence Intervals:\u003c/p\u003e\n\u003cp\u003eAhern TP\u003csup\u003e\u0026nbsp;[3]\u003c/sup\u003e: OR = 0.30 [0.26, 0.35], with a weight of 34.1%. This study shows a strong association between statin use and risk reduction, contributing significantly to the overall pooled effect. However, it also has the smallest confidence interval, indicating high precision, likely due to its large sample size. Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003e: OR = 0.70 [0.57, 0.88], with a weight of 33.4%. This study shows a moderate effect size that is smaller than Ahern TP\u003csup\u003e\u0026nbsp;[3]\u0026nbsp;\u003c/sup\u003ebut still statistically significant. Its result is less extreme than Ahern TP\u003csup\u003e[3]\u0026nbsp;\u003c/sup\u003eand has a wider confidence interval. Sim Y 2022: OR = 0.55 [0.42, 0.72], with a weight of 32.5%. This study also shows a moderate effect size, with its confidence interval overlapping with that of Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e but not \u0026nbsp;Ahern TP\u003csup\u003e[3]\u003c/sup\u003e . Despite the considerable variation in ORs, the conclusions drawn from the three studies are relatively consistent, indicating that the use of statins indeed reduces the recurrence rate in early-stage ER+ breast cancer patients.\u003c/p\u003e\n\u003cp\u003e1.2 Possible Sources of Heterogeneity:\u003c/p\u003e\n\u003cp\u003e1.2.1 The differences in the study populations are as follows:\u003c/p\u003e\n\u003cp\u003eSim Y\u003csup\u003e[4]\u003c/sup\u003e focuses on breast cancer patients from the SingHealth Public Health Cluster in Singapore (2005-2015), including ductal carcinoma in situ (DCIS) and stages I to III invasive cancer. Ahern TP\u003csup\u003e[3]\u003c/sup\u003e involves all female residents in Denmark diagnosed with stages I-III invasive breast cancer (1996-2003). Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003eincludes postmenopausal women with stages I-III invasive breast cancer from the BIG 1-98 trial (1988-2003). Since the recurrence risk for DCIS is lower than that for invasive breast cancer, this may result in a lower recurrence risk in the Sim Y\u003csup\u003e[4]\u003c/sup\u003e study compared to the other two studies. Additionally, Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e study population consists of postmenopausal early-stage breast cancer patients, which may lead to a lower recurrence risk compared to the other two studies that include patients of all ages. Sim Y\u003csup\u003e[4]\u003c/sup\u003e excluded patients who used statins before surgery, while the other two studies included breast cancer patients who used lipid-lowering drugs before diagnosis and after diagnosis. Patients using lipid-lowering drugs may be older than those who have not used such drugs, which could lead to a younger study population in Sim Y\u003csup\u003e[4]\u003c/sup\u003e with a higher baseline recurrence risk.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSample Size Differences: Ahern TP\u003csup\u003e[3]\u003c/sup\u003e has a much larger total sample size compared to the other two studies, which could lead to its greater weight and influence on the pooled effect size. The larger sample size may provide more precise estimates, but it can also introduce variability if the study population is significantly different from the others.\u003c/p\u003e\n\u003cp\u003eAnd the age baseline of the populations included in the three studies is inconsistent, but due to insufficient detailed data, statistical analysis is not possible, and only descriptive analysis can be conducted: In Ahern TP\u003csup\u003e[3]\u003c/sup\u003e, the age distribution of the statin use group is 50\u0026ndash;59 years old (33.7%) and 60\u0026ndash;69 years old (40.9%), while for the nonuser group, it is 50\u0026ndash;59 years old (33.2%) and 60\u0026ndash;69 years old (27.4%). In Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e, the statin user group represents 6% of those under 65 years old and 11% of those 65 and older. In Sim Y\u003csup\u003e[4]\u003c/sup\u003e, the statin user group is predominantly aged 50-59 (35.0%) and 60-69 (35.8%), while the nonusers group is mainly 40-49 years old (33.9%) and 50-59 years old (33.2%).\u003c/p\u003e\n\u003cp\u003e1.2.2 Differences in Research Methods\u003c/p\u003e\n\u003cp\u003eAhern TP\u003csup\u003e[3]\u003c/sup\u003e utilizes a nationwide population-based prospective cohort study, registered through the Danish Breast Cancer Cooperative Group (DBCG), employing the Cox proportional hazards model to estimate the association between statin use and breast cancer recurrence. Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e conducts a retrospective study, employing marginal structural Cox proportional hazards models to address potential biases due to cholesterol levels, specified endocrine treatments, patient-specific risk factors, practice variations, and enrollment locations, comparing patient use of CLM and breast cancer outcomes under different treatment allocations. Sim Y\u003csup\u003e[4]\u003c/sup\u003e is a retrospective study focusing on patients who used statins post-diagnosis, adjusting for variables such as cardiac events and diabetes through statistical models to eliminate the impact of confounding factors on the results.\u003c/p\u003e\n\u003cp\u003eThe three studies include populations of different ethnicities, and the confounding factors excluded to interfere with the trials are not consistent, which may contribute to heterogeneity among the studies. Ahern TP\u003csup\u003e[3]\u003c/sup\u003e, being a prospective cohort study, can better establish causal relationships compared to the other two retrospective cohort studies, reducing selection and recall biases and providing better control over the data collection process, thus making the results more persuasive.\u003c/p\u003e\n\u003cp\u003e1.3 Specific Differences in Outcome Evaluation\u003c/p\u003e\n\u003cp\u003eAhern TP\u003csup\u003e\u0026nbsp;[3]\u003c/sup\u003e conducted subgroup analyses that established a correlation between the use of lipophilic statins, such as simvastatin, and a reduced risk of breast cancer recurrence, while hydrophilic statins showed no significant association. Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e observed significant improvements in disease-free survival (DFS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI) for patients using lipid-lowering drugs at the initiation of endocrine therapy; however, these benefits were primarily limited to those undergoing letrozole treatment, with no subgroup analysis conducted on the types of lipid-lowering drugs. Sim Y\u003csup\u003e[4]\u0026nbsp;\u003c/sup\u003edid not perform subgroup analyses regarding drug types or endocrine therapy. Affects the following:\u003c/p\u003e\n\u003cp\u003e1.3.1 Increased heterogeneity: The studies by Ahern TP\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e and Borgquist S\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e performed different levels of subgroup analyses on the use of lipid-lowering drugs and lipophilic statins, while Sim Y\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e did not perform subgroup analyses based on drug types or endocrine therapy. This inconsistency in analysis methods may lead to increased heterogeneity in the meta-analysis, meaning greater variability between study results, which could affect the overall effect estimate.\u003c/p\u003e\n\u003cp\u003e1.3.2 Influence of confounding factors: Studies that do not perform subgroup analyses based on drug types or endocrine therapy (such as Sim Y) may overlook potential confounding factors. For example, different types of statins (lipophilic vs. hydrophilic) or different endocrine therapies (e.g., letrozole vs. other drugs) may have varying impacts on the risk of breast cancer recurrence. Failing to distinguish these differences may lead to biased effect estimates.\u003c/p\u003e\n\u003cp\u003eBy considering these factors, the findings suggest that while there is evidence of a beneficial effect of statin use, the differences between studies are substantial and should be explored further to understand the true magnitude and applicability of the observed effects.\u003c/p\u003e\n\u003cp\u003e2 Mechanisms by Which Statins Improve Prognosis in Breast Cancer\u003c/p\u003e\n\u003cp\u003eER+ breast cancer patients taking endocrine therapy may experience elevated blood lipid levels due to the reduction of estrogen levels. Statins, which lower blood lipid levels, could potentially improve the postoperative incidence of cardiovascular and cerebrovascular diseases in ER+ patients. On the other hand, statins primarily reduce cholesterol levels by inhibiting HMG-CoA reductase.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e9\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e10\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e11\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e This action helps to diminish the lipid-rich environment required by breast cancer cells, thereby inhibiting tumor growth and spread. The specific mechanisms include:\u003c/p\u003e\n\u003cp\u003e2.1 Inhibition of Tumor Cell Proliferation and Migration\u003c/p\u003e\n\u003cp\u003eStatins are capable of inhibiting the proliferation and migration of breast cancer cells, reducing the invasiveness of these cells\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e13\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e14\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e. This may be related to statins\u0026apos; ability to regulate the cell cycle, induce apoptosis, and inhibit tumor angiogenesis.\u003c/p\u003e\n\u003cp\u003e2.2 Enhancement of the Immune System\u0026apos;s Anti-Tumor Effects\u003c/p\u003e\n\u003cp\u003eStatins may also improve the prognosis of breast cancer patients by enhancing the immune system\u0026apos;s anti-tumor effects.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e For example, statins can promote the maturation and activation of dendritic cells, enhancing the body\u0026apos;s ability to recognize and eliminate tumor cells.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e3 Limitations of This Study:\u003c/p\u003e\n\u003cp\u003e3.1The meta-analysis data were not sufficiently detailed to conduct a thorough subgroup analysis based on endocrine therapy medications or lipid-lowering drugs. Additionally, it did not allow for classification based on tumor size, presence of axillary lymph node metastasis, or other immunohistochemical results (such as Her-2 expression). Some laboratory and epidemiological studies have suggested that statins, a class of drugs commonly used to lower cholesterol levels, may have a positive impact on patients with triple-negative breast cancer.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e19\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e]\u0026nbsp;\u003c/sup\u003eDue to the lack of consistent subgroup analysis, the conclusions of the meta-analysis may be limited and unable to clarify the specific relationships between certain drug types or therapy types and disease prognosis. This could result in more generalized findings, making it difficult to provide specific and targeted recommendations for clinical decision-making.\u003c/p\u003e\n\u003cp\u003e3.2 Study Design and Generalizability: The study relied on retrospective data, which is more susceptible to biases such as selection bias and recall bias compared to prospective studies. And due to the limited number of studies and the specific patient populations they represent, the findings may not be generalizable to all ER+ breast cancer patients.\u003c/p\u003e\n\u003cp\u003e3.3 Lack of Long-Term Data: The study did not include long-term follow-up data, which is essential for understanding the long-term effects of statin use on recurrence rates and overall survival.\u003c/p\u003e\n\u003cp\u003e3.4 Dosage and Duration: Information regarding the dosage and duration of statin use was not detailed, which are important factors that could influence the effects of statins on breast cancer outcomes.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e19\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e4 Future Perspectives and Research Directions:\u003c/p\u003e\n\u003cp\u003e4.1 Large-Scale Prospective Studies: Conducting large-scale, multicenter, prospective cohort studies to confirm the effects of statins on breast cancer recurrence rates, especially among ER+ patients. These studies should aim to collect more detailed data on statin usage, including type, dosage, and duration.\u003c/p\u003e\n\u003cp\u003e4.2 Subgroup Analysis: Future studies should aim to perform subgroup analyses based on various factors such as the type of endocrine therapy, specific statin medications, tumor characteristics (size, grade, and molecular subtypes), and patient demographics to better understand the nuances of statin effects.\u003c/p\u003e\n\u003cp\u003e4.3 Mechanistic Studies: Further laboratory and clinical research is needed to elucidate the mechanisms by which statins may influence breast cancer outcomes. This includes exploring the impact of statins on tumor cell proliferation, migration, angiogenesis, and immune response.\u003c/p\u003e\n\u003cp\u003e4.4 Genetic and Pharmacogenomic Studies: Investigating genetic factors that may influence individual responses to statin therapy could identify patients who are more likely to benefit from statin treatment.\u003c/p\u003e\n\u003cp\u003e4.5 Randomized Controlled Trials: While observational studies provide preliminary evidence, randomized controlled trials are needed to establish a causal relationship between statin use and breast cancer outcomes.\u003c/p\u003e\n\u003cp\u003e4.6 Combination Therapy: Exploring the potential synergistic effects of statins in combination with other breast cancer treatments, such as chemotherapy, endocrine therapy, or targeted therapies.\u003c/p\u003e\n\u003cp\u003e4.7Disease Surveillance: Developing and validating predictive models that incorporate statin use along with other clinical variables to improve risk stratification and personalized treatment strategies for breast cancer patients.\u003c/p\u003e\n\u003cp\u003eIn summary, statins have demonstrated significant potential in improving the prognosis of breast cancer patients. However, current research has some limitations, such as insufficient sample sizes and short follow-up durations. Therefore, future studies require large-scale, long-term clinical trials to further validate the efficacy and safety of statins in the treatment of early-stage ER+ breast cancer. Additionally, it is essential to delve into the specific mechanisms by which statins improve the prognosis of breast cancer, providing a scientific basis for personalized treatment of the disease.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHyder T, Marti JLG, Nasrazadani A, Brufsky AM (2021) Statins and endocrine resistance in breast cancer. 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PMID: 38296737\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNowakowska MK, Lei X, Thompson MT, Shaitelman SF, Wehner MR, Woodward WA, Giordano SH, Nead KT (2021) Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. ;127(22):4142\u0026ndash;4150. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.33797\u003c/span\u003e\u003cspan address=\"10.1002/cncr.33797\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2021 Aug 3. PMID: 34342892\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLv H, Shi D, Fei M, Chen Y, Xie F, Wang Z, Wang Y, Hu P (2020) Association Between Statin Use and Prognosis of Breast Cancer: A Meta-Analysis of Cohort Studies. Front Oncol 10:556243. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2020.556243\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2020.556243\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 33178584; PMCID: PMC7596255\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMc Menamin \u0026Uacute;C, Murray LJ, Hughes CM, Cardwell CR (2016) Statin use and breast cancer survival: a nationwide cohort study in Scotland. BMC Cancer 16:600. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12885-016-2651-0\u003c/span\u003e\u003cspan address=\"10.1186/s12885-016-2651-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 27491389; PMCID: PMC4973520\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, statins, recurrence, hormone receptor-positive","lastPublishedDoi":"10.21203/rs.3.rs-5084342/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5084342/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStatins have been recognized for their significant role in mitigating drug resistance to endocrine therapy in breast cancer. A substantial body of research has indicated that statin usage is associated with a marked improvement in both overall survival rates and breast cancer-specific survival (BCSS) among patients. The objective of this research is to determine whether the use of statins influences the local recurrence in early-stage estrogen receptor-positive (ER+) breast cancer patients. This investigation could provide crucial insights into the potential of statins as an adjunct therapy to reduce the risk of recurrence in this patient population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods\u003c/strong\u003e: Our review encompassed three studies comparing the recurrence rates in stage I-III ER+ breast cancer patients who did and did not use statins. The endpoint focused on recurrence, with the inclusion criterion being studies that reported fully adjusted hazard ratios (HRs). Summary odds ratios (ORs) were derived using random-effects models. Publication bias and heterogeneity were evaluated through sensitivity analyses, Q statistic tests, and I² tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Three population-based studies, comprising a total of 102,525 patients with ER+ breast cancer, were included in our analysis: 24,598 of whom were on statin therapy, and 77,349 were not. The pooled OR revealed a notably significant 52% reduction in the risk of recurrence for patients who used statins compared to those who did not (Summary OR = 0.48; 95% CI: 0.27–0.86). Our analysis of three population-based studies, which included a total of 102,525 ER+ breast cancer patients 24,598 on statin therapy and 77,349 not on statins demonstrates a significant 52% reduction in recurrence risk for those treated with statins. However, it is crucial to acknowledge the substantial heterogeneity present among the studies, as indicated by an I² of 96% and a highly significant chi-square test (P \u0026lt; 0.00001). In the Leave-One-Out Sensitivity Analysis, the meta-analysis results proved to be relatively stable with the exclusion of studies Sim Y 2022\u003csup\u003e \u003c/sup\u003eand Borgquist S 2017. Nevertheless, the study by Ahern TP 2011 exerted a more significant influence on the overall effect size, suggesting a potential contribution to the observed heterogeneity. Regarding publication bias, Egger’s test yielded a P-value of 0.1964, indicating no evidence of small-study effects or publication bias in this meta-analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The pooled OR for statin use compared to non-use is 0.48 with a 95% CI of [0.27, 0.86]. Despite the considerable variation in ORs and high heterogeneity, the conclusions drawn from the three studies are relatively consistent, indicating that the use of statins indeed reduces the recurrence rate in early-stage ER+ breast cancer patients.\u003c/p\u003e","manuscriptTitle":"The influence of statin therapy on the recurrence of early-stage estrogen receptor-positive breast cancer: A meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-18 01:30:12","doi":"10.21203/rs.3.rs-5084342/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7993d88e-20b3-4a27-a792-e6438a3d0b95","owner":[],"postedDate":"September 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":37587482,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2024-09-18T01:30:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-18 01:30:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5084342","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5084342","identity":"rs-5084342","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}