Microsatellite Instability as a Maker of Prognosis: a Systematic Review and Meta-analysis of Endometrioid Endometrial Cancer Survival Data

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Methods The PubMed, EMBASE and the Cochrane Cooperative Library databases were searched from inception to July 2021. Overall survival, disease-free survival, progression-free survival, EEC-specific survival, recurrence-free survival and the recurrence rate were pooled to analyze the correlation between MSI and EEC. In addition, Egger’s regression analysis and Begg’s test were used to detect publication bias. Results 17 studies met the inclusion criteria and were included in our meta-analysis with a sample size of 4723, and the included patients with endometrioid cancer (EC) all were EEC. The pooled hazard ratios (HR) in patients with EEC shown that MSI was significantly associated with shorter overall survival [HR=1.37, 95% confidence interval (CI) (1.00-1.86), p= 0.048, I 2 = 60.6%], shorter disease-free survival [HR=1.99, 95% CI (1.31-3.01), p= 0.000, I 2 = 67.2%], shorter EEC-specific survival [HR=2.07, 95% CI (1.35-3.18), p= 0.001, I 2 = 31.6%] and a higher recurrence rate [Odds ratios (OR)=2.72, 95% CI (1.56-4.76), p= 0.000, I 2 = 0.0%]. In the early-stage EEC subgroup, MSI was significantly associated with shorter overall survival [HR=1.47, 95% CI (1.11-1.95), p= 0.07], shorter disease-free survival [HR=4.17, 95% CI (2.37-7.41), p= 0.000], and shorter progression-free survival [HR=2.41, 95% CI (1.05-5.54), p= 0.039]. No significant heterogeneity was observed in overall survival ( I 2 = 20.9%), disease-free survival ( I 2 = 0.0%), or progression-free survival ( I 2 = 0.0%) in patients with early-stage EEC. Meanwhile, publication bias was not observed, and the p-value for Egger’s test of overall survival, disease-free survival, and EEC-specific survival were p= 0.131, p= 0.068 and p= 0.987, respectively. Conclusion MSI is likely an important biomarker for poor prognosis in patients with EEC, and this correlation is even more certain in patients with early-stage EEC. Obstetrics & Gynecology Endometrioid endometrial cancer Early-stage endometrioid endometrial cancer Microsatellite instability Prognosis Meta-analysis Figures Figure 1 Figure 2 Figure 3 Introduction Endometrial cancer (EC) is one of the most common cancers of the female reproductive tract. Its incidence and mortality are increasing annually, and an increasing number of patients present with cancer progression and recurrence [ 1 , 2 ]. EC is classified into two types, type I and type II, based on histological and clinicopathological features. Type I EC, known as endometrioid endometrial cancer (EEC), accounts for the majority of EC cases (approximately 70–80%) [ 3 ]. Therefore, an increasing number of studies are focusing on the treatment and prognostic assessment of EEC, and the key to the prognostic assessment is the ability to identify a prognostic biomarker. Microsatellite instability (MSI) is present in approximately 20–40% of patients with sporadic EEC [ 4 , 5 ], so that many studies focused on correlation between MSI and prognosis in patients with EEC [ 6 – 11 ]. However, the studies on the correlation between MSI and EEC prognosis are currently divided, with some studies concluding that MSI has no significant correlation with the prognosis of EEC, some studies concluding that MSI is a biomarker for a good prognosis of EEC, and other studies concluding that MSI is a biomarker for a poor prognosis of EEC. However, a uniform conclusion has not been established and no relevant meta-analysis has been reported. We conducted this systematic review and meta-analysis to clarify the correlation between MSI and the prognosis of EEC. Methods Data Sources and Search Strategy This meta-analysis was rigorously evaluated using the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines [12]. PubMed, EMBASE, and the Cochrane Collaboration Library databases were searched from inception to July 2021, and the language was restricted to English. We adjusted the MeSH terms combined with related text words to comply with the relevant rules for searching for relevant studies in each database. Our search strategy was as follows: (Endometrial Neoplasm or Endometrial Neoplasms or Endometrial Carcinoma or Endometrial Carcinomas or Endometrial Cancer or Endometrial Cancers or Endometrium Cancer or Cancer of the Endometrium or Carcinoma of Endometrium or Endometrium Carcinoma or Endometrium Carcinomas or Cancer of Endometrium or Endometrium Cancers) AND (Mismatch repair or Microsatellite instability or Replication Error Phenotype or Replication Error Phenotypes) AND survival. Study Selection Two independent researchers (Jing-ping Xiao and Yun-zi Wang) filtered all the titles and abstracts of the retrieved studies to identify potentially relevant studies. The full texts of the retrieved studies that met the inclusion criteria were evaluated. Each of these discrepancies was resolved through discussion, and if conflicts remained, a third reviewer (Ji-sheng Wang) was involved. Inclusion and Exclusion Criteria Studies describing the correlation between MSI and the prognosis of EEC were included if they met the following criteria: (1) patients with EEC or early-stage EEC (stage I-II); (2) reported overall survival, disease-free survival, progression-free survival, EEC-specific survival or recurrence-free survival associated with MSI or mismatch repair deficiency; (3) directly reported HR or OR with 95% CI or generated Kaplan-Meier survival curves that could be used to extract HR. Editorials, meeting reports and letters to the editors were all excluded. Data Extraction Two researchers (Jing-ping Xiao and Yun-zi Wang) independently screened studies based on the inclusion criteria, and any differences were resolved by consensus. From each study, we extracted the study characteristics, baseline characteristics, and pre-established outcomes for overall survival, disease-free survival, progression-free survival, EEC-specific survival or recurrence-free survival. Definition of MSI MSI was defined as a lack of expression of at least 1 of the mismatch repair proteins (MLH1, MSH2, PMS2 and MSH6) detected using immunohistochemistry [11,13,14]; alternatively, microsatellite markers were identified by DNA isolation and molecular analysis, and tumors were considered to present MSI when they shown alterations in at least 2 of the 3-6 markers or in at least 1 of the 2 markers [7,15-19]. Quality Assessment Two researchers (Jing-ping Xiao and Yun-zi Wang) separately applied the Newcastle-Ottawa Statement [20] to evaluate the quality of eligible studies, including selection, comparability, and exposure. Nine points were included in the scale, and a score greater than or equal to 7 was considered a high-quality study. A score of 4-6 was considered a good-quality study, a score of 3 or less was considered a low-quality study, and discrepancies were resolved through discussion, with the involvement of a third reviewer (Ji-sheng Wang) if a conflict remained. Data Synthesis and Analysis Stata (version 14) software was used to analyze all results. The HR were extracted and calculated from Kaplan-Meier survival curves if HR were not directly reported in the study. An I 2 -value greater than or equal to 50% indicated significant heterogeneity, and then the HR were merged with the corresponding 95% CI using a random-effects model; otherwise, the fixed-effects model was used. Publication bias was statistically assessed using Egger’s regression test and Begg’s test, where a p- value < 0.05 was considered to indicate significant publication bias. Results Literature Search Figure 1 illustrates the flow chart for the selection of eligible studies. 720 studies were identified by searching PubMed, Cochrane, and EMBASE databases. 469 studies remained after removing duplicate files. After scanning the titles and abstracts, 50 studies were selected for full-text review. Finally, we included 17 studies that met the inclusion criteria for our meta-analysis [ 7 , 8 , 11 , 13 – 19 , 21 – 27 ]. Study Characteristics Table 1 shows the characteristics of the 17 studies included. Of these studies, 7 studies were conducted in Europe (Spain, Italy, Norway, and the European region) [ 8 , 11 , 13 , 15 , 21 , 22 , 24 ], and 9 studies were conducted in the Americas (United States, Canada and North American region) [ 7 , 14 , 16 – 19 , 23 , 24 , 27 ]. 1 study was conducted in Asia (Korea) [ 25 ], and 1 study was conducted in Oceania (Australia) [ 26 ]. 15 studies were retrospective cohort studies [ 8 , 11 , 13 – 19 , 21 , 23 – 27 ], and 2 studies were clinical trials [ 7 , 22 ]. 8 studies assessed MSI using quasimonomorphic mononucleotide markers [ 7 , 8 , 15 – 19 , 21 ], and 9 studies assessed MSI using immunohistochemistry [ 11 , 13 , 14 , 22 – 27 ]. Table 1 Characteristics of studies included in the meta-analysis author Year Country or region Number of patients MSI, n MSS, n Stage distribution histology Microsatellite markers Microsatellte instability definition Outcome assessment Study design Follow-up time Fiumicino et al. 2001 Italy 65 11 54 I-II EEC D2S123, D2S119, D9S171, D9S157, D10S216, BAT26 ≥ 2 of 6 markers with mutant alleles DFS Retrospective cohort study 76ms (12ms-139ms) Maxwell et al. 2001 United States 131 29 102 I-IV EEC BAT26, D14S65, D14S197 ≥ 2 of 3 markers with mutant alleles OS Retrospective cohort study 75.6ms (least 3 years) Zighelboim et al. 2007 United States 446 147 299 I-IV EEC BAT26, BAT25, D2S123, D5S346, D17S250 ≥ 2 of 5 markers with mutant alleles OS/DFS Retrospective cohort study 54.8ms (0.7ms-176ms) Bilbao et al. 2010 United States 93 20 73 I-III EEC BAT26, BAT25, NR-21, NR-24, NR-27 ≥ 2 of 5 markers with mutant alleles DFS Retrospective cohort study 138ms (16-232ms) Bilbao et al. (early-stage) 2010 United States 79 14 65 I-II EEC BAT26, BAT25, NR-21, NR-24, NR-27 ≥ 2 of 5 markers with mutant alleles DFS Retrospective cohort study 138ms (16-232ms) Mackey et al. 2010 Canada 84 23 61 I-II EEC BAT26, BAT25 ≥ 1 of 2 markers with mutant alleles DFS Clinical trials NR Steinbakk et al. 2011 Norway 171 27 144 I EEC BAT26, BAT25, NR-21, NR-24, NR-27 ≥ 2 of 5 markers withmutant alleles OS Retrospective cohort study 1-209ms Nout et al. 2012 Italy 64 22 42 I EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost DFS Retrospective cohort study 88ms (4-106ms) Ruiz et al. 2014 Spain 163 50 113 I-II EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost OS/DFS Clinical trials NR Bilbao-Sieyro et al. 2014 Spain 155 32 123 I-III EEC BAT26, BAT25, NR21, NR24, NR27 ≥ 2 of 5 markers with mutant alleles DFS/ESS Retrospective cohort study 112ms (6-227ms) Zighelboim et al. 2015 United States 475 368 107 I-IV EEC BAT26, BAT25, D2S123, D5S346, D17S250 ≥ 2 of 5 markers with mutant alleles OS/DFS Retrospective cohort study 79ms (0.2ms-122.5ms) McMeekin et al. 2016 United States 1024 639 385 I-IV EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost PFS Retrospective cohort study NR Kim et al. 2018 Korea 151 34 117 I-II EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost OS/PFS Retrospective cohort study 27ms (1-123ms) Nagle et al. 2018 Australia 581 458 123 I-IV EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost OS/ESS Retrospective cohort study 36-102ms Bosse et al. 2018 Europe and North America 249 136 113 I-IV EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost OS/RFS/Recurrence Retrospective cohort study 73.2ms (2.4-204ms) Backes et al. 2018 United States 197 64 133 I-II EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost RFS/Recurrence Retrospective cohort study 54ms (0-120ms) Ruz-Caracuel et al. 2019 Spain 199 31 168 I-II EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost OS/DFS Retrospective cohort study 83.96ms (0-174ms) Kim et al. 2020 Canada 475 131 344 IA EEC MLH1, MSH2, MSH6, PMS2 ≥ 1 of 4 MMR protein was lost OS/PFS Retrospective cohort study 23.4ms (14-39ms) EEC: endometrioid endometrial cancers; MMR: mismatch repair; OS: overall survival; PFS: progression-free survival; DFS: disease-free survival; ESS: EEC-specific survival; ms: months; NR: not reported As shown in Table 2 , all studies scored 7 or higher and were high-quality studies. Table 2 Methodological quality of cohort studies included in the meta-analysis. Authors Year Representativeness of the exposed cohort Selection of the unexposed cohort Ascertainment of exposure Outcome of interest not present at start of study Control for important factor or additional factor Outcome assessment Follow up long enough for outcomes to occur Adequacy of follow up of cohorts Total quality scores Fiumicino et al. 2001 +* + + + + + + + 9 Maxwell et al. 2001 + + + + ++ + + + 9 Zighelboim et al. 2007 + + + + ++ + + + 9 Bilbao et al. 2010 + + + + ++ + -** + 8 Mackey et al. 2010 + + + + ++ + - - 7 Steinbakk et al. 2011 + + + + - + + + 7 Nout et al. 2012 - - + + ++ + + + 7 Ruiz et al. 2014 + + + + ++ + - + 8 Bilbao-Sieyro et al. 2014 - - + + ++ + + + 7 Zighelboim et al. 2015 + + + + + + - - 7 McMeekin et al. 2016 - - + + ++ + + + 7 Kim et al. 2018 + + + + ++ + + + 9 Nagle et al. 2018 + + + + ++ + + + 9 Bosse et al. 2018 + + + + ++ + + + 9 Backes et al. 2018 + + + + ++ + + + 9 Ruz-Caracuel et al. 2019 + + + + ++ + + + 9 Kim et al. 2020 + + + + + + - + 7 * If there is a positive symbol that means score one point ** A negative symbol means no point Correlation Between MSI and Overall Survival in the EEC or Early-Stage EEC The pooled HR for patients with EEC shown that MSI was significantly associated with shorter overall survival [HR = 1.37, 95% CI (1.00-1.86), p = 0.048]. Meanwhile, significant heterogeneity was observed ( I 2 = 60.6%), as shown in Fig. 2 a. In the subgroup analysis of patients with early-stage EEC, patients with MSI had a shorter overall survival [HR = 1.47, 95% CI (1.11–1.95), p = 0.07], and no heterogeneity was observed ( I 2 = 20.9%), as shown in Fig. 3 a. Correlation Between MSI and Disease-Free Survival in the EEC or Early-Stage EEC The pooled HR for patients with EEC shown that MSI was associated with shorter disease-free survival [HR = 1.99, 95% CI (1.31–3.01), p = 0.000]. Meanwhile, heterogeneity was observed ( I 2 = 65.7%, p = 0.001), as shown in Fig. 2 b. In the subgroup analysis of early-stage EEC, patients with MSI had a shorter disease-free survival [HR = 4.17, 95% CI (2.37–7.41), p = 0.000], and no heterogeneity was identified ( I 2 = 0.0%), as shown in Fig. 3 b. Correlation Between MSI and EEC-Specific Survival in Patients with EEC As shown in Fig. 2 c, the pooled HR for patients with EEC shown a significant association between MSI with shorter EEC-specific survival [HR = 2.07, 95% CI (1.35–3.18), p = 0.001]. Meanwhile, no significant heterogeneity was observed ( I 2 = 31.6%). Correlation Between MSI and Progression-Free Survival in Patients with Early-Stage EEC As shown in Fig. 3 c, the pooled HR for the early-stage EEC subgroup shown that MSI was significantly associated with shorter progression-free survival [HR = 2.41, 95% CI (1.05–5.54), p = 0.039]. Meanwhile, no heterogeneity was detected ( I 2 = 0.0%). Correlation Between MSI and Recurrence-Free Survival in Patients with EEC The pooled HR for patients with EEC shown that MSI was not significantly associated with shorter recurrence-free survival [HR = 1.35, 95% CI (0.27–6.60), p = 0.714]. Meanwhile, significant heterogeneity was observed ( I 2 = 92.7%) (Supplemental Fig. 1). Correlation Between MSI and Recurrence Rate in Patients with EEC The pooled OR for EEC shown that MSI was significantly associated with a higher recurrence rate [OR = 2.72, 95% CI (1.56–4.76), p = 0.000]. Heterogeneity in the recurrence rate was not observed ( I 2 = 0.0%) (Supplemental Fig. 2). Publication Bias No significant publication bias was detected in the funnel plot (Supplemental Fig. 3). Additionally, significant publication bias was not observed, and the p -values of Egger’s test for overall survival, disease-free survival and EEC-specific survival were significant ( p = 0.131, p = 0.068 and p = 0.987, respectively). Sensitivity Analysis We omitted each study individually from the pooled analysis to explore the sensitivity of the pooled HR for overall survival, disease-free survival, and progression-free survival in EEC. The exclusion of any study did not have a significant effect on the results (Supplemental Fig. 4). Discussion The study of the correlation between MSI and the EC prognosis has been a hot topic in recent years. A previous meta-analysis [ 9 ] shown no significant correlation between MSI and the prognosis of patients with EC. However, when a pooled analysis of EEC was performed, we found a strong correlation between MSI and EEC. Since EEC accounts for the majority of EC patients, our study is of some significance. In our meta-analysis, Patients with MSI had a significantly poorer prognosis in terms of overall survival, disease-free survival, EEC-specific survival and the recurrence rate. However, there was significant heterogeneity in the pooled data for overall survival and disease-free survival. And we performed sensitivity analyses and did not detect studies that caused heterogeneity. Due to patients with early-stage EEC rarely receive adjuvant therapy, we performed a subgroup analysis of the prognostic value of MSI in patients with early-stage EEC. The pooled analysis shown that Patients with MSI had a significantly poor prognosis in terms of overall survival, disease-free survival, and progression-free survival, and the heterogeneity disappeared in all pooled data. In addition, in our meta-analysis, there was no significant correlation was observed between MSI and recurrence-free survival. The pooled analysis shown that MSI was associated with better recurrence-free survival in the study by Bosse et al. [ 24 ]. We found that EEC was FIGO grade 3 only in this study, the most patients received adjuvant therapy. In contrast, in the study by Backes et al. [ 27 ], MSI was associated with a significantly worse recurrence-free survival, in which EEC was FIGO grade1-3, and patients receive adjuvant at a much lower rate. Therefore, We assume that more adjuvant therapy is an important influencing factor on the prognostic value of MSI. Our study has some limitations. First, some data were extracted from survival curves, which may produce some bias compared with the real data. Second, the number of studies on recurrence-free survival was small, and more studies are needed to support our conclusions. Third, the vast majority of studies we included were retrospective case studies, which carries the risk of selective reporting. However, the heterogeneity of the combined data for our meta-analysis was not significant generally, and no significant publication bias was detected in the included studies, so our general results were reliable. Conclusion In summary, MSI has a significant prognostic value in EEC, and this prognostic value is more definite in patients with early-stage EEC. Declarations Acknowledgments With thanks to all participants in this study. Author contributions Jing-ping Xiao and Yun-zi Wang designed the study and wrote the manuscript. Yuan-yu Zhao and Jiang Du developed the search strategy and completed the literature search. Ji-sheng Wang developed the inclusion and exclusion criteria for the eligible studies. Jing-ping Xiao, Yun-zi Wang, and Ji-sheng Wang reviewed the eligible studies and extracted the data. Jing-ping Xiao and Yuan-yu Zhao did the methodological judgement. Yuan-yu Zhao and Jiang Du performed the statistical analysis methods. Jing-ping Xiao, Yun-zi Wang, and Jiang Du summarized the original data. Contributions to the interpretation of the data and review of the manuscript were made by all authors. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Conflict of interest The authors declare that they have no conflict of interest. Availability of data and materials Meta-analysis is a secondary analysis, which the data are all fully available without restriction, and all the material can be found in the included original studies. References Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. 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Cancer. 2019 Feb 1;125(3):398-405 Supplementary Files SupplementalfigureMSIandprognosis.doc PRISMA2009checklist.doc Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 21 Feb, 2022 Reviewers invited by journal 31 Dec, 2021 Editor invited by journal 08 Sep, 2021 Editor assigned by journal 27 Aug, 2021 First submitted to journal 20 Aug, 2021 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-834538","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":73490747,"identity":"da9da890-e203-46d3-9c42-5ca7ce9f67e1","order_by":0,"name":"Jing-ping Xiao","email":"","orcid":"","institution":"The Third Hospital of Mianyang, Sichuan Mental Health Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing-ping","middleName":"","lastName":"Xiao","suffix":""},{"id":73490748,"identity":"b21ac496-3461-459c-95a4-933e904b974c","order_by":1,"name":"Ji-sheng Wang","email":"","orcid":"","institution":"The Third Hospital of Mianyang, Sichuan Mental Health Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ji-sheng","middleName":"","lastName":"Wang","suffix":""},{"id":73490749,"identity":"9ef3b2a7-9e1b-4a12-9f96-e2ccf0952ce4","order_by":2,"name":"Yuan-yu Zhao","email":"","orcid":"","institution":"Sichuan Science City Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuan-yu","middleName":"","lastName":"Zhao","suffix":""},{"id":73490750,"identity":"8feb45ea-3c86-48e0-a585-1af63fac6cac","order_by":3,"name":"Jiang Du","email":"","orcid":"","institution":"Sichuan Science City Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiang","middleName":"","lastName":"Du","suffix":""},{"id":73490751,"identity":"ef43f6dc-0ec5-4043-8cc8-afcdaeaaad68","order_by":4,"name":"Yunzi Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDADNmbGhgMSFRJy8sRrYWdufGBxxsLYsIFoPfzszQaVbRWJDAcIKDQ4fvbwa962O/Z8zIxtEjfnSSQwNjA/fHQDn5YzeWnWvG3PmIF+aZOcuU0ij52Bzdg4B48WswM5Zsa8bYfZQFqkJbdJFDM28LBJ49Vy/g1YCw9Yy985EokNBwhpuZFj/BioRQKopdlAsoEILfY33pgxzjl32ACopfGBxDEJY8NmAn6R7M8x/vCm7LC9fP/xBwckaurk5NmbHz7GpwUI2KR4UPjM+JWDlXz8QVjRKBgFo2AUjGQAAGm0R60VU5bwAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-0087-6988","institution":"Sichuan Science City Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yunzi","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2021-08-22 01:53:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-834538/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-834538/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":16958128,"identity":"f2add5f7-724e-4d01-b16e-199ce144c8de","added_by":"auto","created_at":"2022-01-03 23:32:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":194542,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow diagram of studies included in this meta-analysis\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-834538/v1/562abda54d3c514c25f3dadb.jpg"},{"id":16958126,"identity":"dbb66e45-d173-4603-855e-c982deb926cd","added_by":"auto","created_at":"2022-01-03 23:32:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":405030,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of HR for the correlation between MSI and the prognosis of EEC. the overall survival (a), the disease-free survival (b), and the EEC-special survival (c)\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-834538/v1/9ab0e62f9f1bf44283e4e50c.jpg"},{"id":16958231,"identity":"c2e378aa-4779-4b95-bcc8-ecf05bfaeb2d","added_by":"auto","created_at":"2022-01-03 23:35:19","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":308296,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of HR for the correlation between MSI and the prognosis of early-stage EEC (stage I-II). the overall survival (a), the disease-free survival (b), and the EEC-special survival (c)\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-834538/v1/f06c607e2366fb8d38ac5a85.jpg"},{"id":16958232,"identity":"f8f3f264-4072-4c0f-b345-e1619dc742d5","added_by":"auto","created_at":"2022-01-03 23:35:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":756207,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-834538/v1/1b6ff6de-bffe-49f9-8f56-b1f66ff4bc4c.pdf"},{"id":16957874,"identity":"407049d4-deb2-450f-ae1d-a679134371e9","added_by":"auto","created_at":"2022-01-03 23:29:19","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":374784,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalfigureMSIandprognosis.doc","url":"https://assets-eu.researchsquare.com/files/rs-834538/v1/e702fefc13bf826840655abe.doc"},{"id":16957876,"identity":"5358dca0-0868-499b-b1a4-e201ba723d7f","added_by":"auto","created_at":"2022-01-03 23:29:19","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":58880,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2009checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-834538/v1/00229c8774455f202b8e2fe5.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eMicrosatellite Instability as a Maker of Prognosis: a Systematic Review and Meta-analysis of Endometrioid Endometrial Cancer Survival Data\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometrial cancer (EC) is one of the most common cancers of the female reproductive tract. Its incidence and mortality are increasing annually, and an increasing number of patients present with cancer progression and recurrence [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEC is classified into two types, type I and type II, based on histological and clinicopathological features. Type I EC, known as endometrioid endometrial cancer (EEC), accounts for the majority of EC cases (approximately 70\u0026ndash;80%) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefore, an increasing number of studies are focusing on the treatment and prognostic assessment of EEC, and the key to the prognostic assessment is the ability to identify a prognostic biomarker.\u003c/p\u003e \u003cp\u003eMicrosatellite instability (MSI) is present in approximately 20\u0026ndash;40% of patients with sporadic EEC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], so that many studies focused on correlation between MSI and prognosis in patients with EEC [\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the studies on the correlation between MSI and EEC prognosis are currently divided, with some studies concluding that MSI has no significant correlation with the prognosis of EEC, some studies concluding that MSI is a biomarker for a good prognosis of EEC, and other studies concluding that MSI is a biomarker for a poor prognosis of EEC. However, a uniform conclusion has not been established and no relevant meta-analysis has been reported.\u003c/p\u003e \u003cp\u003eWe conducted this systematic review and meta-analysis to clarify the correlation between MSI and the prognosis of EEC.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eData Sources and Search Strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis was rigorously evaluated using the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines [12]. PubMed, EMBASE, and the Cochrane Collaboration Library databases were searched from inception to July 2021, and the language was restricted to English.\u003c/p\u003e\n\u003cp\u003eWe adjusted the MeSH terms combined with related text words to comply with the relevant rules for searching for relevant studies in each database. Our search strategy was as follows: (Endometrial Neoplasm or Endometrial Neoplasms or Endometrial Carcinoma or Endometrial Carcinomas or Endometrial Cancer or Endometrial Cancers or Endometrium Cancer or Cancer of the Endometrium or Carcinoma of Endometrium or Endometrium Carcinoma or Endometrium Carcinomas or Cancer of Endometrium or Endometrium Cancers) AND (Mismatch repair or Microsatellite instability or Replication Error Phenotype or Replication Error Phenotypes) AND survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo independent researchers (Jing-ping Xiao and Yun-zi Wang) filtered all the titles and abstracts of the retrieved studies to identify potentially relevant studies. The full texts of the retrieved studies that met the inclusion criteria were evaluated. Each of these discrepancies was resolved through discussion, and if conflicts remained, a third reviewer (Ji-sheng Wang) was involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and Exclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies describing the correlation between MSI and the prognosis of EEC were included if they met the following criteria: (1) patients with EEC or early-stage EEC (stage I-II); (2) reported overall survival, disease-free survival, progression-free survival, EEC-specific survival or recurrence-free survival associated with MSI or mismatch repair deficiency; (3) directly reported HR or OR with 95% CI or generated Kaplan-Meier survival curves that could be used to extract HR.\u003c/p\u003e\n\u003cp\u003eEditorials, meeting reports and letters to the editors were all excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo researchers (Jing-ping Xiao and Yun-zi Wang) independently screened studies based on the inclusion criteria, and any differences were resolved by consensus. From each study, we extracted the study characteristics, baseline characteristics, and pre-established outcomes for overall survival, disease-free survival, progression-free survival, EEC-specific survival or recurrence-free survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of MSI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMSI was defined as a lack of expression of at least 1 of the mismatch repair proteins (MLH1, MSH2, PMS2 and MSH6) detected using immunohistochemistry [11,13,14]; alternatively, microsatellite markers were identified by DNA isolation and molecular analysis, and tumors were considered to present MSI when they shown alterations in at least 2 of the 3-6 markers or in at least 1 of the 2 markers [7,15-19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo researchers (Jing-ping Xiao and Yun-zi Wang) separately applied the Newcastle-Ottawa Statement [20] to evaluate the quality of eligible studies, including selection, comparability, and exposure. Nine points were included in the scale, and a score greater than or equal to 7 was considered a high-quality study. A score of 4-6 was considered a good-quality study, a score of 3 or less was considered a low-quality study, and discrepancies were resolved through discussion, with the involvement of a third reviewer (Ji-sheng Wang) if a conflict remained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Synthesis and Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStata (version 14) software was used to analyze all results. The HR were extracted and calculated from Kaplan-Meier survival curves if HR were not directly reported in the study. An \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e-value greater than or equal to 50% indicated significant heterogeneity, and then the HR were merged with the corresponding 95% CI using a random-effects model; otherwise, the fixed-effects model was used. Publication bias was statistically assessed using Egger\u0026rsquo;s regression test and Begg\u0026rsquo;s test, where a \u003cem\u003ep-\u003c/em\u003evalue \u0026lt; 0.05 was considered to indicate significant publication bias.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eLiterature Search\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the flow chart for the selection of eligible studies. 720 studies were identified by searching PubMed, Cochrane, and EMBASE databases. 469 studies remained after removing duplicate files. After scanning the titles and abstracts, 50 studies were selected for full-text review. Finally, we included 17 studies that met the inclusion criteria for our meta-analysis [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the characteristics of the 17 studies included. Of these studies, 7 studies were conducted in Europe (Spain, Italy, Norway, and the European region) [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e], and 9 studies were conducted in the Americas (United States, Canada and North American region) [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. 1 study was conducted in Asia (Korea) [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], and 1 study was conducted in Oceania (Australia) [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. 15 studies were retrospective cohort studies [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], and 2 studies were clinical trials [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. 8 studies assessed MSI using quasimonomorphic mononucleotide markers [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e], and 9 studies assessed MSI using immunohistochemistry [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of studies included in the meta-analysis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eauthor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eYear\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCountry or region\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNumber of patients\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMSI, n\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMSS, n\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStage distribution\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ehistology\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMicrosatellite markers\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMicrosatellte instability definition\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOutcome assessment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy design\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow-up time\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFiumicino et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eItaly\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eD2S123, D2S119, D9S171, D9S157, D10S216, BAT26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 6 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76ms\u003c/p\u003e\n\u003cp\u003e(12ms-139ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaxwell et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e102\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, D14S65, D14S197\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 3 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.6ms\u003c/p\u003e\n\u003cp\u003e(least 3 years)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eZighelboim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e446\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e147\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e299\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25, D2S123, D5S346, D17S250\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 5 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/DFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.8ms\u003c/p\u003e\n\u003cp\u003e(0.7ms-176ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBilbao et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2010\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25, NR-21, NR-24, NR-27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 5 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138ms\u003c/p\u003e\n\u003cp\u003e(16-232ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBilbao et al.\u003c/p\u003e\n\u003cp\u003e(early-stage)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2010\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25, NR-21, NR-24, NR-27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 5 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138ms\u003c/p\u003e\n\u003cp\u003e(16-232ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMackey et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2010\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCanada\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 2 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinical trials\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNR\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSteinbakk et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2011\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNorway\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e171\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e144\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25, NR-21, NR-24, NR-27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 5 markers withmutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1-209ms\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNout et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2012\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eItaly\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88ms\u003c/p\u003e\n\u003cp\u003e(4-106ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRuiz et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSpain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e163\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e113\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/DFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinical trials\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNR\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBilbao-Sieyro et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSpain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e155\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e123\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25, NR21, NR24, NR27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 5 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDFS/ESS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112ms\u003c/p\u003e\n\u003cp\u003e(6-227ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eZighelboim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2015\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e475\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e368\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e107\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBAT26, BAT25, D2S123, D5S346, D17S250\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2 of 5 markers with mutant alleles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/DFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79ms\u003c/p\u003e\n\u003cp\u003e(0.2ms-122.5ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMcMeekin et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2016\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1024\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e639\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e385\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNR\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKorea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e151\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e117\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/PFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27ms\u003c/p\u003e\n\u003cp\u003e(1-123ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNagle et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAustralia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e581\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e458\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e123\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/ESS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36-102ms\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBosse et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEurope and North America\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e249\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e136\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e113\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/RFS/Recurrence\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.2ms\u003c/p\u003e\n\u003cp\u003e(2.4-204ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBackes et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnited States\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e197\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e133\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRFS/Recurrence\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54ms\u003c/p\u003e\n\u003cp\u003e(0-120ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRuz-Caracuel et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2019\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSpain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e199\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e168\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI-II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/DFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.96ms\u003c/p\u003e\n\u003cp\u003e(0-174ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2020\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCanada\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e475\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e344\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMLH1, MSH2, MSH6, PMS2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;1 of 4 MMR protein was lost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOS/PFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetrospective cohort study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.4ms\u003c/p\u003e\n\u003cp\u003e(14-39ms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"13\" align=\"left\"\u003e\n\u003cp\u003eEEC: endometrioid endometrial cancers; MMR: mismatch repair; OS: overall survival; PFS: progression-free survival; DFS: disease-free survival; ESS: EEC-specific survival; ms: months; NR: not reported\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, all studies scored 7 or higher and were high-quality studies.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMethodological quality of cohort studies included in the meta-analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAuthors\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eYear\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRepresentativeness of the exposed cohort\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSelection of the unexposed cohort\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAscertainment of exposure\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOutcome of interest not present at start of study\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl for important factor or additional factor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOutcome assessment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow up long enough for outcomes to occur\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAdequacy of follow up of cohorts\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal quality scores\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFiumicino et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaxwell et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eZighelboim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBilbao et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2010\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMackey et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2010\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSteinbakk et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2011\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNout et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2012\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRuiz et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBilbao-Sieyro et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eZighelboim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2015\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMcMeekin et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2016\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNagle et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBosse et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBackes et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRuz-Caracuel et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2019\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e++\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKim et al.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2020\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"11\" align=\"left\"\u003e\n\u003cp\u003e* If there is a positive symbol that means score one point\u003c/p\u003e\n\u003cp\u003e** A negative symbol means no point\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between MSI and Overall Survival in the EEC or Early-Stage EEC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pooled HR for patients with EEC shown that MSI was significantly associated with shorter overall survival [HR\u0026thinsp;=\u0026thinsp;1.37, 95% CI (1.00-1.86), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.048]. Meanwhile, significant heterogeneity was observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;60.6%), as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea.\u003c/p\u003e\n\u003cp\u003eIn the subgroup analysis of patients with early-stage EEC, patients with MSI had a shorter overall survival [HR\u0026thinsp;=\u0026thinsp;1.47, 95% CI (1.11\u0026ndash;1.95), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.07], and no heterogeneity was observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;20.9%), as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between MSI and Disease-Free Survival in the EEC or Early-Stage EEC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pooled HR for patients with EEC shown that MSI was associated with shorter disease-free survival [HR\u0026thinsp;=\u0026thinsp;1.99, 95% CI (1.31\u0026ndash;3.01), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.000]. Meanwhile, heterogeneity was observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;65.7%, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.001), as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb.\u003c/p\u003e\n\u003cp\u003eIn the subgroup analysis of early-stage EEC, patients with MSI had a shorter disease-free survival [HR\u0026thinsp;=\u0026thinsp;4.17, 95% CI (2.37\u0026ndash;7.41), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.000], and no heterogeneity was identified (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;0.0%), as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between MSI and EEC-Specific Survival in Patients with EEC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec, the pooled HR for patients with EEC shown a significant association between MSI with shorter EEC-specific survival [HR\u0026thinsp;=\u0026thinsp;2.07, 95% CI (1.35\u0026ndash;3.18), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.001]. Meanwhile, no significant heterogeneity was observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;31.6%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between MSI and Progression-Free Survival in Patients with Early-Stage EEC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, the pooled HR for the early-stage EEC subgroup shown that MSI was significantly associated with shorter progression-free survival [HR\u0026thinsp;=\u0026thinsp;2.41, 95% CI (1.05\u0026ndash;5.54), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.039]. Meanwhile, no heterogeneity was detected (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;0.0%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between MSI and Recurrence-Free Survival in Patients with EEC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pooled HR for patients with EEC shown that MSI was not significantly associated with shorter recurrence-free survival [HR\u0026thinsp;=\u0026thinsp;1.35, 95% CI (0.27\u0026ndash;6.60), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.714]. Meanwhile, significant heterogeneity was observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;92.7%) (Supplemental Fig.\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between MSI and Recurrence Rate in Patients with EEC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pooled OR for EEC shown that MSI was significantly associated with a higher recurrence rate [OR\u0026thinsp;=\u0026thinsp;2.72, 95% CI (1.56\u0026ndash;4.76), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.000]. Heterogeneity in the recurrence rate was not observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;0.0%) (Supplemental Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication Bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant publication bias was detected in the funnel plot (Supplemental Fig.\u0026nbsp;3). Additionally, significant publication bias was not observed, and the \u003cem\u003ep\u003c/em\u003e-values of Egger\u0026rsquo;s test for overall survival, disease-free survival and EEC-specific survival were significant (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.131, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.068 and \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.987, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe omitted each study individually from the pooled analysis to explore the sensitivity of the pooled HR for overall survival, disease-free survival, and progression-free survival in EEC. The exclusion of any study did not have a significant effect on the results (Supplemental Fig.\u0026nbsp;4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study of the correlation between MSI and the EC prognosis has been a hot topic in recent years. A previous meta-analysis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] shown no significant correlation between MSI and the prognosis of patients with EC. However, when a pooled analysis of EEC was performed, we found a strong correlation between MSI and EEC. Since EEC accounts for the majority of EC patients, our study is of some significance.\u003c/p\u003e \u003cp\u003eIn our meta-analysis, Patients with MSI had a significantly poorer prognosis in terms of overall survival, disease-free survival, EEC-specific survival and the recurrence rate. However, there was significant heterogeneity in the pooled data for overall survival and disease-free survival. And we performed sensitivity analyses and did not detect studies that caused heterogeneity.\u003c/p\u003e \u003cp\u003eDue to patients with early-stage EEC rarely receive adjuvant therapy, we performed a subgroup analysis of the prognostic value of MSI in patients with early-stage EEC. The pooled analysis shown that Patients with MSI had a significantly poor prognosis in terms of overall survival, disease-free survival, and progression-free survival, and the heterogeneity disappeared in all pooled data.\u003c/p\u003e \u003cp\u003eIn addition, in our meta-analysis, there was no significant correlation was observed between MSI and recurrence-free survival. The pooled analysis shown that MSI was associated with better recurrence-free survival in the study by Bosse et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. We found that EEC was FIGO grade 3 only in this study, the most patients received adjuvant therapy. In contrast, in the study by Backes et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], MSI was associated with a significantly worse recurrence-free survival, in which EEC was FIGO grade1-3, and patients receive adjuvant at a much lower rate. Therefore, We assume that more adjuvant therapy is an important influencing factor on the prognostic value of MSI.\u003c/p\u003e \u003cp\u003eOur study has some limitations. First, some data were extracted from survival curves, which may produce some bias compared with the real data. Second, the number of studies on recurrence-free survival was small, and more studies are needed to support our conclusions. Third, the vast majority of studies we included were retrospective case studies, which carries the risk of selective reporting. However, the heterogeneity of the combined data for our meta-analysis was not significant generally, and no significant publication bias was detected in the included studies, so our general results were reliable.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, MSI has a significant prognostic value in EEC, and this prognostic value is more definite in patients with early-stage EEC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith thanks to all participants in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJing-ping Xiao and Yun-zi Wang designed the study and wrote the manuscript. Yuan-yu Zhao and Jiang Du developed the search strategy and completed the literature search. Ji-sheng Wang developed the inclusion and exclusion criteria for the eligible studies. Jing-ping Xiao, Yun-zi Wang, and Ji-sheng Wang reviewed the eligible studies and extracted the data. Jing-ping Xiao and Yuan-yu Zhao did the methodological judgement. Yuan-yu Zhao and Jiang Du performed the statistical analysis methods. Jing-ping Xiao, Yun-zi Wang, and Jiang Du summarized the original data. Contributions to the interpretation of the data and review of the manuscript were made by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeta-analysis is a secondary analysis, which the data are all fully available without restriction, and all the material can be found in the included original studies.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSiegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a cancer journal for clinicians. 2019 Jan;69(1):7-34.\u003c/li\u003e\n \u003cli\u003eSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020 Jan;70(1):7-30.\u003c/li\u003e\n \u003cli\u003eRutgers JK. Update on pathology, staging and molecular pathology of endometrial (uterine corpus) adenocarcinoma. Future oncology. 2015;11(23):3207-18.\u003c/li\u003e\n \u003cli\u003eSoreide K, Janssen EA, Soiland H, et al. Microsatellite instability in colorectal cancer. The British journal of surgery. 2006 Apr;93(4):395-406.\u003c/li\u003e\n \u003cli\u003eAkagi K, Oki E, Taniguchi H, et al. The real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer science. 2021 Jan 6.\u003c/li\u003e\n \u003cli\u003eBlack D, Soslow RA, Levine DA, et al. Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Apr 10;24(11):1745-53.\u003c/li\u003e\n \u003cli\u003eMackay HJ, Gallinger S, Tsao MS, et al. Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: results from studies of the NCIC Clinical Trials Group (NCIC CTG). European journal of cancer. 2010 May;46(8):1365-73.\u003c/li\u003e\n \u003cli\u003eSteinbakk A, Malpica A, Slewa A, et al. Biomarkers and microsatellite instability analysis of curettings can predict the behavior of FIGO stage I endometrial endometrioid adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2011 Sep;24(9):1262-71.\u003c/li\u003e\n \u003cli\u003eDiaz-Padilla I, Romero N, Amir E, et al. Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis. Critical reviews in oncology/hematology. 2013 Oct;88(1):154-67.\u003c/li\u003e\n \u003cli\u003eKim SR, Pina A, Albert A, et al. Does MMR status in endometrial cancer influence response to adjuvant therapy? Gynecologic oncology. 2018 Oct;151(1):76-81.\u003c/li\u003e\n \u003cli\u003eRuz-Caracuel I, Ramon-Patino JL, Lopez-Janeiro A, et al. Myoinvasive Pattern as a Prognostic Marker in Low-Grade, Early-Stage Endometrioid Endometrial Carcinoma. Cancers. 2019 Nov 22;11(12).\u003c/li\u003e\n \u003cli\u003eMoher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Journal of clinical epidemiology. 2009 Oct;62(10):1006-12.\u003c/li\u003e\n \u003cli\u003eNout RA, Bosse T, Creutzberg CL, et al. Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K-AKT, Wnt/beta-catenin and P53 pathway activation. Gynecologic oncology. 2012 Sep;126(3):466-73.\u003c/li\u003e\n \u003cli\u003eKim SR, Pina A, Albert A, et al. Mismatch repair deficiency and prognostic significance in patients with low-risk endometrioid endometrial cancers. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2020 Jun;30(6):783-788.\u003c/li\u003e\n \u003cli\u003eFiumicino S, Ercoli A, Ferrandina G, et al. Microsatellite instability is an independent indicator of recurrence in sporadic stage I-II endometrial adenocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2001 Feb 15;19(4):1008-14.\u003c/li\u003e\n \u003cli\u003eMaxwell GL, Risinger JI, Alvarez AA, et al. Favorable survival associated with microsatellite instability in endometrioid endometrial cancers. Obstetrics and gynecology. 2001 Mar;97(3):417-22.\u003c/li\u003e\n \u003cli\u003eZighelboim I, Goodfellow PJ, Gao F, et al. 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Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. The American journal of surgical pathology. 2018 May;42(5):561-568.\u003c/li\u003e\n \u003cli\u003eKim J, Kong JK, Yang W, et al. DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer. Cancers. 2018 Aug 21;10(9).\u003c/li\u003e\n \u003cli\u003eNagle CM, O\u0026apos;Mara TA, Tan Y, et al. Endometrial cancer risk and survival by tumor MMR status. Journal of gynecologic oncology. 2018 May;29(3):e39.\u003c/li\u003e\n \u003cli\u003eBackes FJ, Haag J, Cosgrove CM, et al. Mismatch repair deficiency identifies patients with high-intermediate-risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: A prognostic biomarker. Cancer. 2019 Feb 1;125(3):398-405\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Endometrioid endometrial cancer, Early-stage endometrioid endometrial cancer, Microsatellite instability, Prognosis, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-834538/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-834538/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction \u003c/strong\u003eTo investigate whether microsatellite instability (MSI) is an important prognostic biomarker for endometrioid endometrial cancer (EEC).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThe PubMed, EMBASE and the Cochrane Cooperative Library databases were searched from inception to July 2021. Overall survival, disease-free survival, progression-free survival, EEC-specific survival, recurrence-free survival and the recurrence rate were pooled to analyze the correlation between MSI and EEC. In addition, Egger’s regression analysis and Begg’s test were used to detect publication bias.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003e17 studies met the inclusion criteria and were included in our meta-analysis with a sample size of 4723, and the included patients with endometrioid cancer (EC) all were EEC. The pooled hazard ratios (HR) in patients with EEC shown that MSI was significantly associated with shorter overall survival [HR=1.37, 95% confidence interval (CI) (1.00-1.86), \u003cem\u003ep=\u003c/em\u003e0.048, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e60.6%], shorter disease-free survival [HR=1.99, 95% CI (1.31-3.01), \u003cem\u003ep=\u003c/em\u003e0.000, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e67.2%], shorter EEC-specific survival [HR=2.07, 95% CI (1.35-3.18), \u003cem\u003ep=\u003c/em\u003e0.001, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e31.6%] and a higher recurrence rate [Odds ratios (OR)=2.72, 95% CI (1.56-4.76), \u003cem\u003ep=\u003c/em\u003e0.000, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e0.0%]. In the early-stage EEC subgroup, MSI was significantly associated with shorter overall survival [HR=1.47, 95% CI (1.11-1.95), \u003cem\u003ep=\u003c/em\u003e0.07], shorter disease-free survival [HR=4.17, 95% CI (2.37-7.41), \u003cem\u003ep=\u003c/em\u003e0.000], and shorter progression-free survival [HR=2.41, 95% CI (1.05-5.54), \u003cem\u003ep=\u003c/em\u003e0.039]. No significant heterogeneity was observed in overall survival (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e20.9%), disease-free survival (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e0.0%), or progression-free survival (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e=\u003c/em\u003e0.0%) in patients with early-stage EEC. Meanwhile, publication bias was not observed, and the p-value for Egger’s test of overall survival, disease-free survival, and EEC-specific survival were \u003cem\u003ep=\u003c/em\u003e0.131, \u003cem\u003ep=\u003c/em\u003e0.068 and \u003cem\u003ep=\u003c/em\u003e0.987, respectively.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eMSI is likely an important biomarker for poor prognosis in patients with EEC, and this correlation is even more certain in patients with early-stage EEC.\u003c/p\u003e","manuscriptTitle":"Microsatellite Instability as a Maker of Prognosis: a Systematic Review and Meta-analysis of Endometrioid Endometrial Cancer Survival Data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-01-03 23:29:17","doi":"10.21203/rs.3.rs-834538/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2022-02-21T22:27:13+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-12-31T10:04:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Archives of Gynecology and Obstetrics","date":"2021-09-08T09:36:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-08-28T01:55:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2021-08-21T00:46:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c179abef-a7e4-476f-a23b-67d95148682b","owner":[],"postedDate":"January 3rd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":9476675,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2022-05-18T11:15:26+00:00","versionOfRecord":[],"versionCreatedAt":"2022-01-03 23:29:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-834538","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-834538","identity":"rs-834538","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}